Long-Term Clinical Outcomes After Filter Protection During Percutaneous Coronary Intervention in Patients With Attenuated Plaque　― 1-Year Follow up of the VAMPIRE 3 (Vacuum Aspiration Thrombus Reemoval 3) Trial ―

Abstract

Background: Selective use of distal filter protection during percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) decreased the incidence of no-reflow phenomena and in-hospital serious adverse cardiac events compared with conventional PCI in patients with attenuated plaque ≥5 mm; however, its long-term clinical outcome remains unknown.

Methods and Results: Patients who had ACS with attenuated plaque ≥5 mm were assigned to receive distal protection (DP) (n=98) or conventional treatment (CT) (n=96). The rate of major adverse cardiovascular events (MACE), a composite of death from any cause, non-fatal myocardial infarction, or target vessel revascularization (TVR) at 1 year, was the pre-specified secondary endpoint of the trial. MACE at 1 year occurred in 12 patients (12.2%) in the DP group and 3 patients (3.1%) in the CT group (P=0.029), which was driven by a higher risk of TVR (11 [11.2%] vs. 2 [2.1%], P=0.018). In patients treated with bare-metal stents (n=42), MACE occurred in 25.0% of the patients in the DP group and in none of the patients in the CT group (P=0.029), whereas in patients treated with drug-eluting stents (n=151), rates of MACE were similar in the groups (8.1% vs. 3.9%, P=0.32).

Conclusions: In ACS patients with attenuated plaque ≥5 mm, the 1-year rates of MACE were higher in the DP group than in the CT group. This effect might be mitigated by the use of drug-eluting stents.

Primary percutaneous coronary intervention (PCI) is the most common and widely accepted effective strategy for treating ST-segment elevation myocardial infarction (STEMI). However, reduced coronary flow and myocardial perfusion sometimes occur after otherwise successful PCI, and are associated with poor clinical outcomes, including greater infarct size and mortality.^1,2 PCI-induced distal embolization of atherosclerotic debris and thrombus was believed to cause impaired myocardial perfusion and adverse clinical outcomes. Thrombectomy and distal embolic protection devices have been proposed to reduce distal embolization after primary PCI. Nevertheless, previous large-scale randomized trials have failed to demonstrate the effectiveness of “routine” thrombectomy^3,4 or the “routine” use of distal embolic protection devices.^5,6 Recently, the multicenter, prospective, randomized VAMPIRE 3 (VAcuuM asPIration thrombus REemoval 3) trial⁷ reported that among patients who had acute coronary syndromes (ACS) with attenuated plaque ≥5 mm in length, distal filter protection devices resulted in superior rates of epicardial coronary flow and were associated with fewer serious adverse cardiac events after revascularization, suggesting that the selective use of embolic protection devices may confer short-term clinical benefits in patients at high risk for distal embolization. In the Drug Elution and Distal Protection in ST Elevation Myocardial Infarction (DEDICATION) trial,⁶ which evaluated the efficacy of the “routine” use of filter-based distal protection (DP) devices in primary PCI for STEMI, increased incidences of stent thrombosis and clinically driven target lesion/vessel revascularization were observed during 15 months of follow up. Therefore, longer-term clinical and angiographic follow up is needed to characterize the ultimate benefits of “selective” use of distal filter protection devices in patients with ACS. In the present study, we report the 10-month angiographic and pre-specified 1-year clinical outcomes of the VAMPIRE 3 study.

Methods

Study Design and Subjects

The VAMPIRE 3 Trial was an open-label, prospective, randomized, multicenter trial of DP vs. conventional treatment (CT) during PCI in patients with ACS. The design of the VAMPIRE Trial has been described previously.⁷ In brief, patients with STEMI/non-STEMI within 2 months from symptom onset or with unstable angina for which PCI was indicated were eligible for enrollment. A diagnosis of acute myocardial infarction required a rise in serum troponin levels to more than twice the upper limit of normal. Patients with cardiogenic shock or cardiac arrest were excluded. Coronary angiography and intravascular ultrasonography (IVUS) were performed to evaluate appropriateness for randomization to receive PCI with or without DP. Angiographic eligibility required a reference vessel diameter at the target lesion of 2.5–5 mm by visual estimation. The main exclusion criteria were the presence of culprit lesions in the left main trunk or saphenous vein graft; in-stent restenotic lesions; lesions requiring balloon dilatation before IVUS interrogation; or patients receiving hemodialysis or those with renal insufficiency. The study protocol was approved by the local ethics committee of each center, and written informed consent was obtained from each patient. The procedures followed were in accordance with the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation (institutional or regional).

Procedures

All patients were pretreated with aspirin and clopidogrel or prasugrel. The doses of these drugs differed according to the clinical situation (i.e., STEMI or non-STEMI). Glycoprotein IIb/IIIa inhibitors were not used because these drugs were not approved in Japan. Intravenous heparin was administered before angiography to maintain an activated clotting time of ≥250 s during the procedure. A guidewire was advanced through the lesion, and a 40-MHz IVUS catheter (Boston Scientific, Boston, Massachusetts, USA) was advanced through the lesion before any balloon dilatation. IVUS eligibility required the presence of attenuated plaque of ≥180° with a longitudinal length of ≥5 mm.^8,9 If the operator predicted that a filter device could be advanced through the lesion, the patient was randomly assigned to distal filter protection (Filtrap^TM; Nipro, Tokyo, Japan) or CT. Thrombus aspiration was performed according to the clinical situation and was left to the discretion of the individual cardiologist. The size of the protection filter (3.5 mm or 5 mm) was based on the lumen diameter at the distal reference site, as measured by IVUS.⁸ In the DP group, aspiration immediately after stent implantation was strongly encouraged. After removal of the filter device, sufficient leakage of blood from the guiding catheter was encouraged to prevent the injection of embolic debris dropped off from the balloon catheter.

Endpoints and Follow-up Schedule

Angiographic follow up at 10 months was planned in a subgroup of 149 patients and clinical follow up was performed at 1 year. The primary endpoint was the incidence of no-reflow phenomenon during PCI, and this has been reported elsewhere.⁷ Patients were followed up for 1 year to assess the occurrence of cardiac and non-cardiac death, cerebral events, re-infarction, and definite stent thrombosis (Academic Research Consortium definition). Major adverse cardiovascular events (MACE), a composite of death from any cause, non-fatal myocardial infarction, or unplanned target vessel revascularization (TVR) at 1 year, were the pre-specified secondary endpoints of the trial. Non-fatal infarction was defined as recurrent myocardial infarction (an elevation of the levels of creatine kinase or troponin greater than or equal to threefold the upper limit of the normal range) after discharge. All events were adjudicated by an independent Clinical Event Committee.

Quantitative Coronary Angiography Analysis

All angiograms were analyzed by an independent core laboratory (Cardiocore, Tokyo, Japan). Quantitative coronary angiography was performed using an automated edge-detection system (QAngio XA; MEDIS, Leiden, the Netherlands). Binary restenosis was defined as diameter stenosis >50% at the follow-up angiogram and was determined in-stent and in-segment (including stent and segments 5 mm proximal and distal to the stent edge). Late lumen loss was calculated as the post-procedural minimal lumen diameter minus the follow-up minimal lumen diameter.

IVUS Image Analysis

IVUS images were analyzed by an independent core laboratory (Cardiocore, Tokyo, Japan). Qualitative analysis, including assessment of presence of the necrotic core and thrombus formation, was performed. The arc of backward signal attenuation without dense calcium was measured in degrees with a protractor centered on the lumen.⁹ Quantitative analysis of final IVUS images after stent implantation included measurement at every 1 mm of the stent, and the mean stent area was calculated.

Statistical Analysis

Analyses were based on the intention-to-treat. Quantitative data are expressed as means±SD for continuous variables and frequencies for categorical variables. For normally distributed data, differences between patient groups were tested with the Student’s t-test. Because the Student’s t-test assumes homogeneity of variance, Levene’s test was applied to assess the equality of variances in each group. If the P value obtained from Levene’s test was <0.05, Welch’s t-test was performed. For skewed data distributions, differences in group data were tested by using the Wilcoxon/Kruskal-Wallis test. Categorical data were compared by using the χ² test or Fisher’s exact test, as appropriate. All tests were 2-tailed, and P values <5% were considered to indicate statistical significance. Statistical analysis was performed by using JMP^® 13 software (SAS Inc., Cary, NC, USA).

Results

Patient Characteristics and Procedural Results

We randomly assigned 200 patients with ACS who had native coronary artery lesions and attenuated plaque with a longitudinal length of ≥5 mm on pre-PCI IVUS to receive distal filter protection or CT. Six patients were excluded after randomization owing to the following reasons: 3 patients withdrew consent; 1 patient received an incorrect group assignment; and 2 patients had protocol violations. As a result, 98 patients in the DP group and 96 patients in the CT group were included in the intention-to-treat analysis. Baseline clinical and angiographic characteristics of the 194 patients were well balanced in both groups.⁷ There were no differences in age, sex, body mass index, or frequency of STEMI, or frequencies of coronary risk factors. The culprit artery was predominantly located in the right coronary artery followed by the left anterior descending coronary artery in both groups. The frequency of American Heart Association B2/C lesions did not differ significantly between the DP and CT groups. Of the patients assigned to the DP group, the filter device successfully crossed the lesion and unfolded distally in 98% of the patients. Drug-eluting stents (DES) were used in 78% of the patients and bare-metal stents (BMS) in 22%. In a patient assigned to the CT group, a stent was not deployed because of significant no-reflow phenomena and cardiac arrest requiring cardiopulmonary resuscitation after pre-dilatation. The stent diameter (3.36±0.40 vs. 3.36±0.41, P=0.909) and stent length (23 [18–30] vs. 24 [18–33], P=0.293) were similar in the groups.

At the culprit lesion, there were no significant differences in the frequency of necrotic core (44.79% vs. 37.78%, P=0.331) or thrombus formation (70.97% vs. 71.11%, P=0.997) on IVUS between the groups. Quantitative IVUS analysis after stent implantation revealed that the mean stent area (9.79±2.86 vs. 9.70±2.79, P=0.830) and minimum stent area (8.05±2.70 vs. 7.78±2.38, P=0.490) were similar in the groups.

As reported previously,⁷ the primary endpoint of the incidence of no-reflow phenomena was significantly lower in the DP group than in the CT group (26.5% vs. 41.7%, P=0.026). DP resulted in a significantly lower corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC) than did CT (median 23.0 vs. 30.5, P=0.0003).

Clinical Outcomes

As previously reported,⁷ the rates of in-hospital cardiac adverse events (cardiac arrest/cardiogenic shock after revascularization requiring defibrillation, cardiopulmonary resuscitation, or extracorporeal membrane oxygenation) were lower in the DP group than in the CT group (0% vs. 5.2%, P=0.028) during a mean duration of hospitalization of 12.0±6.4 days.

One-year follow-up data were collected for all patients. As shown in Figure and Table 1, the rate of MACE after discharge was significantly higher in the DP group (12.2% vs. 3.1%, P=0.029), primarily driven by more frequent TVR. A total of 13 TVR occurred, with 11 (11.2%) in the DP group and 2 (2.1%) in the CT group (P=0.018). No difference in the rate of TVR other than target lesion revascularization (TLR) was observed (5.1% vs. 2.1%, P=0.445). Stent thrombosis did not occur in either group. Myocardial infarction after discharge occurred in 3 patients in the DP group and in none of the patients in the CT group (P=0.246). One patient had myocardial infarction caused by in-stent restenosis 3 months after BMS implantation during the baseline procedure. Two patients had myocardial infarction in the distal reference segment where 50% residual stenosis was observed at the baseline procedure. In 1 patient, the filter device was deployed in that segment at the baseline procedure.

Figure.

MACE at 1 year according to randomization. Def ST, definite stent thrombosis; MACE, major adverse cardiac events; MI, myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.

Table 1. Event Rates at 1 Year According to Randomized Groups

	All			BMS			DES
	Distal protection (n=98)	Conventional treatment (n=96)	P value	Distal protection (n=24)	Conventional treatment (n=18)	P value	Distal protection (n=74)	Conventional treatment (n=77)	P value
MACE	12 (12.2)	3 (3.1)	0.029	6 (25.0)	0 (0.0)	0.029	6 (8.1)	3 (3.3)	0.321
Cardiac mortality	1 (1.0)	1 (1.0)	1.000	1 (4.1)	0 (0.0)	1.000	0 (0.0)	1 (1.3)	1.000
MI	3 (3.0)	0 (0.0)	0.246	2 (8.3)	0 (0.0)	0.498	1 (1.4)	0 (0.0)	0.490
TLR	6 (6.1)	0 (0.0)	0.029	4 (16.7)	0 (0.0)	0.122	2 (2.7)	0 (0.0)	0.239
TVR	11 (11.2)	2 (2.1)	0.018	5 (20.8)	0 (0.0)	0.060	6 (8.1)	2 (2.6)	0.161
Definite ST	0 (0.0)	0 (0.0)	1.000	0 (0.0)	0 (0.0)	1.000	0 (0.0)	0 (0.0)	1.000

Values are presented as n (%). BMS, bare metal stent; DES, drug eluting stent; MACE, major adverse cardiac events; MI, myocardial Infarction; ST, stent thrombosis; TLR, target lesion revascularization; TVR, target vessel revascularization.

We divided the subjects into 2 groups according to the use of BMS or DES and evaluated the clinical outcomes in each group (Table 1). Among patients who received BMS (n=42), the incidence of MACE was significantly higher in the DP group than in the CT group (25.0% vs. 0%, P=0.029), driven by the higher incidence of TVR in the former group (20.8% vs. 0%, P=0.060). In contrast, when we evaluated clinical outcomes in patients who received DES (n=151), the findings obviously differed from those for patients who received BMS. No significant differences were noted in any clinical variables between the DP and CT groups.

Angiographic Outcomes

A total of 149 patients consented to receive 10-month follow-up angiography (Table 2). A trend toward larger in-segment late lumen loss was observed in the DP group as compared with the CT group (0.26 mm vs. 0.09 mm, P=0.054). Angiographic binary restenosis rates were comparable but numerically higher in the DP group, both in-stent and in-segment.

Table 2. Results of 10-Month Angiographic Follow-up

	Distal protection	Conventional treatment	P value
n	75	74
Reference vessel diameter, mm	3.22±0.63	3.25±0.56	0.720
Minimal lumen diameter (in-stent), mm	2.56±0.64	2.61±0.48	0.628
Minimal lumen diameter (in-segment), mm	2.34±0.71	2.42±0.50	0.393
Diameter stenosis (in-stent), %	21.67±15.53	19.57±8.94	0.313
Diameter stenosis (in-segment), %	23 (17–35)	25 (17.75–31.25)	0.855
Late lumen loss (in-stent), mm	0.28±0.46	0.21±0.38	0.300
Late lumen loss (in-segment), mm	0.26±0.60	0.09±0.42	0.054
Binary restenosis (in-stent)	4 (5.33)	0 (0.00)	0.120
Binary restenosis (in-segment)	6 (8.00)	1 (1.35)	0.116

Values are presented as mean±SD, n (%), or median (interquartile range).

Discussion

The main findings of the current study were as follows: (1) the event rate of death from any cause, non-fatal myocardial infarction, or TVR at 1 year after discharge was significantly higher in the DP group, primarily driven by a higher risk of TVR; (2) more clinically relevant endpoints including myocardial infarction (3.0% vs. 0.0%, P=0.246) and all-cause death (1.0% vs. 1.0%, P=1.000) did not significantly differ between the groups; (3) the difference in the rate of MACE was noted only in patients who received BMS; and (4) in patients who received 10-month follow-up angiography, angiographic late lumen loss tended to be greater in the DP group, although the difference was not statistically significant.

As we reported previously, the use of a distal filter device protection device significantly reduced the incidence of no-reflow phenomena in patients at high risk for atherothrombotic embolization, achieving its primary endpoint. Furthermore, serious peri-procedural adverse events such as cardiac arrest or cardiogenic shock were significantly reduced by distal filter protection.⁷ However, prior studies cast doubt on the beneficial effect of the routine use of distal filter devices on long-term follow up.^6,10 Therefore, we set a composite of death from any cause, non-fatal myocardial infarction, or unplanned TVR at 1 year as the secondary endpoint before we started this study. Although the rate of MACE was significantly higher in the DP group, it was primarily attributed to the increased incidence of TVR and TLR at 1-year follow up in the DP group. Our findings are consistent with the results of the DEDICATION Trial,⁶ which also showed an increased rate of TVR/TLR in the patients who underwent distal filter protection. Filter device deployment may damage the intima where the filter device is deployed. In fact, 1 patient had myocardial infarction from the distal reference site with 50% diameter stenosis where the filter device was deployed, leading to TVR. Therefore, careful selection of normal segments may be required to prevent vessel damage during filter device deployment. Another possible explanation is that increased procedural complexity, which might have caused coronary stent under-expansion and/or damage of the intima when the filter device passed through. However, quantitative IVUS analysis after stent implantation revealed that the stent was well expanded in both groups. Furthermore, TVR other than TLR was similar in the DP and CT groups. Therefore, this effect might not be a major mechanism.

In the present study, no stent thrombosis was observed in either group. In contrast, the DEDICATION Trial⁶ showed an increased rate of definite stent thrombosis in the distal filter protection group as compared with the CT group (2.9% vs. 0.3%, P=0.01). The reason for the discrepancy between our study and the DEDICATION Trial can be explained by the use of IVUS. According to a large-scale registry¹¹ and a recent randomized study,¹² IVUS guidance was reported to reduce stent thrombosis as compared with angiographic guidance.¹³ By trial design, lesion morphology and vessel size were assessed before balloon dilatation in all patients in our study, enabling adequate stent sizing. In addition, operators confirmed adequate stent expansion and apposition in the final IVUS examination according to the trial protocol, which prevented both under-sizing and under-expansion of the stent.

Floating debris immediately after stent implantation or irregular protrusion inside stents may play a role in the progression of atherosclerosis or intimal proliferation. Post-stent irregular protrusion is a well-validated predictor of TLR,¹⁴ which is more frequently associated with attenuated plaque.¹⁵ An optimal coherent tomography study showed that a larger arc of attenuation was associated with unstable lesion morphology, including a greater maximal angle of lipid and the presence of macrophages.¹⁶ Another study revealed that accumulation of macrophages as assessed by optical coherence tomography was associated with irregular protrusions just after stenting.¹⁷ Monocytes/macrophages have been shown to play major roles in the progression of atherosclerosis. We have previously shown that an increased monocyte count after AMI was associated with non-culprit coronary plaque progression and the incidence of TLR as well as angiographic binary restenosis,¹⁸ suggesting that circulating monocytes might be recruited into the arterial wall followed by differentiation into macrophages, leading to coronary plaque progression and neointimal proliferation. Filter devices are known to cause “filter no-reflow phenomena” after stenting by clogging the filter net with embolic debris,¹⁹ allowing a considerable amount of embolic debris to float proximal to the filter device. Taken together, it is plausible that macrophages contained in the embolic debris or in-stent plaque protrusion might cause plaque progression, neointimal proliferation, or both.

In the present study, adverse cardiac events within 1 year were observed only in patients who received BMS, whereas no such events were observed in patients who received DES. This result was supported by several experimental and human studies. In atherosclerotic arteries of cholesterol-fed rabbits, stents eluting everolimus induced cell death in macrophages within the atherosclerotic plaque without influencing the viability of smooth muscle cells.²⁰ In a similar model, DES reduced inflammatory protease activity in vivo and reduced neointimal and medial arterial macrophages on histopathological analyses as compared with BMS,²¹ suggesting that DES may provide a local approach for stabilizing inflamed plaques. Plasma neopterin levels, an activation marker of monocytes/macrophages, were reported to be associated with cardiovascular events after stent implantation in patients with stable angina pectoris treated by BMS. However, this association was not observed in patients treated by DES.²² Our present study results suggest that DES use might solve the majority of long-term issues associated with distal filter protection. As distal filter protection abolished life-threatening in-hospital adverse events,⁷ we believe that the use of DP during DES implantation still should be considered a therapeutic option in patients with long attenuated plaque, especially in those with a baseline TIMI flow of grade 0 or 1.²³

Study Limitations

Our study results have to be interpreted in view of the following limitations. First, this trial indicated superiority with respect to the primary endpoint of the incidence of no-reflow phenomena and was not adequately powered to discriminate differences in clinical outcomes. Therefore, the present study results regarding clinical outcomes can only be considered exploratory and hypothesis generating. Second, the qualitative and quantitative analysis of thrombus and atherosclerotic debris entrapped by the filter was not performed, and its correlation with long-term clinical outcomes remains unknown. Third, 76.8% of the patients received 10-month angiographic follow up. Therefore, the 1-year TVR rate may suffer from the influence of angiography in this subgroup; however, the rate of TVR in patients with angiographic follow up was similar to that of patients without angiographic follow up (6.7% vs. 6.7%). Fourth, our study did not address late events beyond 1 year. Finally, our results were obtained in highly selected ACS patients with attenuated plaque ≥5 mm, and the results may apply only to patients with characteristics similar to those of our enrolled subjects.

Conclusions

Although the selective use of a distal embolic protection device during stenting of lesions with attenuated plaque measuring ≥5 mm resulted in a lower rate of in-hospital serious adverse cardiac events as compared with CT, the 1-year rates of major adverse events were higher in the DP group than in the CT group. This effect was driven by the difference in the incidence of TVR and might have been mitigated by the use of DES. Larger randomized trials powered for clinical outcomes are required to ultimately estimate the competing risks and benefits of DP devices in patients with ACS.

Sources of Funding

This work was supported, in part, by a grant from Nipro, Boston Scientific Corporation, and Japan Lifeline. The funding agency had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

Disclosures

Drs. Ikari, Morino, Yoshino, and Kimura are members of the Editorial Board for the Circulation Journal. Dr. Hibi has received remuneration for lectures from Nipro and Boston Scientific Corporation and has received a research grant from Nipro, Boston Scientific Corporation, and Japan Lifeline. Dr. Kozuma has received remuneration for lectures from Boston Scientific Corporation. Dr. Sonoda has received remuneration for lectures from Nipro and Boston Scientific Corporation and has received a research grant from Boston Scientific Corporation. Dr. Koshida has received remuneration for lectures from Boston Scientific Corporation. Dr. Kyono has received remuneration for lectures from Boston Scientific Corporation. Kume has received remuneration for lectures from Nipro and Boston Scientific Corporation. Dr. Tanabe has received remuneration for lectures from Boston Scientific Corporation and Japan Lifeline. Dr. Morino has received remuneration for lectures from Boston Scientific Corporation. Dr. Ikari has received a research grant from Boston Scientific Corporation. Dr. Yamasaki has received remuneration for lectures from Boston Scientific Corporation. Dr. Isshiki is a stockholder of Nipro and has received remuneration for lectures from Boston Scientific Corporation; received remuneration as a consultant from Nipro; and received patent royalty from Nipro. All other authors declare no conflicts of interest.

IRB Information

This study was approved by the Institutional Review Board of Yokohama City University Medical Center (Reference No. D110922004). Clinical Trial Registration: www.clinicaltrials.gov (NCT 1460966).

Data Availability

The deidentified participant data will not be shared.

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