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Six-Month Clinical and Angiographic Results of a Dedicated Drug-Eluting Stent for the Treatment of Coronary Bifurcation Narrowings
Six-Month Clinical and Angiographic Results of a Dedicated DrugEluting Stent for the Treatment of Coronary Bifurcation Narrowings Eberhard Grube, MDa,*, Lutz Buellesfeld, MDa, Franz J. Neumann, MDb, Stefan Verheye, MDc, Alexandre Abizaid, MDd, Dougal McClean, MDe, Ralf Mueller, MDa, Alexandra Lansky, MDf, Roxana Mehran, MDf, Ricardo Costa, MDf, Ulrich Gerckens, MDa, Brett Trauthen, MSg, and Peter J. Fitzgerald, MDh Percutaneous intervention for coronary bifurcation lesions has been associated with increased clinical complication rates compared with nonbifurcation lesions, primarily as a result of restenosis. Therefore, there is a need for new techniques. The purpose of this study was to evaluate a new drug-eluting stent and implantation technique for the treatment of de novo coronary bifurcation lesions. The Axxess Plus trial was a prospective multicenter single-arm study that enrolled 139 patients. Each patient received a self-expanding, conically shaped nickel-titanium Axxess Plus biolimus A9-eluting stent at the level of the carina. Depending on the lesion anatomy, additional nonstudy stents were placed distally if necessary. Clinical and angiographic follow-up were scheduled at 6 months after the procedure. The overall rate of target lesion revascularization was 7.5% at 6 months. A mean of 2.4 stents were implanted per patient; 51.2% of patients received a stent to the side branch, 29.4% received balloon angioplasty only, and 20.6% of side branches were not treated. In-stent late loss in the Axxess stents was 0.09 mm. Incidences of angiographic in-stent restenosis were 7.1% in the parent vessel stents and 9.2% in the group receiving stents in the side branch (7.9% excluding bare metal stents placed distal to the Axxess stent), compared with 25% for balloon angioplasty treatment and 12% for no treatment. Late stent thrombosis was observed in 3 cases, 2 of which were associated with confirmed premature cessation of antiplatelet therapy. In conclusion, the Axxess Plus conical stent effectively treats bifurcation lesions alone or in conjunction with other drug-eluting stents. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1691–1697)
In the “stent era,” percutaneous coronary interventions in bifurcations are associated with increased adverse clinical event rates and inferior angiographic outcomes compared with nonbifurcation lesions.1,2 In recent publications reporting the performance of drug-eluting stents in bifurcation lesions, results appear to be improved compared with bare metal stents, but adverse clinical event rates remain high, with increased restenosis rates, especially in the side branch.3,4 Lesions at coronary bifurcations thus represent a challenging lesion subset in the current practice of interventional cardiology. The principal cause of increased adverse event rates in bifurcation lesions appears to be the inability of current devices and techniques to adequately scaffold and preserve
a HELIOS Heart Center, Siegburg; and bHeart Center Bad Krozingen, Bad Krozingen, Germany; cAZ Middelheim, Antwerp, Belgium; dDante Pazzenese Institute of Cardiology, Sao Paulo, Brazil; eChristchurch Hospital, Christchurch, New Zealand; fCardiovascular Research Foundation, New York, New York; gDevax, Inc., Irvine; and hStanford University Medical Center, Stanford, California. Manuscript received October 15, 2006; revised manuscript received January 13, 2007 and accepted January 17, 2007. *Corresponding author: Tel: 49-2241-182322; fax: 49-2241-183040. E-mail address: [email protected] (E. Grube).
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.01.043
the side branch ostium. Serial intravascular ultrasound (US) analysis of side branch stents suggest underexpansion of the stent may be a contributing factor.5 Several customized metal stent designs have been developed to address this problem. However, their use is associated with procedural complexity, and first published experiences indicate that the long-term outcome is still limited.6 The incorporation of an antiproliferative compound might help to overcome this problem. Therefore, we conducted a prospective multicenter evaluation of a new specialized bifurcation stent that elutes the antiproliferative agent biolimus A9. Methods This prospective single-arm multicenter evaluation of the Axxess Plus stent (Devax, Irvine, California) enrolled 139 patients from 13 sites located in Germany, Belgium, The Netherlands, United Kingdom, Brazil, and New Zealand. Clinical follow-up was performed at 30 ⫾ 14 days after the procedure and again 6 ⫾ 1 months after the procedure. Elective angiographic follow-up was scheduled in conjunction with the 6-month follow up visit. A 1-year evaluation is ongoing before termination of the study. A data safety and monitoring committee periodically reviewed safety data, and all clinical end points were adjudicated by an independent clinical events committee. www.AJConline.org
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Eligible patients were 18 to 80 years of age with a history of stable or unstable angina. Angiographic eligibility required a de novo target lesion with ⬎50% stenosis in a native coronary artery within 3 mm of the juncture of a side branch measuring ⱖ2.2 mm in diameter at the ostium. Maximum lesion lengths were 30 mm in the parent vessel (15 mm maximum on either side of the bifurcation) and up to 15 mm in the side branch. The side branch was not required to be diseased for inclusion in the study. A second lesion in another vessel not involved in the bifurcation could be treated in the same setting as the bifurcation as long as the secondary lesion was treated successfully before the bifurcation lesion intervention. Major exclusion criteria were myocardial infarction within 72 hours of the planned procedure date, an ejection fraction ⬍30%, a co-morbidity that might require cessation of antiplatelet therapy within 6 months of the procedure, and any known allergy to any of the study materials or medications. All patients gave their written informed consent. The study was approved by the local medical ethics committees. The primary objective of the Axxess Plus Trial was to evaluate the feasibility, safety, and efficacy of the biolimus A9 – eluting Axxess stent in de novo bifurcated coronary lesions. The secondary objectives were to establish the best treatment method for the side branch based on angiographic efficacy measures, evaluate the overall efficacy of the procedure, and evaluate the procedural and long-term safety profile of the device based on comparative clinical outcomes versus other published bifurcation series that involved standard devices and techniques. The primary end point of the Axxess Plus study was in-stent angiographic late loss at 6-month follow-up, as measured by quantitative computerized angiographic analysis (QCA). The safety end point was a composite of major adverse cardiac events (MACEs) at 6 months after the procedure. A MACE was defined as any death, Q-wave or non–Q-wave myocardial infarction, or ischemia-driven revascularization of the target lesion (i.e., emergency or elective coronary artery bypass grafting or repeated percutaneous coronary intervention). Secondary safety end points included MACEs at 1 and 12 months and any stent thrombosis or total occlusion. Myocardial infarction was defined as a cardiac event with development of pathologic Q-waves, or in the absence of pathologic Q-waves, an increase in creatine kinase levels to more than twice the upper limit of normal with an increased creatine kinase-MB level. Target lesion revascularization was considered driven by ischemia if the stenosis of the target vessel was ⱖ50% of the luminal diameter on the basis of QCA with electrocardiographic changes while the patient was at rest or a functional study indicating ischemia in the target vessel region, or if there was stenosis of ⱖ70%. The novel self-expanding Axxess stent is laser cut from a nickel-titanium alloy in the austenitic (i.e., superelastic) phase with a 0.006-inch (0.015 mm) strut thickness. The stent is coated with biolimus A9, a sirolimus analog, suspended within a polylactic acid bioabsorbable coating. The Axxess stents were provided in straight and conical configurations in different diameters and lengths. The Axxess stent’s conical design allows it to expand into the irregular
Figure 1. The Axxess biolimus-eluting stent. Note the 3 markers at the distal stent edge and the single marker at the proximal stent edge.
anatomy of a bifurcation lesion at the level of the carina (Figure 1). This device, which is better adapted to the artery anatomy, might enhance the interaction between adequate mechanical scaffolding and accurate delivery and dosage of the antirestenosis drugs. The straight configuration was intended to be used distally to the conical stent to cover lesions that extended beyond the carina. The protocol allowed for the use of commercially available stents in conjunction with the Axxess stent in the event that the appropriate straight stent was not available. The drug biolimus A9 is a derivative of sirolimus (i.e., rapamycin), an immunosuppressive compound with proven antiproliferative properties when eluted from the Cypher stent (Cordis, Miami Lakes, Florida).7 Like sirolimus, biolimus binds to FK506-binding protein 12 and inhibits mammalian target of rapamycin protein activity; therefore, sirolimus and biolimus inhibit growth factor– driven cell proliferation, including that of T cells and vascular smooth muscle cells. The drug is loaded in a bioabsorbable polylactic acid polymer. The coating is applied to the abluminal (i.e., mural-facing) surface of the stent to a thickness of approximately 15 m. The polymer is a commonly used suture material that is metabolized in the cell to carbon dioxide and water. Hence, there is no permanent residual drug trapped on the stent. The nominal drug loading is 22 g/mm of stent length for all sizes. Before the index procedure, all patients received oral aspirin (ⱖ80 mg) and oral clopidogrel (300 mg 24 hours before the procedure). During the procedure, intravenous heparin boluses were administered to achieve an activated clotting time ⬎250 seconds. The use of intravenous glyco-
Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial
protein IIb/IIIa inhibitors was at the discretion of the physician. Wires were introduced into the parent vessel and side branch, and mandatory predilatation was performed in the parent vessel, followed by side branch dilatation at the discretion of the investigator (Figure 2). The Axxess stent was then introduced over 1 of the wires (generally the wire in the vessel with the most extensive disease). The Axxess stent delivery system was placed as close to the carina as possible, and the cover sheath was retracted partially, exposing the distal 3 radiopaque markers. The position of the stent was assessed with a contrast medium injection and adjusted to align the markers with the carina. When the stent was observed to open into the side branch, the sheath was retracted further and the stent was advanced into the carina. The sheath was then fully retracted and the delivery system was withdrawn. At this point, the need for additional stents was assessed by the operator. If necessary to cover the lesion in the parent vessel, a second stent was added. If the side branch was not well dilated or if there was extensive disease, a stent was added to the side branch as well. In cases in which both side branches required stent implantation, the structure of the Axxess stent allows for simultaneous placement and deployment of the branch vessel stents, as shown in Figure 2. In this example, 2 Cypher stents are used in the branch vessels. To avoid gaps in stent coverage (and thus in drug coverage), the ends of the additional stents were aligned just inside the markers of the Axxess stents and the side branch stents were deployed simultaneously (i.e., v-stenting technique). After intervention, an electrocardiogram was obtained, and cardiac enzymes were measured within 8 and 16 hours and before discharge. Patients took aspirin ⱖ80 mg/day and 75 mg of clopidogrel for 6 months. There was no mandatory intravascular US guidance for implantation. Coronary angiograms obtained at baseline, at the completion of the procedure, and at the 6-month follow-up were independently analyzed (Cardiovascular Research Foundation, New York, New York). The parent vessel and side branch were analyzed separately. Restenosis was defined as stenosis of ⬎50% of the luminal diameter in the target lesions. Late luminal loss was defined as the difference between the minimal luminal diameter at the completion of the procedure and that measured at follow-up. Quantitative angiographic measurements of the target lesion were obtained in the “in-stent” zone and “in-lesion” zone, which included a 5-mm segment proximal and distal to the stentimplanted segments. Because there was ⬎1 brand of stent used in the parent vessel, a QCA subanalysis was performed to separate the outcomes of the Axxess stents from those of any other stent placed. Intravascular US examinations were performed after the stent placement procedure in 20% of the patients and at 180-day follow-up in 30% of the patients. These data were used to make quantitative determinations of the tissue volume within the stents. All intravascular US analyses were made by an independent core laboratory (Cardiovascular Core Analysis Laboratory, Stanford, California).
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Results Baseline clinical and angiographic characteristics are listed in Table 1. The bifurcations were mostly “true” bifurcation lesions involving the parent vessel and at least the ostium of the side branch. The mean lesion length measured 16.28 ⫾ 7.44 mm in the parent vessel and 7.43 ⫾ 3.90 mm in the side branch. Implantation of the conical Axxess stent in the parent vessel was successful in 130 of 139 cases (device success rate, 93.5%). There were 3 instances in which the device was withdrawn before deployment; in 2 of these cases, the device would have extended into the left main coronary artery, and in the other case the delivery system could not reach the target lesion. These 3 patients are included in the 30-day results, but are omitted from the long-term analysis. The remaining 6 device failures occurred when the stent was placed distal or proximal to the intended location. These cases did not impact overall treatment success, as there were no patient complications associated with these failures, resulting in a lesion success rate (defined by ⬍50% residual stenosis at the end of the procedure) of 100%. When the conical stent was in place, the remaining treatment varied considerably according to the extent of disease in the vessels branching distal to the bifurcation. The Axxess concept generated 4 different stent patterns: Axxess conical stent only (19.1%), the cone plus a distal parent vessel stent (29.4%), the cone plus a side branch stent (9.6%), and the cone plus stents to the distal parent vessel and side branch (41.9%). In lesions that required distal stent implantation, attempts to place the straight Axxess stent were undertaken in 36 cases, but only 21 were successful. The failures were caused by an inability to advance the system to the desired location as a result of device stiffness and the profile of this stent type. For this reason, the straight stent was abandoned as a branch vessel treatment option in favor of the more deliverable Cypher stent (Cordis, Johnson & Johnson) or Taxus stent (Boston Scientific). Bare metal stents were placed in 2 patients. In 1 instance, no drugeluting stent was available and the operator used 2 bare metal stents in distal branch vessels, and in a second patient a short metal stent was used to treat a dissection distal to a Cypher stent (Table 2). Follow-up angiographic data were available for 126 patients (92.6%). The results are listed in Tables 3 to 5. The angiographic late loss of the Axxess conical stent (i.e., primary end point) was 0.09 ⫾ 0.56 mm. Table 4 shows the results in the parent vessel by analysis zone, from the proximal vessel through the distal vessel segment for all patients, with the bare metal stents omitted. The frequencies of binary in-stent restenosis were 4.8% within the Axxess stent, 4.5% in the stent distal to the Axxess stent, and 10.5% including 5-mm nonstented segments proximal and distal to the stents. Treatment decisions in the side branch varied according to the degree of involvement of the side branch in the lesion; 51.5% received a stent, and balloon angioplasty alone was performed in 29%. The patients who received a stent in the side branch had only a 9.2% restenosis rate at 6 months; the restenosis rate was 7.9% for patients who received a drugeluting stent in the side branch. Patients with balloon an-
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Figure 2. Case example. (A) Bifurcation stenosis with disease in parent vessel and both distal vessels. (B) Balloon dilation. (C) Positioning of Axxess stent at the carina and expansion. (D) Kissing dilation of both distal vessels. (E,F) Positioning and simultaneous implantation of 2 Cypher stents to treat the distal disease. (G) Final kissing balloon. (H) Final angiographic result. (I) Angiographic result at 6-month follow-up.
Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial Table 1 Patient and lesion characteristics (n ⫽ 139)
Table 3 Quantitative angiographic results of the parent vessel at 180 days
Characteristic
Value
Men Age (yrs) Diabetes mellitus Insulin dependent Hypertension* Hypercholesterolemia† Current smoker Previous percutaneous coronary intervention Previous myocardial infarct Canadian Cardiovascular Society Classification grade III or IV Lesion location Left anterior descending artery/diagonal branch Left circumflex artery/marginal branch Posterior descending artery/Posterolateral branch Left main stem Bifurcation lesion type “True” parent vessel and side branch Pre-branch Parent vessel only Post-branch/ostial
102 (73.4%) 64.4 ⫾ 10.2 23 (16.5%) 8 (5.8%) 102 (73.4%) 109 (78.8%) 18 (12.9%) 42 (30.2%) 43 (30.9%) 51 (36.7%)
102 (73.4%)
8 (5.8%) 108 (77.7%) 18 (12.9%) 6 (4.3%) 6 (4.3%)
Table 2 Stent usage
Total stents Axxess cone Axxess straight Cypher Taxus Bare metal Ballon dilatation only Wire only Mean no. of stents Mean stent length (mm)
Angiographic Finding Minimal luminal diameter (mm) Before the procedure After the procedure At follow-up Stenosis (% of luminal diameter) Before the procedure After the procedure At follow-up Late luminal loss (mm) Restenosis at follow-up (%) All patients Drug-eluting stents only
In-Stent Zone
In-Segment Zone
0.78 ⫾ 0.30 2.60 ⫾ 0.45 2.74 ⫾ 0.60
0.78 ⫾ 0.30 2.27 ⫾ 0.39 2.03 ⫾ 0.56
72.9 ⫾ 9.4 12.5 ⫾ 9.8 5.29 ⫾ 18.9 0.19 ⫾ 0.42
72.9 ⫾ 9.4 29.3 ⫾ 16.7 29.8 ⫾ 17.2 0.21 ⫾ 48
7.1% 5.6%
11.9% 10.5%
Values are mean ⫾ SD or percentages.
24 (17.3%) 5 (3.6%)
* Defined as current use of medication and/or systolic blood pressure ⬎140 mm Hg and/or diastolic blood ⬎90 mm Hg measured on 3 different days. † Defined as current use of medication and/or a total cholesterol level ⬎220 mg/dL.
Stent Detail
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Proximal Parent Vessel
Distal Parent Vessel
Side Branch
136 136 — — — —
115 — 18 82 13 2 —
73 — 2 63 7 1 40
— 1.8
26 1.1
26.36 ⫾ 11.86
17.32 ⫾ 8.01
gioplasty had a restenosis rate of 25%; the incidence was 12% in cases without side branch treatment at the index procedure. In 2 cases with side branch stenting, the restenosis was located at the side branch ostium within the overlap region. Three patients with 2 parent vessel stents (Axxess and Cypher/Taxus stents) developed restenoses at the overlap site. In total, there were 5 cases with stent restenosis in the overlap region. The treatment mode strongly affected the angiographic success within the side branch at baseline. In patients with side branch stenting, the success rate was 97.1%, followed by 96.2% in patients without side branch treatment and
77.5% for patients with side branch balloon angioplasty only. Removing the index failures for the balloon angioplasty group decreased the restenosis rate in this group to 13.8%. Intravascular US analysis was available at follow-up in 49 patients in the parent vessel and 25 patients in the side branch. Within the Axxess stent, neointimal volume obstruction was 2.28 ⫾ 2.17%, with a minimum lumen area of 7.86 ⫾ 2.63 mm2. Ostium stent areas were 5.52 ⫾ 1.64 mm2 in the parent vessel and 4.58 ⫾ 1.41 mm2 at the side branch ostium. MACEs are listed in Table 6. In-hospital MACEs for 139 enrolled patients consisted of 6 non–Q-wave myocardial infarctions (4.2%) and 1 Q-wave infarction (0.7%) caused by a distal stent dissection that temporarily occluded the left anterior descending artery. There were no additional MACEs by 30-day follow-up. Follow-up at 6 ⫾ 1 months was available in 134 of 136 eligible patients (98.5%). There was 1 death (0.7%), 1 additional Q-wave myocardial infarction (0.7%) associated with a stent thrombosis at 61 days, and 10 cases of target lesion revascularization (7.5%). The cumulative event-free survival rate was 88.8% at 180 days. There were no cases of acute or subacute stent thrombosis. Late stent thrombosis was confirmed in 3 cases (2.2%). The first of these cases occurred in a patient at 61 days who was treated surgically for prostate carcinoma 51 days after a successful procedure, but in whom antiplatelet therapy was discontinued as a result of postsurgical hematuria resulting in a Q-wave myocardial infarct and target lesion revascularization 10 days later. The second case occurred in a patient who stopped receiving clopidogrel after 1 month because of discomfort and then presented with unstable angina at 98 days. A nonocclusive thrombosis at the carina was confirmed by angiography and resolved with pharmacologic treatment. Clopidogrel therapy was restarted, and the patient returned for follow-up at 6 months symptomfree, at which time a patent bifurcation was confirmed by angiography. The third case was found during the 6-month angiographic follow-up in an asymptomatic patient. This patient received 3 Cypher stents in the left anterior descending artery distal to the Axxess stent as a result of a spiral dissection. The thrombosis was located near the overlap of
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Table 4 Quantitative angiographic results in different analysis zones in the parent vessel Group All Patients Late luminal loss (mm) Restenosis (%) Patients receiving drug-eluting stents only Late luminal loss (mm) Restenosis (%)
Proximal 5 mm
Axxess Stent
Distal Stent
Distal 5 mm
0.17 ⫾ 0.46 5.1
0.09 ⫾ 0.56 4.8
0.21 ⫾ 44 4.5
0.09 ⫾ 38 5.1
0.17 ⫾ 47 5.1%
0.08 ⫾ 0.55 4.0%
0.19 ⫾ 42 3.5%
0.09 ⫾ 38 3.3%
Values are means ⫾ SD on percentages. Table 5 Quantitative angiographic results of side branch at 180 days Angiographic Finding Minimal luminal diameter (mm) Before the procedure After the procedure At follow-up Stenosis (% of luminal diameter) Before the procedure After the procedure At follow-up Late luminal loss (mm) Index restenosis Restenosis at follow-up All patients Drug-eluting stents only
Stent
Balloon Angioplasty
Wire Only, No Treatment
0.88 ⫾ 0.39 2.32 ⫾ 0.39 2.05 ⫾ 0.39
0.88 ⫾ 0.39 1.64 ⫾ 0.51 1.49 ⫾ 0.50
0.88 ⫾ 0.39 1.83 ⫾ 0.45 1.59 ⫾ 0.49
62.2 ⫾ 16.2 19.0 ⫾ 9.1 25.4 ⫾ 16.7 0.23 ⫾ 0.52 2.9%
62.2 ⫾ 16.2 28.1 ⫾ 21.8 33.1 ⫾ 21.9 0.18 ⫾ 0.51 22.5%
62.2 ⫾ 16.2 22.4 ⫾ 16.5 31.0 ⫾ 23.5 0.20 ⫾ 0.39 3.8%
9.2% 7.9%
25.0% —
12.0% —
Values are means ⫾ SD or percentage. Table 6 Major adverse cardiac events Event Death Myocardial infarction Q-wave Non–Q-wave Target lesion revascularization Coronary bypass Coronary angioplasty Any major adverse cardiac event Target vessel failure Event-free survival Stent thrombosis
In-Hospital Events
Out-of-Hospital Events
Cumulative to 180 Days
0 7 (5.0%) 1 (0.7%) 6 (4.3%) 0 0 0 7 (5.0%) 7 (5.0%) 95.0% 0
1 (0.7%) 1 (0.7%) 1 (0.7%) 0 10 (7.5%) 0 10 (7.5%) 12 (9.0%) 12 (9.0%) 91.0% 3 (2.2%)
1 (0.7%) 8 (6.0%) 2 (1.5%) 6 (4.5%) 10 (7.5%) 0 10 (7.5%) 15 (11.2%) 15 (11.2%) 88.8% 3 (2.2%)
the second and third Cypher stents, and the bifurcation was patent. Discussion In this first study of a dedicated drug-eluting bifurcation stent, we found that the biolimus A9 drug used in conjunction with the self-expanding, nickel-titanium alloy Axxess stent is effective in reducing neointimal hyperplasia. The procedural success rate with the conical stent was ⬎90%, although the straight stent delivery system proved cumbersome and had to be abandoned in favor of commercially available stents to treat distal vessels. The self-expanding properties of the conical stent were helpful to fit the device into the carina; proximal or distal dislocations during ex-
pansion, sometimes seen with regular self-expanding stents, were absent given this favorable interaction of lesion morphology and device design. The combination of Axxess and (predominantly) Cypher stents was associated with a low out-of-hospital major adverse event rate (9.0%) to 6 months after stent implantation. The angiographic late loss of the Axxess cone stent (i.e., primary end point) was 0.09⫾ 0.56 mm, which is comparable to results of sirolimus- or everolimus-eluting stents in nonbifurcated de novo lesions, indicating a remarkable reduction compared with historical bare metal controls.8,9 Although the Axxess stent effectively reduces neointimal hyperplasia as measured by angiographic late loss at 180 days, the procedure necessitates the frequent use of adjunctive stents in the distal branch vessels to com-
Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial
plete therapy in most patients. The angiographic outcomes with these distal stents were consistent with previous studies with the Cypher stent,3,4 whether the stent was placed in the side branch or the distal parent vessel. Previous studies of bifurcation lesions typically report worse angiographic outcomes in the side branch, and stented side branches usually fare worse than cases of balloon angioplasty only. This is mainly because of ostial restenosis in lesion segments insufficiently covered by the drug-eluting stent. When used with the Axxess stent, however, the angiographic results in the side branch and parent vessel were quite similar, with comparable late loss values, which might be an indicator of better lesion coverage with this new stent design. The incidence of restenosis was slightly higher in side branches compared with the main vessel, but the observed rate was still an encouraging 7.9%. Although the Axxess stent strategy results in overlapping stents in case additional stents are implanted distal to the conical main vessel stent, there was no incidence of an exaggerated neointimal response to the site of the double stent strut layers. However, previous reports have demonstrated that drug-eluting stents further delay arterial healing and promote inflammation at sites of overlap compared with bare metal stents.10 In particular, Taxus stents induced greater fibrin deposition, medial cell loss, heterophils/eosinophils, and late neointimal hyperplasia. Further larger studies and long-term observations are therefore needed to observe and evaluate effects at the overlapping sites, particular when different kinds of drug-eluting stents are overlapped. For this reason, we dominantly used the Cypher stent in addition to the Axxess stent, staying in the same drug family of “limus” analogs. Stent thrombosis is an important issue in drug-eluting stent implantations for treatment of bifurcation lesions. The presence of a bifurcation lesion has been clearly identified as an independent risk factor for stent thrombosis.11 The stent thrombosis rate in our study was 2.2%, with a total of 3 events at ⬎30 days, 2 of them after premature discontinuation of clopidogrel. Considering only patients who continued antiplatelet therapy, the rate was ⬍1%, which is comparable to that with bare metal stents in simple coronary lesions. Therefore, the Axxess stent strategy seems to be safe if the antiplatelet medication is not prematurely stopped. This finding is in accordance with reports on drugeluting stent implantations in real-world settings in general,11 and not only associated with bifurcation lesion treatments. Although it was successful in terms of its stated objec-
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tives, this study has several limitations. The results with the biolimus-eluting Axxess stent were not compared with a randomized control group. In addition, this study did not prospectively assign a particular treatment method to the side branch and the choice of additional stents to be used was at the operator’s discretion, resulting in a heterogeneous study population. 1. Lefevre T, Louvard Y, Morice MC, Dumas P, Loubeyre C, Benslimane A, Premchand RK, Guillard N, Piechaud JF. Stenting of bifurcation lesions: classification, treatments, and results. Cathet Cardiovasc Intervent 2000;49:274 –283. 2. Al Suwaidi J, Yeh W, Cohen HA, Detre KM, Williams DO, Holmes DR Jr. Immediate and one-year Outcome in patients with coronary bifurcation lesions in the modern era (NHLBI Dynamic Registry). Am J Cardiol 2001;87:1139 –1144. 3. Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr, Spanos V, Louvard Y, Desmedt B, Di Mario C, Leon MB. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004;109:1244 –1249. 4. Ge L, Airoldi F, Iakovou I, Cosgrave J, Michev I, Sangiorgi GM, Montorfano M, Chieffo A, Carlino M, Corvaja N, Colombo A. Clinical and angiographic outcome after implantation of drug eluting stents in bifurcation lesions with the crush stent technique. J Am Coll Cardiol 2005;26:613– 620. 5. Costa RA, Mintz GS, Carlier SG, Lansky AJ, Moussa I, Fujii K, Takebayashi H, Yasuda T, Costa JR Jr, Tsuchiya Y, Jensen LO, et al. Bifurcation coronary lesions treated with the “crush” technique: an intravascular ultrasound analysis. J Am Coll Cardiol 2005;46:599 – 605. 6. Lefevre T, Ormiston J, Guagliumi G, Schultheiss HP, Quilliet L, Reimers B, Brunel P, Wijns W, Buettner HJ, Hartmann F, Veldhof S, et al. The Frontier stent registry: safety and feasibility of a novel dedicated stent for the treatment of bifurcation coronary artery lesions. J Am Coll Cardiol 2005;46:592–598. 7. Pan M, Suarez de Lezo J, Medina A, Romero M, Hernandez E, Segura J, Castroviejo JR, Pavlovic D, Melian F, Ramirez A, Castillo JC. Simple and complex stent strategies for bifurcated coronary arterial stenosis involving the side branch origin. Am J Cardiol 1999;83:1320 – 1325. 8. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus eluting stent versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 9. Costa RA, Lansky AJ, Mintz GS, Mehran R, Tsuchiya Y, Negoita M, Gilutz Y, Nikolsky E, Fahy M, Pop R, et al. Angiographic results of the first human experience with everolimus-eluting stents for the treatment of coronary lesions (the FUTURE I trial). Am J Cardiol 2005; 95:113–116. 10. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK, Gold HK, Virmani R. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005;112:270 –278. 11. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126 –2130.
In the “stent era,” percutaneous coronary interventions in bifurcations are associated with increased adverse clinical event rates and inferior angiographic outcomes compared with nonbifurcation lesions.1,2 In recent publications reporting the performance of drug-eluting stents in bifurcation lesions, results appear to be improved compared with bare metal stents, but adverse clinical event rates remain high, with increased restenosis rates, especially in the side branch.3,4 Lesions at coronary bifurcations thus represent a challenging lesion subset in the current practice of interventional cardiology. The principal cause of increased adverse event rates in bifurcation lesions appears to be the inability of current devices and techniques to adequately scaffold and preserve
a HELIOS Heart Center, Siegburg; and bHeart Center Bad Krozingen, Bad Krozingen, Germany; cAZ Middelheim, Antwerp, Belgium; dDante Pazzenese Institute of Cardiology, Sao Paulo, Brazil; eChristchurch Hospital, Christchurch, New Zealand; fCardiovascular Research Foundation, New York, New York; gDevax, Inc., Irvine; and hStanford University Medical Center, Stanford, California. Manuscript received October 15, 2006; revised manuscript received January 13, 2007 and accepted January 17, 2007. *Corresponding author: Tel: 49-2241-182322; fax: 49-2241-183040. E-mail address: [email protected] (E. Grube).
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.01.043
the side branch ostium. Serial intravascular ultrasound (US) analysis of side branch stents suggest underexpansion of the stent may be a contributing factor.5 Several customized metal stent designs have been developed to address this problem. However, their use is associated with procedural complexity, and first published experiences indicate that the long-term outcome is still limited.6 The incorporation of an antiproliferative compound might help to overcome this problem. Therefore, we conducted a prospective multicenter evaluation of a new specialized bifurcation stent that elutes the antiproliferative agent biolimus A9. Methods This prospective single-arm multicenter evaluation of the Axxess Plus stent (Devax, Irvine, California) enrolled 139 patients from 13 sites located in Germany, Belgium, The Netherlands, United Kingdom, Brazil, and New Zealand. Clinical follow-up was performed at 30 ⫾ 14 days after the procedure and again 6 ⫾ 1 months after the procedure. Elective angiographic follow-up was scheduled in conjunction with the 6-month follow up visit. A 1-year evaluation is ongoing before termination of the study. A data safety and monitoring committee periodically reviewed safety data, and all clinical end points were adjudicated by an independent clinical events committee. www.AJConline.org
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Eligible patients were 18 to 80 years of age with a history of stable or unstable angina. Angiographic eligibility required a de novo target lesion with ⬎50% stenosis in a native coronary artery within 3 mm of the juncture of a side branch measuring ⱖ2.2 mm in diameter at the ostium. Maximum lesion lengths were 30 mm in the parent vessel (15 mm maximum on either side of the bifurcation) and up to 15 mm in the side branch. The side branch was not required to be diseased for inclusion in the study. A second lesion in another vessel not involved in the bifurcation could be treated in the same setting as the bifurcation as long as the secondary lesion was treated successfully before the bifurcation lesion intervention. Major exclusion criteria were myocardial infarction within 72 hours of the planned procedure date, an ejection fraction ⬍30%, a co-morbidity that might require cessation of antiplatelet therapy within 6 months of the procedure, and any known allergy to any of the study materials or medications. All patients gave their written informed consent. The study was approved by the local medical ethics committees. The primary objective of the Axxess Plus Trial was to evaluate the feasibility, safety, and efficacy of the biolimus A9 – eluting Axxess stent in de novo bifurcated coronary lesions. The secondary objectives were to establish the best treatment method for the side branch based on angiographic efficacy measures, evaluate the overall efficacy of the procedure, and evaluate the procedural and long-term safety profile of the device based on comparative clinical outcomes versus other published bifurcation series that involved standard devices and techniques. The primary end point of the Axxess Plus study was in-stent angiographic late loss at 6-month follow-up, as measured by quantitative computerized angiographic analysis (QCA). The safety end point was a composite of major adverse cardiac events (MACEs) at 6 months after the procedure. A MACE was defined as any death, Q-wave or non–Q-wave myocardial infarction, or ischemia-driven revascularization of the target lesion (i.e., emergency or elective coronary artery bypass grafting or repeated percutaneous coronary intervention). Secondary safety end points included MACEs at 1 and 12 months and any stent thrombosis or total occlusion. Myocardial infarction was defined as a cardiac event with development of pathologic Q-waves, or in the absence of pathologic Q-waves, an increase in creatine kinase levels to more than twice the upper limit of normal with an increased creatine kinase-MB level. Target lesion revascularization was considered driven by ischemia if the stenosis of the target vessel was ⱖ50% of the luminal diameter on the basis of QCA with electrocardiographic changes while the patient was at rest or a functional study indicating ischemia in the target vessel region, or if there was stenosis of ⱖ70%. The novel self-expanding Axxess stent is laser cut from a nickel-titanium alloy in the austenitic (i.e., superelastic) phase with a 0.006-inch (0.015 mm) strut thickness. The stent is coated with biolimus A9, a sirolimus analog, suspended within a polylactic acid bioabsorbable coating. The Axxess stents were provided in straight and conical configurations in different diameters and lengths. The Axxess stent’s conical design allows it to expand into the irregular
Figure 1. The Axxess biolimus-eluting stent. Note the 3 markers at the distal stent edge and the single marker at the proximal stent edge.
anatomy of a bifurcation lesion at the level of the carina (Figure 1). This device, which is better adapted to the artery anatomy, might enhance the interaction between adequate mechanical scaffolding and accurate delivery and dosage of the antirestenosis drugs. The straight configuration was intended to be used distally to the conical stent to cover lesions that extended beyond the carina. The protocol allowed for the use of commercially available stents in conjunction with the Axxess stent in the event that the appropriate straight stent was not available. The drug biolimus A9 is a derivative of sirolimus (i.e., rapamycin), an immunosuppressive compound with proven antiproliferative properties when eluted from the Cypher stent (Cordis, Miami Lakes, Florida).7 Like sirolimus, biolimus binds to FK506-binding protein 12 and inhibits mammalian target of rapamycin protein activity; therefore, sirolimus and biolimus inhibit growth factor– driven cell proliferation, including that of T cells and vascular smooth muscle cells. The drug is loaded in a bioabsorbable polylactic acid polymer. The coating is applied to the abluminal (i.e., mural-facing) surface of the stent to a thickness of approximately 15 m. The polymer is a commonly used suture material that is metabolized in the cell to carbon dioxide and water. Hence, there is no permanent residual drug trapped on the stent. The nominal drug loading is 22 g/mm of stent length for all sizes. Before the index procedure, all patients received oral aspirin (ⱖ80 mg) and oral clopidogrel (300 mg 24 hours before the procedure). During the procedure, intravenous heparin boluses were administered to achieve an activated clotting time ⬎250 seconds. The use of intravenous glyco-
Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial
protein IIb/IIIa inhibitors was at the discretion of the physician. Wires were introduced into the parent vessel and side branch, and mandatory predilatation was performed in the parent vessel, followed by side branch dilatation at the discretion of the investigator (Figure 2). The Axxess stent was then introduced over 1 of the wires (generally the wire in the vessel with the most extensive disease). The Axxess stent delivery system was placed as close to the carina as possible, and the cover sheath was retracted partially, exposing the distal 3 radiopaque markers. The position of the stent was assessed with a contrast medium injection and adjusted to align the markers with the carina. When the stent was observed to open into the side branch, the sheath was retracted further and the stent was advanced into the carina. The sheath was then fully retracted and the delivery system was withdrawn. At this point, the need for additional stents was assessed by the operator. If necessary to cover the lesion in the parent vessel, a second stent was added. If the side branch was not well dilated or if there was extensive disease, a stent was added to the side branch as well. In cases in which both side branches required stent implantation, the structure of the Axxess stent allows for simultaneous placement and deployment of the branch vessel stents, as shown in Figure 2. In this example, 2 Cypher stents are used in the branch vessels. To avoid gaps in stent coverage (and thus in drug coverage), the ends of the additional stents were aligned just inside the markers of the Axxess stents and the side branch stents were deployed simultaneously (i.e., v-stenting technique). After intervention, an electrocardiogram was obtained, and cardiac enzymes were measured within 8 and 16 hours and before discharge. Patients took aspirin ⱖ80 mg/day and 75 mg of clopidogrel for 6 months. There was no mandatory intravascular US guidance for implantation. Coronary angiograms obtained at baseline, at the completion of the procedure, and at the 6-month follow-up were independently analyzed (Cardiovascular Research Foundation, New York, New York). The parent vessel and side branch were analyzed separately. Restenosis was defined as stenosis of ⬎50% of the luminal diameter in the target lesions. Late luminal loss was defined as the difference between the minimal luminal diameter at the completion of the procedure and that measured at follow-up. Quantitative angiographic measurements of the target lesion were obtained in the “in-stent” zone and “in-lesion” zone, which included a 5-mm segment proximal and distal to the stentimplanted segments. Because there was ⬎1 brand of stent used in the parent vessel, a QCA subanalysis was performed to separate the outcomes of the Axxess stents from those of any other stent placed. Intravascular US examinations were performed after the stent placement procedure in 20% of the patients and at 180-day follow-up in 30% of the patients. These data were used to make quantitative determinations of the tissue volume within the stents. All intravascular US analyses were made by an independent core laboratory (Cardiovascular Core Analysis Laboratory, Stanford, California).
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Results Baseline clinical and angiographic characteristics are listed in Table 1. The bifurcations were mostly “true” bifurcation lesions involving the parent vessel and at least the ostium of the side branch. The mean lesion length measured 16.28 ⫾ 7.44 mm in the parent vessel and 7.43 ⫾ 3.90 mm in the side branch. Implantation of the conical Axxess stent in the parent vessel was successful in 130 of 139 cases (device success rate, 93.5%). There were 3 instances in which the device was withdrawn before deployment; in 2 of these cases, the device would have extended into the left main coronary artery, and in the other case the delivery system could not reach the target lesion. These 3 patients are included in the 30-day results, but are omitted from the long-term analysis. The remaining 6 device failures occurred when the stent was placed distal or proximal to the intended location. These cases did not impact overall treatment success, as there were no patient complications associated with these failures, resulting in a lesion success rate (defined by ⬍50% residual stenosis at the end of the procedure) of 100%. When the conical stent was in place, the remaining treatment varied considerably according to the extent of disease in the vessels branching distal to the bifurcation. The Axxess concept generated 4 different stent patterns: Axxess conical stent only (19.1%), the cone plus a distal parent vessel stent (29.4%), the cone plus a side branch stent (9.6%), and the cone plus stents to the distal parent vessel and side branch (41.9%). In lesions that required distal stent implantation, attempts to place the straight Axxess stent were undertaken in 36 cases, but only 21 were successful. The failures were caused by an inability to advance the system to the desired location as a result of device stiffness and the profile of this stent type. For this reason, the straight stent was abandoned as a branch vessel treatment option in favor of the more deliverable Cypher stent (Cordis, Johnson & Johnson) or Taxus stent (Boston Scientific). Bare metal stents were placed in 2 patients. In 1 instance, no drugeluting stent was available and the operator used 2 bare metal stents in distal branch vessels, and in a second patient a short metal stent was used to treat a dissection distal to a Cypher stent (Table 2). Follow-up angiographic data were available for 126 patients (92.6%). The results are listed in Tables 3 to 5. The angiographic late loss of the Axxess conical stent (i.e., primary end point) was 0.09 ⫾ 0.56 mm. Table 4 shows the results in the parent vessel by analysis zone, from the proximal vessel through the distal vessel segment for all patients, with the bare metal stents omitted. The frequencies of binary in-stent restenosis were 4.8% within the Axxess stent, 4.5% in the stent distal to the Axxess stent, and 10.5% including 5-mm nonstented segments proximal and distal to the stents. Treatment decisions in the side branch varied according to the degree of involvement of the side branch in the lesion; 51.5% received a stent, and balloon angioplasty alone was performed in 29%. The patients who received a stent in the side branch had only a 9.2% restenosis rate at 6 months; the restenosis rate was 7.9% for patients who received a drugeluting stent in the side branch. Patients with balloon an-
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Figure 2. Case example. (A) Bifurcation stenosis with disease in parent vessel and both distal vessels. (B) Balloon dilation. (C) Positioning of Axxess stent at the carina and expansion. (D) Kissing dilation of both distal vessels. (E,F) Positioning and simultaneous implantation of 2 Cypher stents to treat the distal disease. (G) Final kissing balloon. (H) Final angiographic result. (I) Angiographic result at 6-month follow-up.
Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial Table 1 Patient and lesion characteristics (n ⫽ 139)
Table 3 Quantitative angiographic results of the parent vessel at 180 days
Characteristic
Value
Men Age (yrs) Diabetes mellitus Insulin dependent Hypertension* Hypercholesterolemia† Current smoker Previous percutaneous coronary intervention Previous myocardial infarct Canadian Cardiovascular Society Classification grade III or IV Lesion location Left anterior descending artery/diagonal branch Left circumflex artery/marginal branch Posterior descending artery/Posterolateral branch Left main stem Bifurcation lesion type “True” parent vessel and side branch Pre-branch Parent vessel only Post-branch/ostial
102 (73.4%) 64.4 ⫾ 10.2 23 (16.5%) 8 (5.8%) 102 (73.4%) 109 (78.8%) 18 (12.9%) 42 (30.2%) 43 (30.9%) 51 (36.7%)
102 (73.4%)
8 (5.8%) 108 (77.7%) 18 (12.9%) 6 (4.3%) 6 (4.3%)
Table 2 Stent usage
Total stents Axxess cone Axxess straight Cypher Taxus Bare metal Ballon dilatation only Wire only Mean no. of stents Mean stent length (mm)
Angiographic Finding Minimal luminal diameter (mm) Before the procedure After the procedure At follow-up Stenosis (% of luminal diameter) Before the procedure After the procedure At follow-up Late luminal loss (mm) Restenosis at follow-up (%) All patients Drug-eluting stents only
In-Stent Zone
In-Segment Zone
0.78 ⫾ 0.30 2.60 ⫾ 0.45 2.74 ⫾ 0.60
0.78 ⫾ 0.30 2.27 ⫾ 0.39 2.03 ⫾ 0.56
72.9 ⫾ 9.4 12.5 ⫾ 9.8 5.29 ⫾ 18.9 0.19 ⫾ 0.42
72.9 ⫾ 9.4 29.3 ⫾ 16.7 29.8 ⫾ 17.2 0.21 ⫾ 48
7.1% 5.6%
11.9% 10.5%
Values are mean ⫾ SD or percentages.
24 (17.3%) 5 (3.6%)
* Defined as current use of medication and/or systolic blood pressure ⬎140 mm Hg and/or diastolic blood ⬎90 mm Hg measured on 3 different days. † Defined as current use of medication and/or a total cholesterol level ⬎220 mg/dL.
Stent Detail
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Proximal Parent Vessel
Distal Parent Vessel
Side Branch
136 136 — — — —
115 — 18 82 13 2 —
73 — 2 63 7 1 40
— 1.8
26 1.1
26.36 ⫾ 11.86
17.32 ⫾ 8.01
gioplasty had a restenosis rate of 25%; the incidence was 12% in cases without side branch treatment at the index procedure. In 2 cases with side branch stenting, the restenosis was located at the side branch ostium within the overlap region. Three patients with 2 parent vessel stents (Axxess and Cypher/Taxus stents) developed restenoses at the overlap site. In total, there were 5 cases with stent restenosis in the overlap region. The treatment mode strongly affected the angiographic success within the side branch at baseline. In patients with side branch stenting, the success rate was 97.1%, followed by 96.2% in patients without side branch treatment and
77.5% for patients with side branch balloon angioplasty only. Removing the index failures for the balloon angioplasty group decreased the restenosis rate in this group to 13.8%. Intravascular US analysis was available at follow-up in 49 patients in the parent vessel and 25 patients in the side branch. Within the Axxess stent, neointimal volume obstruction was 2.28 ⫾ 2.17%, with a minimum lumen area of 7.86 ⫾ 2.63 mm2. Ostium stent areas were 5.52 ⫾ 1.64 mm2 in the parent vessel and 4.58 ⫾ 1.41 mm2 at the side branch ostium. MACEs are listed in Table 6. In-hospital MACEs for 139 enrolled patients consisted of 6 non–Q-wave myocardial infarctions (4.2%) and 1 Q-wave infarction (0.7%) caused by a distal stent dissection that temporarily occluded the left anterior descending artery. There were no additional MACEs by 30-day follow-up. Follow-up at 6 ⫾ 1 months was available in 134 of 136 eligible patients (98.5%). There was 1 death (0.7%), 1 additional Q-wave myocardial infarction (0.7%) associated with a stent thrombosis at 61 days, and 10 cases of target lesion revascularization (7.5%). The cumulative event-free survival rate was 88.8% at 180 days. There were no cases of acute or subacute stent thrombosis. Late stent thrombosis was confirmed in 3 cases (2.2%). The first of these cases occurred in a patient at 61 days who was treated surgically for prostate carcinoma 51 days after a successful procedure, but in whom antiplatelet therapy was discontinued as a result of postsurgical hematuria resulting in a Q-wave myocardial infarct and target lesion revascularization 10 days later. The second case occurred in a patient who stopped receiving clopidogrel after 1 month because of discomfort and then presented with unstable angina at 98 days. A nonocclusive thrombosis at the carina was confirmed by angiography and resolved with pharmacologic treatment. Clopidogrel therapy was restarted, and the patient returned for follow-up at 6 months symptomfree, at which time a patent bifurcation was confirmed by angiography. The third case was found during the 6-month angiographic follow-up in an asymptomatic patient. This patient received 3 Cypher stents in the left anterior descending artery distal to the Axxess stent as a result of a spiral dissection. The thrombosis was located near the overlap of
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Table 4 Quantitative angiographic results in different analysis zones in the parent vessel Group All Patients Late luminal loss (mm) Restenosis (%) Patients receiving drug-eluting stents only Late luminal loss (mm) Restenosis (%)
Proximal 5 mm
Axxess Stent
Distal Stent
Distal 5 mm
0.17 ⫾ 0.46 5.1
0.09 ⫾ 0.56 4.8
0.21 ⫾ 44 4.5
0.09 ⫾ 38 5.1
0.17 ⫾ 47 5.1%
0.08 ⫾ 0.55 4.0%
0.19 ⫾ 42 3.5%
0.09 ⫾ 38 3.3%
Values are means ⫾ SD on percentages. Table 5 Quantitative angiographic results of side branch at 180 days Angiographic Finding Minimal luminal diameter (mm) Before the procedure After the procedure At follow-up Stenosis (% of luminal diameter) Before the procedure After the procedure At follow-up Late luminal loss (mm) Index restenosis Restenosis at follow-up All patients Drug-eluting stents only
Stent
Balloon Angioplasty
Wire Only, No Treatment
0.88 ⫾ 0.39 2.32 ⫾ 0.39 2.05 ⫾ 0.39
0.88 ⫾ 0.39 1.64 ⫾ 0.51 1.49 ⫾ 0.50
0.88 ⫾ 0.39 1.83 ⫾ 0.45 1.59 ⫾ 0.49
62.2 ⫾ 16.2 19.0 ⫾ 9.1 25.4 ⫾ 16.7 0.23 ⫾ 0.52 2.9%
62.2 ⫾ 16.2 28.1 ⫾ 21.8 33.1 ⫾ 21.9 0.18 ⫾ 0.51 22.5%
62.2 ⫾ 16.2 22.4 ⫾ 16.5 31.0 ⫾ 23.5 0.20 ⫾ 0.39 3.8%
9.2% 7.9%
25.0% —
12.0% —
Values are means ⫾ SD or percentage. Table 6 Major adverse cardiac events Event Death Myocardial infarction Q-wave Non–Q-wave Target lesion revascularization Coronary bypass Coronary angioplasty Any major adverse cardiac event Target vessel failure Event-free survival Stent thrombosis
In-Hospital Events
Out-of-Hospital Events
Cumulative to 180 Days
0 7 (5.0%) 1 (0.7%) 6 (4.3%) 0 0 0 7 (5.0%) 7 (5.0%) 95.0% 0
1 (0.7%) 1 (0.7%) 1 (0.7%) 0 10 (7.5%) 0 10 (7.5%) 12 (9.0%) 12 (9.0%) 91.0% 3 (2.2%)
1 (0.7%) 8 (6.0%) 2 (1.5%) 6 (4.5%) 10 (7.5%) 0 10 (7.5%) 15 (11.2%) 15 (11.2%) 88.8% 3 (2.2%)
the second and third Cypher stents, and the bifurcation was patent. Discussion In this first study of a dedicated drug-eluting bifurcation stent, we found that the biolimus A9 drug used in conjunction with the self-expanding, nickel-titanium alloy Axxess stent is effective in reducing neointimal hyperplasia. The procedural success rate with the conical stent was ⬎90%, although the straight stent delivery system proved cumbersome and had to be abandoned in favor of commercially available stents to treat distal vessels. The self-expanding properties of the conical stent were helpful to fit the device into the carina; proximal or distal dislocations during ex-
pansion, sometimes seen with regular self-expanding stents, were absent given this favorable interaction of lesion morphology and device design. The combination of Axxess and (predominantly) Cypher stents was associated with a low out-of-hospital major adverse event rate (9.0%) to 6 months after stent implantation. The angiographic late loss of the Axxess cone stent (i.e., primary end point) was 0.09⫾ 0.56 mm, which is comparable to results of sirolimus- or everolimus-eluting stents in nonbifurcated de novo lesions, indicating a remarkable reduction compared with historical bare metal controls.8,9 Although the Axxess stent effectively reduces neointimal hyperplasia as measured by angiographic late loss at 180 days, the procedure necessitates the frequent use of adjunctive stents in the distal branch vessels to com-
Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial
plete therapy in most patients. The angiographic outcomes with these distal stents were consistent with previous studies with the Cypher stent,3,4 whether the stent was placed in the side branch or the distal parent vessel. Previous studies of bifurcation lesions typically report worse angiographic outcomes in the side branch, and stented side branches usually fare worse than cases of balloon angioplasty only. This is mainly because of ostial restenosis in lesion segments insufficiently covered by the drug-eluting stent. When used with the Axxess stent, however, the angiographic results in the side branch and parent vessel were quite similar, with comparable late loss values, which might be an indicator of better lesion coverage with this new stent design. The incidence of restenosis was slightly higher in side branches compared with the main vessel, but the observed rate was still an encouraging 7.9%. Although the Axxess stent strategy results in overlapping stents in case additional stents are implanted distal to the conical main vessel stent, there was no incidence of an exaggerated neointimal response to the site of the double stent strut layers. However, previous reports have demonstrated that drug-eluting stents further delay arterial healing and promote inflammation at sites of overlap compared with bare metal stents.10 In particular, Taxus stents induced greater fibrin deposition, medial cell loss, heterophils/eosinophils, and late neointimal hyperplasia. Further larger studies and long-term observations are therefore needed to observe and evaluate effects at the overlapping sites, particular when different kinds of drug-eluting stents are overlapped. For this reason, we dominantly used the Cypher stent in addition to the Axxess stent, staying in the same drug family of “limus” analogs. Stent thrombosis is an important issue in drug-eluting stent implantations for treatment of bifurcation lesions. The presence of a bifurcation lesion has been clearly identified as an independent risk factor for stent thrombosis.11 The stent thrombosis rate in our study was 2.2%, with a total of 3 events at ⬎30 days, 2 of them after premature discontinuation of clopidogrel. Considering only patients who continued antiplatelet therapy, the rate was ⬍1%, which is comparable to that with bare metal stents in simple coronary lesions. Therefore, the Axxess stent strategy seems to be safe if the antiplatelet medication is not prematurely stopped. This finding is in accordance with reports on drugeluting stent implantations in real-world settings in general,11 and not only associated with bifurcation lesion treatments. Although it was successful in terms of its stated objec-
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tives, this study has several limitations. The results with the biolimus-eluting Axxess stent were not compared with a randomized control group. In addition, this study did not prospectively assign a particular treatment method to the side branch and the choice of additional stents to be used was at the operator’s discretion, resulting in a heterogeneous study population. 1. Lefevre T, Louvard Y, Morice MC, Dumas P, Loubeyre C, Benslimane A, Premchand RK, Guillard N, Piechaud JF. Stenting of bifurcation lesions: classification, treatments, and results. Cathet Cardiovasc Intervent 2000;49:274 –283. 2. Al Suwaidi J, Yeh W, Cohen HA, Detre KM, Williams DO, Holmes DR Jr. Immediate and one-year Outcome in patients with coronary bifurcation lesions in the modern era (NHLBI Dynamic Registry). Am J Cardiol 2001;87:1139 –1144. 3. Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr, Spanos V, Louvard Y, Desmedt B, Di Mario C, Leon MB. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004;109:1244 –1249. 4. Ge L, Airoldi F, Iakovou I, Cosgrave J, Michev I, Sangiorgi GM, Montorfano M, Chieffo A, Carlino M, Corvaja N, Colombo A. Clinical and angiographic outcome after implantation of drug eluting stents in bifurcation lesions with the crush stent technique. J Am Coll Cardiol 2005;26:613– 620. 5. Costa RA, Mintz GS, Carlier SG, Lansky AJ, Moussa I, Fujii K, Takebayashi H, Yasuda T, Costa JR Jr, Tsuchiya Y, Jensen LO, et al. Bifurcation coronary lesions treated with the “crush” technique: an intravascular ultrasound analysis. J Am Coll Cardiol 2005;46:599 – 605. 6. Lefevre T, Ormiston J, Guagliumi G, Schultheiss HP, Quilliet L, Reimers B, Brunel P, Wijns W, Buettner HJ, Hartmann F, Veldhof S, et al. The Frontier stent registry: safety and feasibility of a novel dedicated stent for the treatment of bifurcation coronary artery lesions. J Am Coll Cardiol 2005;46:592–598. 7. Pan M, Suarez de Lezo J, Medina A, Romero M, Hernandez E, Segura J, Castroviejo JR, Pavlovic D, Melian F, Ramirez A, Castillo JC. Simple and complex stent strategies for bifurcated coronary arterial stenosis involving the side branch origin. Am J Cardiol 1999;83:1320 – 1325. 8. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus eluting stent versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 9. Costa RA, Lansky AJ, Mintz GS, Mehran R, Tsuchiya Y, Negoita M, Gilutz Y, Nikolsky E, Fahy M, Pop R, et al. Angiographic results of the first human experience with everolimus-eluting stents for the treatment of coronary lesions (the FUTURE I trial). Am J Cardiol 2005; 95:113–116. 10. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK, Gold HK, Virmani R. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005;112:270 –278. 11. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126 –2130.