Methods Study organization

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1 Frequency and time course of reocclusion and restenosis in coronary artery occlusions after balloon angioplasty versus Wiktor stent implantation: Results from the Mayo-Japan Investigation for Chronic Total Occlusion (MAJIC) trial Hideo Tamai, MD, a Peter B. Berger, MD, b Etsuo Tsuchikane, MD, c Takahiko Suzuki, MD, d Hideo Nishikawa, MD, e Tadanori Aizawa, MD, f Kenshi Fujii, MD, g Youichi Nozaki, MD, h Eisho Kyo, MD, a Toru Kobayashi, MD, c Johan Reiber, MD, i and Anton W. M. Van Weert, MD, i for the MAJIC Investigators Moriyama, Osaka, Toyohashi, Ise, Tokyo, and Sapporo, Japan, Rochester, Minn, and Leiden, The Netherlands Background Compared with balloon angioplasty, stent implantation has been shown to reduce restenosis and reocclusion after treatment of chronic total coronary artery occlusions (CTOs). However, little is known about the time course of restenosis and reocclusion after the 2 procedures. The purpose of this study was to examine the frequency and time course of restenosis and reocclusion after treatment of CTOs with balloon angioplasty and Wiktor stent implantation. Methods and Results A total of 221 patients with successfully recanalized CTOs were randomly assigned to either treatment with a coil stent implantation (Wiktor stent, n 110) or standard balloon angioplasty. Repeat angiography was performed the day after treatment and at 6 months. Patients undergoing balloon angioplasty showed 29.8% restenosis and 1.1% reocclusion the following day versus 2% restenosis and no reocclusion in stent patients the following day. The cumulative reocclusion rate was significantly lower in the stent group than in the balloon group at 6 months (2.1% versus 9.3%, P.05). As a result of the more frequent need of target vessel revascularization (49.5% in the balloon group and 30.6% in the stent group, P.005) and earlier final follow-up angiography in the balloon group, the frequency of angiographic restenosis at 6 months was similar in both groups (57.3% in the stent group and 54.5% in the balloon group). Conclusions The frequency and time course of reocclusion and restenosis after balloon angioplasty and stent placement differ within 24 hours of the procedure and remain different on angiography at 6 months. (Am Heart J 2004;147: e9.) Chronic total coronary artery occlusions (CTO) are a major problem for interventional cardiologists because of the low success rate and high reocclusion and restenosis rates after percutaneous balloon angioplasty. 1 6 From a Shiga Medical Center for Adults, Moriyama, Japan, b Mayo Clinic, Rochester, Minn, c Osaka Medical Center, Osaka, Japan, d National Toyohashi Higashi Hospital, Toyohashi, Japan, e Yamada Red Cross Hospital, Ise, Japan, the f Cardiovascular Institute, Tokyo, Japan, g Sakurabashi Watanabe Hospital, Osaka, Japan, h Hokko Memorial Hospital, Sapporo, Japan, and i Heart Core, Leiden, The Netherlands. Submitted March 18, 2003; accepted August 25, Reprint requests: Hideo Tamai, MD, Department of Cardiology, Shiga Medical Center for Adults, , Moriyama, Moriyama, Shiga, Japan. tamai@cct.gr.jp /$ - see front matter 2004, Elsevier Inc. All rights reserved. doi: /j.ahj Although recent advances in devices and in operator experience are associated with higher success rates, 3,7 high reocclusion and restenosis rates limit the longterm benefit after balloon angioplasty of CTOs. implantation has been shown to reduce restenosis not only for nonoccluded, focal, and simple coronary lesions 8,9 but also after treatment of CTOs However, the efficacy of the Wiktor stent, a helicoid coil stent, 13 had not been evaluated by large multicenter, prospective, randomized trials when this trial was performed. Furthermore, none of the other randomized trials comparing balloon angioplasty and stent placement had routinely performed angiography serially after angioplasty to determine the time course and time of occurrence of restenosis and reocclusion after bal-

2 T2 Tamai et al American Heart Journal March 2004 loon angioplasty versus stent placement, an issue about which little is known. In this study, we randomly assigned 221 patients with CTOs to treatment with Wiktor stents or balloon angioplasty alone and determined the rates of reocclusion and restenosis at 24 hours and 6 months as well as the frequency of adverse clinical events within 6 months. Methods Study organization This study was a multicenter, prospective, randomized, controlled trial investigating whether intracoronary Wiktor stent implantation prevents reocclusion and restenosis of recanalized CTOs and improves clinical outcome. This investigator-initiated protocol was supported by a grant from Medtronic AVE. Study patients Patients undergoing clinically indicated coronary interventions with 1 target segment and who met the study definition of occlusion were eligible for enrollment. The study definition of occlusion was (1) an occlusive coronary stenosis accompanied by no more than Thrombolysis in Myocardial Infarction (TIMI) grade 0 or 1 antegrade flow, (2) age of occlusion 2 weeks, (3) reference vessel diameter 2.5 mm, and (4) TIMI flow grade 2 or 3 after crossing with a guide wire and initial balloon dilation. The age of occlusion was estimated with the use of available information (acute myocardial infarction [MI] corresponding to the occluded vessel or sudden change in angina pattern and electrocardiogram). Exclusion criteria were (1) age 18 years, (2) extensive lesion-related thrombus, (3) left ventricular ejection fraction 30%, and (4) evolving myocardial infarction. The trial was carried out according to the Declaration of Helsinki, and the protocol was approved by the institutional review board at each hospital. The study was approved by the institutional review boards of all participating institutions, and all patients provided written informed consent. Random assignment and treatment strategies After attaining TIMI flow grade 2 or 3 antegrade flow with balloon dilation, the investigators and study coordinators telephoned or faxed the randomization center to confirm the eligibility of patients and receive the treatment assignment. Eligible patients were randomly assigned to balloon angioplasty alone or to implantation of one or more Wiktor stents. In the control group, operators were instructed to achieve the best angioplasty results achievable. Prolonged inflations of more than 20 minutes time with a perfusion balloon were required before crossover to stent. Crossover to stent placement was permitted only if a 50% visual stenosis remained, or if ischemia (chest pain or electrocardiographic changes) was present. In the stent group, operators were instructed to use a balloon with a balloon-to-artery ratio of 1 and cover the occluded segment and adjacent lesion completely, using as many contiguous stents as necessary. All the patients enrolled thereafter were treated with aspirin and ticlopidine. Creatine kinase (CK) and CK-MB were measured just before and 8, 16, and 24 hours after the procedure. An electrocardiogram was routinely recorded just before and 24 hours after the procedure. Angiographic analyses After intracoronary injection of nitroglycerin, angiography was performed by using at least 2 orthogonal views immediately before and after the revascularization procedure, the next day, and again at 6 months. Angiographic success was defined as a residual stenosis of 50% and a final TIMI flow grade of 2 or 3. In patients undergoing repeat angiography before 6 months, angiography was not repeated at 6 months if (1) reocclusion was present, or (2) target lesion/vessel revascularization was performed. If a revascularization procedure involving the treated segment was performed before the 6-month angiography, the most recent angiogram obtained before this intervention was used as the final follow-up angiogram. Standardized computer-assisted quantitative coronary angiography (QCA) analysis was performed independently at the central Core Laboratory of Heart Core BV (Leiden, The Netherlands). QCA analysis with the Clinical Measurement System (QCA-CMS v3.32, MEDIS medical imaging systems, Leiden, The Netherlands), was used, which is particularly suitable for radiopaque stents. QCA analysis with QCA-CMS analytical software has been described previously. 14 End points Angiographic reocclusion (TIMI flow grade 0 or 1 beyond a severe stenosis) and restenosis (defined as 50% diameter stenosis) within 6 months, as determined by the Core Angiographic Laboratory, was the primary end point. A secondary end point was the occurrence of major adverse cardiovascular events, defined as cardiac death, lesion-related MI, and repeat target vessel revascularization (TVR) within 6 months. Q-wave MI was defined as a clinical episode of prolonged chest pain suggestive of acute MI and the appearance of 2 new pathologic Q waves on electrocardiography. Non Qwave MI was defined as an increase in serum CK and CK-MB levels to at least 3 times the upper normal limit. Target lesion revascularization (TLR)/TVR was defined as any attempted percutaneous or surgical revascularization of the target lesion/vessel after the initial procedure. Indications to perform TLR/TVR included symptomatic restenosis or asymptomatic angiographic restenosis defined as 75% diameter stenosis by visual estimate on a follow-up angiogram. Statistical analysis All analyses were performed according to an intention-totreat principle. Categorical variables are presented as percent values. Normally distributed continuous variables are presented as mean value SD. Differences between groups were assessed with a 2 test for categorical variables and with a 2-tailed unpaired Student t test for continuous variables; P.05 was considered significant. Logistic regression analysis was used to assess the contribution of multiple clinical and angiographic variables (including coronary risk factors, assigned treatment, preprocedural/postprocedural angiographic data) to the primary and secondary end points such as reocclusion, restenosis, and TLR. Stepwise multivariable models were constructed by entering univariable determi-

3 American Heart Journal Volume 147, Number 3 Tamai et al T3 Table I. Baseline clinical characteristics Table III. Procedural variables Characteristic Variable Age (y) Male Prior MI CCS3 4 angina Ejection fraction CHF Prior PTCA Prior CABG Diabetes Hypertension Peripheral vascular disease Active smoker Prior stroke/transient ischemic attack Values are % except as noted. Plus-minus values are mean SD. CCS, Canadian Cardiovascular Society; CHF, congestive heart failure. Multilesion procedures (%) Vessels diseased (%) Number of stents (n) Maximum balloon size (mm) Maximum balloon pressure (bar) Inflation time (s) Contrast volume (ml) Plus-minus values are mean SD. Table IV. Inhospital outcome Events Table II. Baseline angiographic characteristics Characteristic Occlusion length (mm) Age of occlusion (days).117 Median Mean Target vessel (%) LAD RCA LCX Antegrade TIMI flow (%).454 Grade Grade Plus-minus values are mean SD. LAD, Left anterior descending coronary artery; RCA, right coronary artery; LCX, left circumflex artery. nants according to P values.10. Multivariable determinants were considered significant at P values.05. As a measure of the strength of the association between each multivariate predictor and outcome variables, an adjusted odds ratio with a corresponding 95% confidence intervals was computed from the estimated multiple logistic regression coefficient and standard error. Results Between August 1996 through January 1998, 221 patients were enrolled in this study; 110 were randomly assigned to the stent group and 111 to the balloon group. The baseline clinical and angiographic characteristics are shown in Tables I and II. The balloon group had a significantly higher prevalence of left Angiographic success Non-QMI, CK-MB normal MI 0 0 Death 0 0 CABG 0 0 Bleeding Stroke Values are %. anterior descending artery occlusions (52% versus 37%, P.05). Other baseline clinical and lesion characteristics, including occlusion length, age of occlusion, and frequency of de novo lesions and of TIMI flow grade 0 were well matched between the 2 groups. Treatment (procedural) variables Crossover during the initial procedure occurred in 8 patients (7.2%) assigned to the balloon group and 2 (1.8%) assigned to the stent group. As shown in Table III, maximum balloon size and maximum inflation pressure were similar in the 2 groups, however, total inflation time was significantly longer in the balloon group ( seconds versus seconds, P.01). On average, 1.6 contiguous stents were deployed to the target lesion per stent-assigned patient. Clinical and angiographic outcome The clinical outcome of the patients is shown in Tables IV and V. The angiographic success rate was significantly higher in the stent group (97% versus 84%, P.05). The occurrence of the increase in serum car-

4 T4 Tamai et al American Heart Journal March 2004 Table V. Late clinical outcome Events (n 109) (n 108) P Death CABG MI Renal failure TLR Next day Months Months TVR Next day Months Months Values are %. TLR, Target lesion revascularization; TVR, target vessel revascularization. diac enzyme levels (3 times the upper normal limit) was more frequent in the stent group (16% versus 11%, P.299); Q-wave MI did not occur in either group. No instances of stent thrombosis were apparent. The occurrence of other major adverse cardiovascular events such as death, bypass surgery, major bleeding, and stroke was extremely rare, both during the initial hospitalization and during the 6-months of follow-up in both groups. In the balloon group, 5 patients received TVR 1 day after the procedure, versus 1 patient in the stent group. By 6 months, TLR/TVR had been performed less frequently in the stent group (28.7% versus 45.9%, P.001, 30.6% versus 49.5%, P.005, respectively). Patency and quantitative angiography Angiographic follow-up by 6 months was obtained in 96 patients (87.3%) in the stent group and 99 patients (89.2%) in the balloon group. The quantitative coronary angiographic results are presented in Table VI. Postprocedural and next-day minimal luminal diameters (MLDs) were significantly larger in the stent group than in the balloon group ( versus mm; P.001, versus mm; P.001, respectively). On angiography the day after the procedure, the diameter stenosis was less severe in the stent group than in the balloon group (19% 15% versus 40% 20%; P.001). On the 6-month follow-up angiogram, the MLD was slightly larger in the stent group than in the balloon group, although the difference was not statistically significant ( versus mm; P.237). Angiographic restenosis rates were similar in the 2 groups (57.3% in the stent group versus 54.5% in the balloon group), although more patients required TVR before the 6-month follow-up angiogram in the balloon group, as above, so that time to the final follow-up angiography was shorter in the balloon group ( versus weeks, P.001). Despite this, more severe restenosis ( 70% diameter stenosis) was seen in the balloon group (22.2% versus 16.7%, P.369). Reocclusion was not seen in the stent group on the day after the intervention, and the cumulative reocclusion rate was significantly lower in the stent group than in the balloon group by 6 months (2.1% versus 9.3%, P.05). Predictors of reocclusion, restenosis, and TLR Variables significantly predictive by univariate analysis are shown in Table VII. Baseline reference diameter was associated with reocclusion, (P.040) and there was a trend toward an association with the absence of stent placement (P.064). None of the correlates of reocclusion on univariate analysis of restenosis reached statistical significance by multivariate analysis. However, antegrade TIMI flow grade 0 (versus 1) was the strongest predictor (P.090) among them. Independent predictors of TLR ascertained by multivariate analysis were the MLD immediately after the procedure (P.015), the presence of congestive heart failure (P.008), and the absence of stroke/transient ischemic attack (P.013). Discussion Three prospective randomized trials of 100 patients have been published examining the effectiveness of coronary stents for CTOs : the Total Occlusion Study of Canada (TOSCA), the s in Chronic Coronary Occlusion (SICCO), and Gruppo Italiano di Studio sullo nelle Occlusioni Coronariche (GISSOC). All these studies evaluated the efficacy of the Palmaz- Schatz stent (with heparin coating, in the TOCSA trial), which is a tubular stent; no prospective, randomized, multicenter trial evaluating the efficacy of a coil stent such as the Wiktor stent have been reported. This study was undertaken before a great many improved stent designs became available, before a decision to abandon further development and marketing of the Wiktor stent was made by Medtronic. However, this study is not merely the fourth randomized study to indicate that placement of a coil stent, like tubular stents, is associated with a better clinical outcome than balloon angioplasty alone. This study also provides unique and valuable data about the frequency and time course of restenosis with both balloon angioplasty and stent placement as a result of angiography being performed at 24 hours in all patients, which was not performed in any of the other studies comparing stents and balloon angioplasty.

5 American Heart Journal Volume 147, Number 3 Tamai et al T5 Table VI. Quantitative coronary angiography Variable (n 99) (n 96) P Baseline Proximal RD (mm) Initial postprocedure Proximal RD (mm) MLD (mm) % Stenosis % Diameter stenosis (%) Following day angiography Proximal RD (mm) MLD (mm) % Stenosis % Diameter stenosis (%) Reocclusion rate (%) Final angiography Time to final follow-up angiography (week) Proximal RD (mm) MLD (mm) % Stenosis % Diameter stenosis (%) % Diameter stenosis (%) Reocclusion rate (%) Plus-minus values are mean SD. RD, Reference diameter; MLD, minimal luminal diameter. Table VII. Significant correlates by logistic regression analysis Multivariate analysis Univariate analysis P Adjusted odds ratio 95% CI P TLR CHF Stroke/TIA Antegrade TIMI flow, grade 1/grade RD immediately after the procedure 2.5 mm/ 2.5 mm MLD immediately after the procedure 2.5 mm/ 2.5 mm Reocclusion CHF Prior PTCA Antegrade TIMI flow grade 1/grade Restenosis lesion/de novo lesion Baseline RD 2.5 mm/ 2.5 mm Restenosis CHF Peripheral vascular disease Target vessel LAD/non-LAD Antegrade TIMI flow grade 1/grade Baseline RD 2.5 mm/ 2.5 mm CHF, Congestive heart failure; TIA, transient ischemic attack; RD, reference diameter; MLD, minimal luminal diameter; LAD, left anterior descending coronary artery. Reocclusion The reocclusion rate was significantly lower in the stent group at final follow-up. Furthermore, compared with previous reports, the reocclusion rate of both the stent and balloon groups in this study was extremely low. There are at least 2 possible explanations for this observation. First, in this study, follow-up angiography was routinely carried out the next day

6 T6 Tamai et al American Heart Journal March 2004 after the procedure, and 5 patients in the balloon arm and 1 patient in the stent arm underwent TVR. Previous reports showed that up to 8% of CTOs reocclude silently within the first 24 hours 15 ; therefore, some of these patients in might have had reocclusion that was prevented by the early repeat revascularization procedure. Second, in this study, ticlopidine was administered not only to the stent group but also to the balloon group to reduce potential bias if there were to be benefit from ticlopidine rather than from stent placement alone. The effectiveness of theinopyridines such as clopidogrel and ticlopidine in preventing adverse ischemic events in stent patients has been demonstrated in the previous reports 16,17 and was apparent among even balloon angioplasty patients in the PCI- CURE study. 18 Thus, theinopyridines might have contributed to the low incidence of reocclusion in the balloon group. It does not appear that the baseline clinical and angiographic characteristics of patients in our study were more favorable than those in prior studies, certainly not different enough to explain the lower reocclusion rate. Clinical outcome In this study, major adverse cardiovascular events including death, MI, major bleeding, stroke, and bypass surgery were rare. In particular, clinically apparent stent thrombosis was extremely rare. However, as previously mentioned, repeat revascularization was performed in both groups 1 day after the initial procedure, which may have reduced the frequency of reocclusion and clinical events occurring by 6 months. TVR and restenosis Target lesion/vessel revascularization was significantly less frequent in patients with stenting than in patients with balloon angioplasty throughout our study. The MLD at the final follow-up of the stent group was larger than that of the balloon group; however, the difference between the 2 groups did not reach statistical significance. The discrepancy between the much higher TVR rate and the only slightly lower final MLD among balloon patients may be attributed in part because in the balloon angioplasty group, more patients received TVR before the 6-month follow-up; in such patients, the angiogram from the TVR procedure was treated as the final angiogram. Additional evidence supporting this possible explanation is the shorter time to repeat angiography in the balloon angioplasty group. When compared with TOSCA, the final follow-up MLD of the stent group in our study was similar to the final MLD in that study, although the MLD of the balloon angioplasty group in our trial was larger than in TOSCA. This comparison lends support to our inference that the MLD at final follow-up of the patients in the balloon group was affected and improved by the performance of repeat revascularization procedures driven in part by repeat angiography at 1 day and at other times before the 6-month follow-up protocol angiogram in this trial. One of the most important findings in our study is that 30% of patients in the balloon angioplasty group had 50% diameter stenosis the next day, but this was true in only 2% of patients in the stent group. This suggests that stent implantation prevents the acute renarrowing that is frequently seen in balloon angioplasty for CTOs. This finding is novel and was not discovered in any of the other studies comparing stents and balloon angioplasty for CTOs. Limitations This study was not and could not be blinded. The possibility that there existed a different threshold for reintervention in the 2 groups of patients cannot be excluded, although the angiographic data do not seem to indicate that such bias existed. Although a core angiographic laboratory was used and a computerized edge detection system used to assist in determining the severity of stenoses, there is human input into such determinations, and, again, the inability to blind whether an artery had been treated with a radiopaque stent or balloon angioplasty is also a limitation of the study. Conclusions Compared with balloon angioplasty, implantation of Wiktor stents, a coil stent, results in a higher rate of procedural success, a lower rate of reocclusion, and a less frequent need for TLR/TVR than balloon angioplasty alone. Restenosis and reocclusion tend to be more frequent after balloon angioplasty than stent placement even 1 day after treatment, and reocclusion is significantly less frequent at 6 months in occlusions treated with stents. Whether the less frequent occurrence of reocclusion in this study than prior studies is due to the frequent performance of follow-up angiography in this trial requires further study. We thank Dr Masaharu Okada, Dr Kunihiko Kosuga, and Kazuaki Yoh for their help in the preparation of the manuscript. References 1. Stone GW, Rutherford BD, McConahay DR, et al. Procedural outcome of angioplasty for total coronary occlusion: an analysis of 971 lesions in 905 patients. J Am Coll Cardiol 1990;15: Ivanhoe R, Weintraub W, Douglas J, et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions. Circulation 1992;85: Puma JA, Sketch MH Jr, Tcheng JE, et al. Percutaneous revascularization of chronic coronary occlusions: an overview. 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