Ultrasound-Guided Strategy for Provisional Stenting With Focal Balloon Combination Catheter
Results From the Randomized Strategy for Intracoronary Ultrasound-Guided PTCA and Stenting (SIPS) Trial
Background—Intracoronary ultrasound (ICUS) has provided insights into vascular pathology and interventional therapy. The Strategy for ICUS-Guided PTCA and Stenting (SIPS) trial tested the hypothesis that routine ICUS guidance of coronary interventions improves outcome.
Methods and Results—A single-center consecutive-patient randomized design (with 6-month angiographic and 2-year clinical follow-up) was used. Consecutive patients (no chronic total occlusions or emergency procedures) were randomized to ICUS-guided provisional stenting or standard angiographic guidance. Quantitative angiographic minimal lumen diameter (MLD), angiographic restenosis, clinically driven target lesion revascularization, and major adverse cardiac events (MACEs) were evaluated. A total of 291 procedures (356 lesions) were included. Procedure success was higher in the ICUS-guided group than the group randomized to standard guidance (94.7% versus 87.4%, respectively; P=0.033), whereas time (65.2±31.0 versus 60.5±34.0 minutes, P=0.18) and contrast use (209.3±94.1 versus 197.5±89.5 mL, P=0.23) were not significantly different. Stenting rates were similar (49.7% versus 49.5%, P=0.89). Acute gain was greater in the ICUS-guided group than in the standard guidance group (1.85±0.72 versus 1.67±0.76 mm, respectively; P=0.02). Angiographic 6-month analysis revealed no difference in MLD (1.71±0.94 versus 1.57±0.90, P=0.19) or binary restenosis rate (>50% diameter stenosis) (29% versus 35%, P=0.42). Clinical follow-up (602±307 days) showed a significant decrease in clinically driven target lesion revascularization in the ICUS group compared with the standard guidance group (17% versus 29%, respectively; P=0.02).
Conclusions—Although angiographic MLD did not differ significantly after 6 months, ICUS-guided provisional stenting improved 2-year clinical results after intervention.
Intracoronary ultrasound (ICUS) has provided insights into the mechanism of percutaneous coronary interventions1 2 3 4 as well as the pattern and mechanism of restenosis.5 6 7 Prior studies have demonstrated that ICUS provides information not generated by angiography8 9 10 11 and that the use of sonographic measurements of vascular dimensions improves angiographic results.12 13 14
The Strategy for ICUS-Guided PTCA and Stenting (SIPS) trial randomized consecutive patients to either a strategy of initial ICUS-guided treatment or use of angiographic guidance (Angio) alone. The primary end point of the study was 6-month angiographic minimal lumen diameter (MLD). Secondary end points included acute MLD as well as acute and chronic cost, quality of life, composite clinical event rates, and clinically driven target lesion revascularization (TLR). The present report addresses the angiographic and clinical end points.
The SIPS trial was a single-center, consecutive-patient, randomized-design study. Demographic data, quality-of-life questionnaires, quantitative coronary angiography, resource utilization, and adverse events were evaluated acutely and at 6-month angiographic follow-up. Clinical follow-up was continued for 2 years. The protocol was approved by the local ethics committee.
Between February and May 1996, all patients undergoing elective or urgent PTCA or primary stenting in vessels of diameter 2.2 and 4.6 mm were asked to participate. All interventional procedures were performed after review of the diagnostic angiography; ad hoc or same-setting PTCA occurred only for emergency procedures. Vessel-size criteria were based on the available device sizes. Exclusions included emergency intervention, planned atherectomy, chronic total occlusion of the target vessel, and failure to give informed consent. A total of 491 consecutive patients underwent 595 interventions during the study period. Approximately one third of these patients had intervention for chronic total occlusion (n=203) and were excluded. Exclusion for other reasons was rare (n=19) and was primarily for lesions in saphenous vein grafts >4.6 mm.
A total of 291 procedures in 269 patients were included. Patients were scheduled several days in advance. The patients were randomized on a day-to-day block schedule; randomization was performed in the morning of each day. Add-on patients were rare. After randomization, 166 lesions were treated by ICUS guidance, and 190 were treated by Angio.
Catheterization Laboratory Protocol
A strategy of provisional stenting was used. Stenting was discouraged unless a significant dissection was present (type C or greater by National Heart, Lung, and Blood Institute [NHLBI] criteria15 ) or unless angiographic results were unacceptable. Selection of planned therapy was at the discretion of the operator. Initial and final angiography was performed after intracoronary administration of nitroglycerin (50 to 100 μg) and, whenever possible, in 2 views. Periprocedural medication included oral aspirin (100 mg daily) and heparin (10 000 to 20 000 IU given intravenously during the procedure). Patients receiving stents were treated with 250 to 500 mg aspirin intravenously and begun on 250 mg ticlopidine twice daily. No other medications were given routinely. Patients received glycoprotein IIb/IIIa receptor inhibitors only under emergency situations (n=5).
A balloon size with a diameter 50% between the ICUS-defined lumen and external elastic lamina diameters of the smallest reference was calculated (Clinical Outcomes With Ultrasound Trial [CLOUT] criteria12 ). This balloon size was obtained by high-pressure inflation of the combination ICUS/variable diameter balloon (Oracle Focus, Endosonics). This balloon incorporates both compliant (central 10-mm segment) and noncompliant (5-mm end segment) material,16 resulting in expansion up to 0.7 mm above nominal of the central compliant balloon segment.16 17 18 In cases in which the diameter determined by ICUS could not be achieved simply by high-pressure dilation, a larger conventional balloon was chosen. If, after use of a balloon with diameter based on ICUS measurements, the lesion lumen area did not meet the ICUS criteria, stenting was considered.
ICUS measures of the lumen and total vessel diameters and areas were made proximal and distal to the lesion in the angiographically uninvolved reference segments. Repeat interventions were performed in an iterative fashion with ICUS imaging until the minimal lumen area within the lesion was >65% of the mean reference area. This target value was predefined on the basis of data from the CLOUT Trial.12 When the lesion was ostial, the nearest appropriate single reference was used. Stents were delivered by use of the manufacturer’s delivery system (if applicable) or hand-crimped on the combination ICUS/balloon device. Quantitative measures for successful stent implementation were based on the criteria of the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC)19 investigators.
If multiple lesions were present, they were all treated with the same device whenever possible.
As in the ICUS group, a general strategy of provisional stenting was used. Procedural guidance in this group was performed by use of fluoroscopy and cine angiography. Primary dilation was performed by use of a standard unidiameter balloon of the operator’s choice, which was based on visual angiographic estimation of size. The operator was encouraged to achieve an optimal result predefined as <35% residual angiographic diameter stenosis by visual estimation. When a stent was deployed, the angiographic target criterion for success was <10% diameter stenosis with no evidence of uncovered dissection.
If patients underwent multiple procedures during the study period, they retained their originally assigned randomization for the subsequent procedures.
All patients were requested to return at 6 months. Angiographic follow-up was complete in 77% of the ICUS lesions and 79% of the Angio group lesions. Angiography performed for clinical indications occurring before 6 months was included in the analysis. Restudy was performed in the same projections. Vessel segments for sequential comparison were selected by use of side-by-side viewing of the cine angiograms to ensure exact matching.
Patients were contacted at 6 months and 2 years after their index procedure. Referral physician records, hospital records, and patient questionnaires were collected to assess rates of clinically driven TLR, myocardial infarction, and death. Follow-up was 100% complete. Patients were censored at the time of their first major adverse clinical event. For patients with no events, data were assessed 720 days after their procedures.
For quantitative coronary angiography (QCA), angiograms were analyzed by use of validated commercial software (CAAS II) in a core laboratory. The reproducibility and accuracy of measurements performed in this core laboratory have been reported previously. Specifically, the long-term variability for repeated measures (2.3 years) of sequential angiograms was 0.34 mm (stenosis diameter), 0.66 mm (reference diameter), and 6.52% (percent diameter stenosis).20
Frames for analysis were chosen by a physician not involved in the performance of the procedure; however, the characteristic appearance of the ICUS/balloon catheter precluded blind selection. Values were calculated for the single worst view on the basis of the initial MLD. The reference segment was user-defined as the closest normal-appearing segment proximal to the lesion (except for ostial locations, for which a distal reference was chosen). Lesions were classified according to the modified American Heart Association/American College of Cardiology classification.21 Residual dissections were classified according to the NHLBI type.15
Clinically Driven TLR
All patients with anginal pain before and at the time of admission to the hospital (either before or at the time specified by the study protocol) and who had angiographic restenosis in the target segment treated with either repeat PTCA or CABG were considered to have clinically driven TLR. Their clinical status was assessed in a blinded fashion independent from the operator by a quality of life questionnaire and exercise tolerance testing.
Myocardial infarction was defined as a rise in creatinine phosphokinase >2 times the upper limit of normal with a myocardial band fraction of >10%.
Procedure success was defined as discharge from the hospital without repeat revascularization, myocardial infarction, or death, with a core laboratory QCA-determined percentage diameter stenosis for all lesions treated of <50%.
Acute Gain, Late Loss, and Net Gain
Acute gain was defined as the difference between the initial MLD and final MLD. Late loss was the difference between follow-up MLD and final MLD. Net gain was the difference between follow-up MLD and initial MLD.
Data were analyzed by use of Statistica (StatSoft). Comparisons were made by either ANOVA (continuous variables) or χ2 analysis (categorical variables). Kaplan-Meier survival analysis with a Gehans-Wilcoxon test for significance was used for the follow-up comparisons. Power calculations for sample size assumed a 35% stent implantation rate, a 0.19-mm acute group difference in MLD, a 0.104-mm chronic difference in MLD, and an SD of 0.48 mm for QCA analysis (α=0.05, β=0.20). With these assumptions, 140 lesions per group were needed to detect the chronic MLD difference. Significance was assumed at P<0.05. Data are displayed as mean±1 SD unless otherwise noted.
The ICUS-guided and Angio-guided groups were well matched (Table 1⇓). There was also no difference between groups for the specific operators.
Procedure success was achieved in 94.7% of the ICUS group and 87.4% of the Angio group (P=0.033). Balloon-only procedures were performed in 50.3% and 50.5%, respectively (P=0.96). Because the decision to place a stent was not randomized between groups, the fact that nearly equal numbers of patients in each group received stents is coincidental. The majority of stents placed were of the Palmaz-Schatz design (83.4%). Two patients had secondary atherectomy. Dissections of NHLBI type C or worse15 were infrequent at the procedure termination (3.0% of ICUS lesions and 3.2% of Angio lesions). With the exception of fluoroscopy time, the number of inflations, and the nominal balloon size, procedure-related variables were not different (Table 2⇓).
Of the 356 dilated lesions, 353 were suitable for QCA. QCA results are shown in Table 3⇓. There were no significant baseline differences. After intervention, the major finding by QCA was a significantly greater acute gain in the ICUS-guided group. At the 6-month follow-up, the ICUS-guided group had trend toward a larger MLD and net gain and a lower restenosis rate.
ICUS data were obtained and used to guide the procedure in 87.7% of the lesions. Reasons for failure to complete measurements were vessel tortuosity, size, or calcification or a failure of the catheter. In 69% of the lesions, ICUS guidance achieved the optimal goal as described above. This goal was reached for 87.5% of the nonstented lesions and 50% of the stented lesions. The mean luminal area stenosis was 26.1±11.1% (5.49±1.73 mm2) after PTCA alone and 7.3±22.1% (7.95±2.37 mm2) after stent implantation (Table 4⇓.) The mean proximal reference lumen diameter was slightly larger than that measured by QCA. Because of reference plaque burden, the calculated CLOUT balloon size resulted in a balloon/artery ratio of 1.17, close to the 1.25 ratio for the nominal combination balloon size.
In-hospital acute and 2-year MACEs are shown in Table 5⇓. In general, the total event rates for the ICUS-guided group were less than those for the Angio-guided group, but this difference achieved statistical significance only for the 2-year TLR rate (Figure⇓).
All revascularization rates and all MACE rates, including all revascularization procedures, myocardial infarction, and deaths expressed per patient, were not significantly different (Table 5⇑). Some patients underwent catheterization outside our hospital. Several of the visually assessed “restenotic” lesions resulted in a reintervention that was not clinically driven, by our definition of TLR.
To control for bias, we also compared the clinical status by evaluating anginal score and maximum exercise tolerance. For the patients with TLR (clinically driven procedures), the anginal score was 2.5 (ICUS) versus 2.5 (Angio), and the maximum exercise tolerance was 50 versus 75 W. Patients with “nonclinically” driven procedures had an anginal score of 0 (ICUS) versus 0 (Angio) and an exercise tolerance of 125 versus 112 W, respectively (Table 6⇓). Thus, independent blinded assessment of clinical status was not different for patients receiving TLR in the 2 groups.
The present study demonstrates that a strategy of ICUS-guided intervention results in a significantly improved acute angiographic outcome and is associated with a trend toward lower acute cardiac event rates than a strategy guided by angiography alone. Importantly, the 2-year clinically driven TLR rate was significantly reduced for the ICUS-guided group. However, the primary end point (6-month angiographic MLD) was not different between groups. Although the achieved chronic MLD difference of 0.15 mm exceeded our estimates, the SD of the QCA analysis was twice projected. This is probably due to the broad range of vessel sizes treated in the present study.
The use of preintervention ICUS imaging has led to changes in therapy in a high percentage of cases.22 In the present study, assessment of plaque burden by ICUS again demonstrated the feasibility of safely using a bigger balloon in diseased vessels to achieve a better result without increasing complications or dissections. The acute angiographic advantage in the ICUS patients (0.18 mm) is slightly lower than that reported in the CLOUT trial. Stone et al12 noted a 0.26-mm improvement in MLD after ICUS-guided balloon upsizing. Nonetheless, the lower rate of TLR for our ICUS-guided procedures is similar to that reported by Haase et al.23 They observed a 1-year MACE rate of 12% in 144 patients treated with an oversized ICUS-guided balloon strategy (no stents). Although similar to our strategy, the criteria for study entry were more strict; type C, or restenotic, lesions as well low quality ICUS recordings (16%) were excluded.
Our results are also similar to contemporary studies of primary stent placement in Europe. ICUS-guided stent placement in selected lesions has been associated with restenosis rates of 9.7%, 13.5%, and 22.5% in 3 trials.19 24 25 By comparison, in the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial,26 with broader inclusion criteria, the restenosis rate in the antiplatelet group was 26.8%, and the 6-month TLR rate was 14.6%. Jeremias et al27 have also used ICUS guidance for stent placement in consecutive patients, achieving a 33.3% restenosis rate at 6 months. Our consecutive ICUS-guided group (in whom only 50% received stents) had a comparable 29% restenosis rate and 17% TLR rate.
In the present study, a strategy of provisional stenting was used. Many physicians believe that stenting is the treatment of choice for the vast majority of lesions. Although this may be true in certain well-defined lesion subsets,28 29 we believe that when all patients presenting for intervention are considered, the stent rate might be similar to that seen in the present study (50%). The Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) I trial, which used Doppler ultrasound to guide intervention, demonstrated excellent 6-month event rates and restenosis when Doppler flow and angiographic results were superior.30 Rodriguez et al31 have randomized patients to a strategy of primary stenting versus provisional stenting (Optimal Coronary Balloon Angioplasty With Provisional Stenting Versus Primary Stent [OCBAS] trial). They showed an angiographic restenosis rate of 19.2% in primarily stented lesions and 16.4% in lesions randomized to provisional stenting (stenting rate 13.5%).
The present study was performed in a realistic clinical setting. Chronic total occlusions were excluded for 3 reasons. First, we do not believe that the combined catheter would be an effective first-line device for these lesions. Second, the high restenosis rates suggest that primary stenting is the best treatment option. Finally, the clinical success rate is much lower.32
The present study used a variable-diameter balloon catheter. If the variable-diameter balloon is sized at 0.5 mm above nominal (expected growth ex vivo at 12 atm), the balloon/artery ratio in the ICUS-guided group is significantly larger than that in the Angio-guided group (1.23±0.21 versus 1.03±0.22, respectively; P<0.0001). There could be a non–ICUS-related impact of the special balloon design used in the ICUS group.
The present study was not designed to assess ICUS-guided direct stenting. In a strategy of provisional stenting, the primary goal is to achieve an “optimal” PTCA result without stenting. We did not randomize a group to primary stenting.
Some of the revascularization procedures were clinically driven, and some were performed after scheduled angiographic follow-up, driven by the decision of the interventionist. Even though the independently assessed clinical status was nearly the same in the ICUS and Angio groups, this could be a limitation of the present study. The operator may also have been biased because of recognition of the specific catheter design used in the ICUS group when viewing the former cine run.
Although prospectively randomized and controlled, these results should be confirmed in larger multicenter trials.
A strategy of ICUS-guided intervention can be applied to a wide range of patients in routine clinical practice. Although there was no significant difference in MLD at 6 months, we conclude that this strategy provides an angiographically superior acute result and reduces the 2-year clinically driven TLR rate.
The following laboratories and personnel were involved in the present study: Quantitative Angiography Lab, Ute Popperburg, RN, and Ingrid Rietdorf, RN; Cardiac Catheterization Lab, Valereo Bassignana, MD, Heinz J. Büttner, MD, Nicolas Jander, MD, and Klaus Werner, MD; and Clinical Research Section, Sabine Dippmann, BSc, Brigitte Frorath, BSc, Andreas Grove, MD, and Evelyn Langer, MTA.
This study was funded in part by Endosonics Europe BV, Rijswijk, the Netherlands, and Cordis Corp, a Johnson & Johnson Co, Miami, Fla. The authors thank S. Dippmann and Marilyn Murray for assistance in manuscript preparation.
Dr Hodgson serves as a consultant to Endosonics, a funder of this study.
- Received February 21, 2000.
- Revision received June 26, 2000.
- Accepted June 28, 2000.
- Copyright © 2000 by American Heart Association
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