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(Circulation. 2000;102:2930.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Randomized Comparison of Primary Stenting and Provisional Balloon Angioplasty Guided by Flow Velocity Measurement

Patrick W. Serruys, MD; Bernard de Bruyne, MD; Stéphane Carlier, MD; José Eduardo Sousa, MD; Jan Piek, MD; Toshiya Muramatsu, MD; Chris Vrints, MD; Peter Probst, MD; Ricardo Seabra-Gomes, MD; Ian Simpson, MD; Vasilis Voudris, MD; Olivier Gurné, MD; Nico Pijls, MD; Jorge Belardi, MD; Gerrit-Anne van Es, PhD; Eric Boersma, PhD; Marie-Angèle Morel, MS; Ben van Hout, PhD; on behalf of the Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) II Study Group

From the Thoraxcenter, Rotterdam, the Netherlands (P.W.S., S.C.); the Cardiovascular Center, OLV Hospital, Aalst, Belgium (B.d.B.); Instituto Dante Pazzanese, Sao Paulo, Brazil (J.E.S.); Academisch Medisch Centrum, Amsterdam, the Netherlands (J.P.); Kawasaki Central Hospital, Kawaka-Shi Kanagawa, Japan (T.M.); University Hospital Antwerp, Edegem-Antwerp, Belgium (C.V.); Allgemeines Krankenhaus der Stadt Wien, Vienna, Austria (P.P.); Hospital Santa Cruz, Linda-A-Velha, Portugal (R.S.-G.); Wessex Cardiology Center, Southampton, United Kingdom (I.S.); Onassis Cardiac Surgery Center, Athens, Greece (V.V.); Hôpital Universitaire de Mont-Godinne, Yvoir, Belgium (O.G.); Catharina Hospital, Eindhoven, the Netherlands (N.P.); Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina (J.B.); Cardialysis, Rotterdam, the Netherlands (G.-A.v.E., M.-A.M.); Erasmus University, Rotterdam, the Netherlands (E.B.); and the Institute for Medical Technology Assessment, Rotterdam, the Netherlands (B.v.H.).

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background—Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive.

Methods and Results—To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is "optimal." An optimal result was defined as a flow reserve >2.5 and a diameter stenosis <36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885; P=0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%; P=0.066).

Conclusions—After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty.

Key Words: stents • angioplasty • balloon • random allocation • cost-benefit analysis

	Introduction

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Over the last 2 decades, percutaneous transluminal coronary angioplasty has proven to be a safe and effective option for treating patients with coronary artery disease.¹ However, treatment results may be transient because of recoil, restenosis, and reocclusion. Although these disadvantages are partly overcome by coronary stenting,^{2 3 4 5 6} the costs of coronary stenting are high compared with balloon angioplasty, and the long-term outcome remains a matter of concern.^{7 8}

It has been suggested that optimal balloon angioplasty could yield a clinical outcome similar to stenting.^{9 10 11 12} The Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) I results support this hypothesis in that the outcome for patients with both a diameter stenosis (DS) 35% and a coronary flow reserve (CFR) >2.5 was comparable to that achieved with stenting in the Belgian Netherlands Stent (BENESTENT) trials.^{3 13} Thus, the following provisional approach emerges: stent only those patients likely to reap an additional benefit. Such an approach challenges the intervener who must decide on overall patient care. "Provisional angioplasty" refers to a status of angioplasty that satisfies predefined criteria of optimal results based on pressure gradients,¹¹ early loss of minimal lumen diameter,¹⁰ or intravascular ultrasound measurements.¹² A failure to meet the criteria would change the intended treatment and results in stent implantation.

DEBATE II was a prospective, randomized study that used criteria identified in DEBATE I. It addressed the following questions. (1) Should elective treatment be by stenting or balloon angioplasty (provisional angioplasty being guided by the stated criteria)? (2) What is the relative cost/benefit ratio of these strategies? (3) Do patients with optimal balloon angioplasty obtain an additional benefit from stenting?

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patient Selection
Patients were eligible for the study if they were scheduled to undergo angioplasty for stable or unstable angina pectoris (excluding Braunwald classification III),¹⁴ documented myocardial ischemia due to a single de novo coronary stenosis potentially amenable to stent implantation, or both. The target lesion was to supply viable myocardium and be <25 mm long. Excluded patients manifested total coronary occlusion; lesions that were ostial or at a bifurcation; lesions in vessels that were previously bypassed, tortuous, or contained thrombus; or previous Q-wave infarction (in the target vessel territory or from an evolving myocardial infarction of the previous week). The study was performed according to the principles in the Declaration of Helsinki. Every patient provided written, informed consent.

Study Objectives and Trial Design
The primary trial objective was to compare the cost-effectiveness of elective stent implantation (primary stenting) with provisional balloon angioplasty guided by quantitative angiography and Doppler flow velocity measurements. The strategy after provisional angioplasty was to limit stent implantation to bailout situations and cases in which an "optimal result" (DS 35% and CFR >2.5)¹³ was not achievable. The secondary objective was to evaluate the benefit differences from additional stenting in patients with and without an optimal result. Therefore, double randomization was required (Figure 1).

View larger version (26K): [in this window] [in a new window]   Figure 1. Study flowchart. R1 indicates first randomization; R2, second randomization; and BA, balloon angioplasty. Patient groups with provisional stenting are framed in bold. Actual number of patients in clinical subsets lie between parentheses; theoretical assumptions are denoted by n. Twelve patients were excluded from study between randomizations 1 and 2 (10 due to inconsistencies between randomization service and investigators, and 2 due to missing CFR values).

It would be incorrect to estimate the costs and benefits of provisional angioplasty using average costs and benefits combining (1) patients with bailout stents, (2) patients with optimal balloon angioplasty, and (3) patients with stenting after a suboptimal result. Patients left after bailout stenting would then receive too much weight, because the bailout decision was made before the second randomization, leading to 4 groups instead of the 2 created by the provisional angioplasty strategy. Therefore, a weighted average was used that weighted bailout stenting by the probability of bailout stenting and stenting in patients who did not require bailout stenting by the probabilities of belonging to either the optimal balloon angioplasty or suboptimal angioplasty groups. Thus, the provisional angioplasty group is a constructed or virtual group.

Primary Stenting
A conventional guidewire was used in patients randomized to primary stenting, and predilatation was performed in all patients before stent implantation.

Guided Balloon Angioplasty
During guided balloon angioplasty, quantitative angiography and CFR measurements were made using standardized protocols^{13 15} to achieve an optimal result (criteria defined earlier in article).

A 0.014-inch Doppler guidewire (Cardiometrics FloWire, EndoSonics) was advanced distal to the lesion, and velocity recordings were obtained under basal and hyperemic conditions. Maximal hyperemia was induced by adenosine, which was administered as an intracoronary bolus (right coronary artery, 12 µg; left coronary artery, 18 µg) or as an intravenous infusion (140 µg · kg^-1 · min^-1).^{16 17} These 2 methods were proven to be equivalent.

If an optimal result was not achieved, the operator was urged to perform iterative dilatations by upsizing the balloon, increasing the inflation pressure, or both. Bailout stenting was allowed in the presence of residual stenosis >50%; dissection types D, E, or F; persistent myocardial ischemia with dissection type C; reduction of TIMI flow¹⁸ by 1 grade; or the existence of TIMI grades 0 or 1. The final DS and CFR were assessed after an optimal result was achieved or when the operator considered further improvement attempts unsafe. A second randomization was then performed that disregarded the measurements.

Efficacy End Points
The efficacy end point compiled major adverse cardiac events within 12 months of the procedure; these included death from any cause, nonfatal myocardial infarction, and percutaneous or surgical target lesion revascularization. Myocardial infarction was defined as the development of a new Q-wave or a rise of serum creatinine kinases with an abnormal plasma concentration of myocardial isoenzymes. Enzymes were sampled twice in the first 24 hours. Patients visited the outpatient clinic 1, 6, and 12 months after hospital discharge. At each visit, records were kept of anginal status, cardiac medication, 12-lead ECG, and complete physical examination. No follow-up angiogram was performed unless clinically indicated.

Costs
Cost analysis was limited to direct medical costs, which were calculated as resource utilization volume x unit costs in 1999 at the University Hospital Rotterdam-Dijkzigt, the Netherlands.¹⁹ Resources included the materials used in the initial procedure (eg, stents, balloons, and Doppler wires); length of stay in the intensive care unit, coronary care unit, or general ward; major curative and diagnostic procedures; and rehospitalization within 12 months of the initial procedure. Although it could be expected that a guided strategy would lengthen procedures, we decided not to estimate the cost consequences of such an action. We hypothesized that the increased duration would not reduce the number of procedures possible per day; thus, the "fixed costs" would remain fixed. Also, the data may be biased by the time taken for a second randomization, thus breaking the continuity of procedures.

Cost Effectiveness
The balance between costs and benefits was addressed by calculating incremental cost-effectiveness ratios (ie, additional costs per additional event-free survivor after 1 year) and by estimating the probabilities that the provisional angioplasty was (1) more effective and cost saving, (2) more effective and more costly, (3) less effective and cost saving, or (4) less effective and more costly.

Sample Size
Assumptions for sample size calculation were based on BENESTENT-1, BENESTENT-2 pilot, and DEBATE I experiences.^{2 3 13} All additional benefits of stenting were attributed to patients with suboptimal results. With these assumptions, it was calculated that for the randomization scheme in Figure 1, 600 patients were needed to detect, with 80% power, a difference (=0.05) of EUR 680 between provisional angioplasty and primary stenting in cost-effectiveness per survivor (no major adverse cardiac event) after 1 year.²⁰

Statistical Analysis
Continuous variables are expressed as means±SD. Differences between patient groups were studied using Student’s unpaired t test or 1-way ANOVA, whichever was appropriate. Categorical variables are presented as percentages, and differences between groups were evaluated using Fisher’s exact test. Kaplan-Meier event-free survival curves were calculated, and differences between patient groups were compared by a log-rank test.

Because the costs and benefits of provisional angioplasty were calculated as weighted averages, bootstrapping techniques were used to evaluate differences in the balance between costs and benefits after primary stenting and provisional angioplasty.^{21 22} A total of 3000 bootstrap samples were drawn iteratively, with replacement when sample sizes equalled the total number of patients studied. Odds ratios and 95% confidence intervals are presented; a Breslow-Day test for homogeneity of odds ratios between subgroups and ² tests were also applied.

Statistical tests were 2-tailed, with significance stated at the 0.05 level. Uncertainties surrounding cost, benefits, and cost-effectiveness were addressed by probability ellipses in the "cost-effectiveness plane."²¹

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patient Characteristics
Baseline characteristics of the patients in this trial are presented in Table 1. There were no significant differences between patients allocated to primary stenting and to guided balloon angioplasty. Of the 523 patients randomized to guided balloon angioplasty, 129 (25%) underwent bailout stenting at the time of initial dilatation (n=103) or during the optimization process (n= 26). Of the remaining 394 patients, 382 underwent the second randomization. Twelve were not subrandomized for technical and logistical reasons.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical and Angiographic Characteristics

Procedural Results
Table 2 summarizes the procedural results, and Figure 2 shows the relative roles of DS and CFR in classifying patients. Optimal results, with an average DS of 22±8% and a CFR of 3.1±0.6, were achieved in 35% of patients. In the suboptimal group, DS was 23±10% and CFR was 2.0±0.4. Additional stenting in patients with optimal balloon angioplasty resulted in a DS of 8±8% and a CFR of 3.3±0.7; in patients with suboptimal balloon angioplasty, additional stenting resulted in a DS of 7±8% but a CFR of 2.4±0.7.

View this table: [in this window] [in a new window]   Table 2. Angiography and CFR During the Procedure

View larger version (54K): [in this window] [in a new window]   Figure 2. Relative role of DS and CFR in classifying patients in balloon angioplasty group (bailout patients not included).

Primary Stenting Versus Provisional Angioplasty
Table 3 shows the incidence of major adverse cardiac events in both the initial groups and the 4 subgroups, ranked in hierarchical order. In general, patients with optimal results experienced fewer major adverse cardiac events than patients with suboptimal results, and stented patients fared better than those undergoing balloon angioplasty alone (Figure 3).

View this table: [in this window] [in a new window]   Table 3. Frequency of Primary Clinical End Points at 12 Months in Descending Order of Severity

View larger version (20K): [in this window] [in a new window]   Figure 3. Event-free survival (Kaplan-Meier curves) at 12 months. Patients with suboptimal and optimal balloon angioplasty were randomized to additional stenting or no further treatment. OS indicates optimal stenting (n=77); SOS, suboptimal stenting (n=112); OB, optimal balloon angioplasty (n=107); SOB, suboptimal balloon angioplasty (n=86); FE, Fisher’s exact test; and LR, log-rank test. For definitions of optimal and suboptimal, see text.

Freedom from these events, which were calculated as weighted averages, was similar for patients undergoing primary stenting (86.6%) and provisional angioplasty (85.6%) (Figure 4). The weight for patients needing bailout stenting was 129/(129+107+112+86+77) or 25.2%; the weight for patients stented after a suboptimal result was 38.7% (calculated as the probability of not needing a bailout stent [100.0%–25.2%=74.8%] multiplied by the probability of a suboptimal result {[112+86]/[77+107+112+86]=51.8%}); and the weight for patients with a stent after an optimal result was 36.0% (calculated as the probability of not needing a bailout stent [74.8%] multiplied by the probability of an optimal result [100%–51.8%=48.2%]).

View larger version (13K): [in this window] [in a new window]   Figure 4. Event-free survival (Kaplan-Meier curves) at 12 months in patients who had primary stenting (PRIM; n=97) or provisional angioplasty (PROV; n=523).

Table 4 presents cost estimates for the 2 initial groups and 4 subgroups. The cost of FloWire in the initial procedure was only partially covered by the lower stent use. Costs for the provisional angioplasty group during follow-up were higher due to longer hospitalizations and surgical revascularization. After 1 year, the costs of provisional angioplasty outweighed those of direct stenting by EUR 688. Figure 5 presents the estimates of costs, benefits, and cost effectiveness. The point estimate of the incremental cost-effectiveness ratio suggests that provisional angioplasty is less effective and more expensive.

View this table: [in this window] [in a new window]   Table 4. Costs and Event-Free Survival After 12 Months

View larger version (24K): [in this window] [in a new window]   Figure 5. Incremental cost-effectiveness of provisional angioplasty vs primary stenting. Outer ellipse defines smallest area (95% probability) containing incremental costs and effectiveness of provisional angioplasty compared with primary stenting. Middle and inner ellipses define smallest areas (50% and 5% probabilities, respectively). Center of ellipse represents point estimate of incremental costs and effects. Prob indicates estimated probability that cost and effect are in respective quadrant; MACE, major adverse cardiac events.

Stenting Versus Balloon Angioplasty After the Second Randomization
The analysis of subrandomized patients in the balloon angioplasty group (Figure 6) indicates that stenting was associated with fewer major adverse cardiac events than balloon angioplasty alone in both patients with suboptimal (10.7% versus 26.7%; odds ratio, 3.0; P=0.005) and optimal results (6.5% versus 15.9%; odds ratio, 2.7; P=0.066). The Breslow-Day test for homogeneity of odds ratios was not significant (P=0.865). The higher cumulative costs of balloon angioplasty alone during the follow-up period almost matched the high initial costs of balloon angioplasty followed by stenting.

View larger version (9K): [in this window] [in a new window]   Figure 6. Relative risk ratios at 12 months for patients with suboptimal or optimal balloon angioplasty who survived event-free and were randomized to additional stenting or no further treatment. Bars indicate 95% confidence intervals.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The main result of this study was a lack of significant difference between clinical outcomes when comparing primary stenting and provisional balloon angioplasty. However, with the current unit costs of FloWire and stents, a strategy of provisional angioplasty is more costly than primary stenting.

Relevance and Critical Appraisal of Cost-Effectiveness Analysis
Cost considerations dominate many decisions about therapeutic interventions and are very relevant from a societal viewpoint. As emphasized in the literature, an independent person without commercial affiliations must analyze cost-effectiveness in such studies to avoid financial bias.²³ However, cost-effectiveness analyses are limited by multiple factors. First, cost data are transient and are affected by product acceptance, market dynamics, and reimbursement systems. Second, changing patterns of practice affect the selection of treatment devices, how they are used, and overall procedure time. Thus, the costs used here represent only a snapshot in time. For example, direct stenting without predilatation (an increasingly used technique) will undoubtedly affect cost-effectiveness in the future, but this method of treatment was not applied here.

Two crucial factors in the present study exerted a major influence on overall costs: the costs of FloWire and those of stenting. When the study was designed, its power calculation was based on market prices in 1996 and the cost estimates related to bleeding complications and the longer hospital stays associated with stenting. The reported cost estimates were based on unit costs in 1999 (costs of primary stenting versus provisional angioplasty, EUR 5916 versus EUR 6724; P=0.029). However, an application of 1996 unit costs does not change the conclusion. The absence of expected differences is mainly because in the year 2000, stenting is no longer associated with bleeding complications and longer hospital stays, whereas the bailout rate with the balloon angioplasty group has increased from 15% to 25%.

Moreover, we did not take into account differences in procedure time. The time for guided angioplasty in the present study was 26 minutes longer (mean) than that of stenting, which further tipped the cost-effectiveness balance in favor of primary stenting.

The Additional Value of Stenting After Optimal Angioplasty: A Flow-Mediated Phenomenon?
An unexpected observation in this study was a further reduction in the rate of major adverse cardiac events in patients stented after optimal balloon angioplasty. This observation was made possible by the trial’s double randomization design. On the basis of stent-like angioplasty results in other trials,^{9 13 24} we had hypothesized no such additional benefits. However, the perceived benefits of additional stenting may have resulted from a selection process that ignored the outcome of patients with unsatisfactory or complicated balloon angioplasty (ie, bailout and suboptimal groups).

Although a similar DS was achieved in all patients stented after angioplasty (7%), a diminished CFR persisted after stenting in the suboptimal group (2.4) compared with the optimal group (3.3). Fewer major cardiac events were observed in the latter group (10.7% versus 6.5%). Further investigations are needed to fully understand the underlying mechanisms.

Clinical Relevance of the Findings of This Study
The present study failed to demonstrate a favorable economic profile for provisional angioplasty (guided by quantitative angiography and Doppler flow velocity measurements) compared with primary stenting. Indeed, although there was no significant difference in clinical effectiveness, the data pointed to higher costs with provisional angioplasty. Thus, the current data do not provide economic arguments to switch from primary stenting, even though clinical benefits result when stenting follows optimal balloon angioplasty. A limitation of our study was the inclusion of patients with only a single, relatively short lesion. However, it would seem from a literature survey that the patients studied represented possibly up to 70% of patients presently treated by percutaneous techniques worldwide.^{25 26}

	Acknowledgments

 
We are indebted to Cordis, a Johnson & Johnson company, Warren, NY, that provided the stents free of charge. This study was supported by EndoSonics, Rancho Cordova, Calif, which makes the Doppler guidewire used in the study.

	Footnotes

 
Reprint requests to Patrick W. Serruys, Department of Interventional Cardiology, Thoraxcenter Bd-418, University Hospital Dijkzigt, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands.

A complete list of the DEBATE II study group investigators can be found in the Appendix.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Study Investigators, Their Location, and Number of Patients Treated
The Netherlands: P.W. Serruys, M.v.d. Brand, S.G. Carlier, P. de Feyter, D. Foley, W.v.d. Giessen, J. Hamburger (n=67); J.J. Piek, F.v.d. Wal (n=36); N.H.J. Pijls, J.P.M. van Asseldonk (n=20); V.A.W.M. Umans (n=13); G.J. Laarman, F. Kiemeneij (n=13); Belgium: B. de Bruyne, W. Wijns, G.R. Heyndrickx (n=60); C. Vrints (n=29); O. Gurné (n=24); C. Hanet, N. Debbas, D. Huyberechts (n=13); Brazil: J.E. Sousa, I. Pinto, L. Mattos, A. Chaves, A. Abizaid, A. Sousa (n=43); Japan: T. Muramatu (n=32); K. Kurogane (n=5); S. Mizuno (n=3); Austria: P. Probst, G. Porenta (n=28); Portugal: R. Seabra-Gomes, J. Baptista, J.L. Palos, F.P. Machado (n=28); United Kingdom: I.A. Simpson, K.D. Dawkins, H.H. Gray (n=28); P.M. Schofield (n=14); C. Ilsley, M. Mason, M. Bustami (n=13); K.G. Oldroyd (n=4); Greece: V. Voudris, J. Malakos, D.Y. Cokkinos (n=27); Argentina: J. Belardi, L. Guzmán, Rubén Piraino, F. Cura (n=17); France: J.-L.Guermonprez, F. Ledru (n=15); P. Dupouy (n=7); M. Bory (n=4); J. Puel (n=3); F. Tarragano (n=2); Italy: E. Verna (n=13); Germany: A.W. Frey, A. Grove, A. Henning, V. Bassignana (n=12); E. Fleck, E. Wellnhofer (n=11); R. Simon, M. Lins, P. Papechrysanthou (n=10); Israel: R. Beyar, M. Kapeliovich (n=10); M.S. Gotsman, M. Mosseri (n=4); Denmark: P. Thayssen (n=7); Czech Republic: P. Widimsky (n=5).

Received May 31, 2000; revision received September 8, 2000; accepted September 19, 2000.

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