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(Circulation. 1997;96:3369-3377.)
© 1997 American Heart Association, Inc.

Articles

Prognostic Value of Intracoronary Flow Velocity and Diameter Stenosis in Assessing the Short- and Long-term Outcomes of Coronary Balloon Angioplasty

The DEBATE Study (Doppler Endpoints Balloon Angioplasty Trial Europe)

Patrick W. Serruys, MD, PhD; Carlo di Mario, MD, PhD; Jan Piek, MD, PhD; Erwin Schroeder, MD; Christian Vrints, MD; Peter Probst, MD, PhD; Bernard de Bruyne, MD; Claude Hanet, MD; Eckart Fleck, MD; Michael Haude, MD; Edoardo Verna, MD; Vasilis Voudris, MD; Herbert Geschwind, MD; Håkan Emanuelsson, MD; V. Mühlberger, MD; Giambattista Danzi, MD; Hans O. Peels, MD; Andrew J. Ford, Jr; Eric Boersma, MSc; ; for the DEBATE Study Group¹

Correspondence to P.W. Serruys, Department of Coronary Diagnostics and Interventions, Thoraxcenter, PO Box 1738, 3000 Dr Rotterdam, Netherlands.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background The aim of this prospective, multicenter study was the identification of Doppler flow velocity measurements predictive of clinical outcome of patients undergoing single-vessel balloon angioplasty with no previous Q-wave myocardial infarction.

Methods and Results In 297 patients, a Doppler guidewire was used to measure basal and maximal hyperemic flow velocities proximal and distal to the stenosis before and after angioplasty. In 225 patients with an angiographically successful percutaneous transluminal coronary angioplasty (PTCA), postprocedural distal coronary flow reserve (CFR) and percent diameter stenosis (DS%) were correlated with symptoms and/or ischemia at 1 and 6 months, with the need for target lesion revascularization, and with angiographic restenosis (defined as DS 50% at follow-up). Logistic regression and receiver operator characteristic curve analyses were applied to determine the prognostic cutoff value of CFR and DS separately and in combination. Optimal cutoff criteria for predictors of these clinical events were DS, 35%; CFR, 2.5. A distal CFR after angioplasty >2.5 with a residual DS 35% identified lesions with a low incidence of recurrence of symptoms at 1 month (10% versus 19%, P=.149) and at 6 months (23% versus 47%, P=.005), a low need for reintervention (16% versus 34%, P=.024), and a low restenosis rate (16% versus 41%, P=.002) compared with patients who did not meet these criteria.

Conclusions Measurements of distal CFR after PTCA, in combination with DS%, have a predictive value, albeit modest for the short- and long-term outcomes after PTCA, and thus may be used to identify patients who will or will not benefit from additional therapy such as stent implantation.

Key Words: stenosis • balloon • prognosis • angioplasty

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
It has been repeatedly demonstrated that qualitative and quantitative angiographic morphology before and after PTCA are poor predictors of immediate and long-term prognosis.^{1 2} This limitation of angiography after an angioplasty procedure has prompted clinicians to use alternative methods for the functional assessment of angioplasty results. Various digital angiographic techniques and Doppler catheters were introduced and tested for that purpose.^{3 4 5 6 7 8 9 10} However, only with the introduction of a Doppler angioplasty guidewire did the continuous measurement of blood flow velocity during a routine angioplasty procedure become feasible and clinically useful.^{11 12 13 14} A normalization of flow velocity parameters after successful angioplasty will indicate that an adequate lumen enlargement has been achieved and a normal vascular conductance is restored. The results of small-sized, single-center studies have shown a heterogeneous improvement of the flow velocity indices after PTCA.^{8 11 12 13} Up to now, however, no appropriately sized prospective studies have assessed the value of flow velocity indices in predicting immediate complications, recurrence of stenosis, and symptoms after PTCA.

The aim of the DEBATE study (Doppler Endpoints Balloon Angioplasty Trial Europe) was to identify Doppler flow velocity indices predictive of the short- and long-term clinical outcomes after angioplasty. The ultimate hypothesis of the DEBATE trial was that a normalization of flow velocity patterns and rheology within the dilated segment would have a favorable impact on the restenosis process.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patient Selection
The study population consisted of 297 patients undergoing balloon angioplasty of a single lesion in a major native coronary artery because of chest pain and/or other documented signs of ischemia (electrocardiographic, scintigraphic, or echocardiographic) at rest or with exertion. All patients gave witnessed written informed consent, and the study protocol was approved by the institutional review boards of all participating hospitals. Baseline characteristics are reported in Table 1.

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

Exclusion criteria were multivessel disease, previous transmural myocardial infarction in the territory of distribution of the vessel to be dilated, acute myocardial infarction less than 1 week before PTCA, total coronary occlusion, presence of left bundle-branch block or second- to third-degree atrioventricular block, open bypass graft distal to the lesion to be treated, extreme tortuosity of the vessel to be dilated, and use of alternative or additional interventional treatments (directional or rotational atherectomy, stent implantation, etc).

Angioplasty Procedure and Flow Velocity Assessment
Before angioplasty, all patients were premedicated with heparin and acetyl salicylic acid. A 0.014-in Doppler tipped guidewire was used as the primary angioplasty guidewire (FloWire, Cardiometrics).¹⁵ The Doppler guidewire was introduced into the proximal segment of the artery to be dilated, and baseline and hyperemic flow velocity measurements were obtained in an angiographically normal segment of the artery. Next, the Doppler guidewire was advanced distal to the lesion and new velocity recordings were obtained under basal and hyperemic conditions. For both proximal and distal measurements, a distance from the stenosis greater than 5 times the vessel diameter was maintained to avoid prestenotic acceleration of flow or poststenotic turbulent flow.

Maximal hyperemia was induced by an intracoronary bolus injection of adenosine 12 µg for the RCA and 18 µg for the LCA (Fig 1).¹⁶ In the protocol of the study it was explicitly recommended to disengage whenever possible the guiding catheter from the ostium at the time of hyperemia measurements because it has been demonstrated that a large guiding catheter (8F), under certain circumstances (small ostium), may impede a maximal hyperemic response.¹³ Compliance to this recommendation was, however, not documented in writing in the case record form or monitored by analysis of the cinefilm in the core lab. The Doppler guidewire was left in place and flow velocity was continuously monitored during balloon inflation and deflation and for 15 minutes after completion of an angiographically successful dilatation. During the 15-minute trend recording, interventions that could interfere with the stability of the velocity signal were avoided (eg, injection through the guiding catheter or repositioning of the Doppler guidewire). Finally, proximal and distal baseline and hyperemic flow velocity recordings were obtained in the same position as before dilatation (Figure 1).

View larger version (100K): [in this window] [in a new window]   Figure 1. Flow velocity signal proximal and distal to the stenotic lesion in baseline (BAS) and under hyperemia (HYP). Quantitative angiographic parameters of the Doppler interrogated lesion are also displayed. A, QCA during coronary interventions; B, distal CFR after PTCA.

Only angiographic criteria (DS <50% in any angiographic view) were used to determine the end point of the angioplasty procedure. Flow velocity measurements recorded during the procedure were not used for guidance of the intervention, although the investigators were not blinded to the Doppler results.

Follow-up Procedures
Four weeks (±2 weeks) after the initial angioplasty procedure, the patient's anginal status was determined with the Canadian Cardiovascular Society (CCS) angina classification. When possible, a symptom-limited bicycle stress test was also performed after withdrawal of all antianginal medication. The objective signs of ischemia as well as the exercise protocols followed in the different centers were left to the discretion and judgment of the respective exercise testing laboratories.

At 6 months (±4 weeks), the patient's anginal status was reevaluated, a repeat stress test was performed, and quantitative angiography (with the same set of matched views obtained during the angioplasty procedure) was performed.

The criteria for reintervention were conventionally based on the presence of a DS >50% in a patient with either symptoms or signs of ischemia. Flow velocity assessment at the time of recatheterization was not used for decision making.

Quantitative Angiographic Measurement
At least two cineangiograms, in orthogonal projections, were obtained before coronary angioplasty and repeated after angioplasty in the same projections. Intracoronary nitroglycerin 0.1 to 0.3 mg or isosorbide dinitrate 1 to 3 mg was administered to achieve maximal coronary vasodilatation. All cinefilms were sent to an independent core laboratory, which was blinded to the clinical and the Doppler information. Matched views and frames were selected for off-line quantitative analysis. A computer-assisted analysis system was used (CAAS II system, Pie Medical Data). Automatic edge detection of the luminal dimensions (MLD and reference diameter) and videodensitometric analysis (minimal luminal cross-sectional area) were performed by use of the guiding catheter filled with contrast as a scaling factor.^{17 18 19}

Flow Velocity Measurement
During the angioplasty procedure, the Doppler flow velocity spectra were recorded continuously on videotape. The Doppler ultrasound instrument (FloMap, Cardiometrics) calculates and displays on-line several spectral variables including the time-averaged peak velocity (normalized to the cardiac cycle), the average systolic peak velocity, and the ratio of the average diastolic to average systolic peak velocities.¹⁵ The following ratios were also computed: CFR, calculated as the ratio between maximal flow velocity during the peak effect of the adenosine injection and the basal flow velocity; and the P/D ratio, calculated as the ratio of the flow velocity proximal and distal to the lesion.

Statistical Analysis
Continuous variables are expressed as mean±SD. Differences within these variables before and immediately after PTCA were evaluated by paired Student's t test. Differences between subgroups of patients were evaluated by unpaired Student's t test.

Both univariable and multivariable logistic regression analyses were performed to study the diagnostic value of QCA and Doppler flow measurements to predict recurrence of symptoms at 1 and 6 months, restenosis, and TLR. By design, no additional clinical variables were introduced in the model because the specific aim of the study was to identify Doppler flow velocity indices predictive of the short- and long-term clinical outcomes after angioplasty; analysis of variables other than Doppler flow velocity and angiographic parameters would have required a larger sample size. Each observed value of the significant predictive variables was considered as a possible "prognostic threshold": a cut-point in the range such that any value at or above that point would be considered as positive (ie, characteristic of an event) and any value below as negative. Sensitivity (percentage of patients with an event that does exceed the threshold—or true positive probability) and specificity (percentage of event-free patients that does not exceed the threshold—or true negative probability) are calculated at each threshold. ROC curves were also constructed, and the area under the ROC curve is reported, representing the diagnostic power of the variable at hand (range, 50% to 100%).²⁰

Finally, we defined the "best" threshold of a significant predictive variable to be the cut-point where sensitivity equals specificity, which is the point with the highest diagnostic accuracy.^{21 22 23} With the help of this "best" threshold, the population was divided in two categories. The frequency of events in both categories was determined, and differences were evaluated by ² analysis. Relative risks are reported. Statistical significance of all tests was stated at the .05 probability level.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
For a variety of reasons, such as bailout stenting and protocol violation (enumerated in the flow chart, Fig 2), the recording of distal CFR was not obtained in 72 of the 297 patients initially enrolled. Among these patients, 8 developed a myocardial infarction and/or underwent a revascularization procedure during their hospital stay. Ultimately, 225 patients left the hospital without a major adverse cardiac event and with a proper recording of the distal CFR after successful balloon angioplasty.

View larger version (21K): [in this window] [in a new window]   Figure 2. Flow chart of the initial study enrollment and those patients subsequently eligible for early and late clinical and angiographic follow-up.

In Table 2 the changes in CFR, baseline DSVR, and baseline P/D ratio are summarized in those patients (n=187) who had a complete set of matched (before and after PTCA) measurements for these three velocity parameters. It must be emphasized that the most relevant parameter in terms of short- and long-term prognoses, namely CFR after PTCA, was recorded in all 225 patients and constituted the basis of our analysis of the prognostic value of flow velocity measurements. The two other parameters (DSVR and P/D ratio) did not appear to have significant physiological values (see below) when analyzed with respect to the three major epicardial vessels (RCA, LAD, and LCx).

View this table: [in this window] [in a new window]   Table 2. Matched Variables for Doppler Flow, Angiographic, and Hemodynamic Measurements Before and After PTCA

Procedural Angiographic and Doppler Flow Measurements
The angiographic and Doppler flow velocity measurements, before and after PTCA, are summarized in Table 2. Diameter stenosis decreased from 62±9% to 37±8% (P<.0001), whereas area stenosis, measured independently with videodensitometry, decreased from 82±11% to 48±15% (P<.0001). Distal CFR increased from 1.60±0.62 before PTCA to 2.74±0.94 after the procedure (P<.0001). After PTCA, CFR was not significantly different in the left versus the right coronary arteries (P=.7951, unpaired t test). The distal baseline DSVR increased from 1.71±0.65 to 2.06±0.92 after the procedure (P<.0001). Before PTCA, DSVR was significantly lower in the RCA compared with the LCA (1.44±0.35 versus 1.82±0.71 respectively, P<.0001). Since previous investigations have demonstrated that some rest phasic Doppler flow velocity indexes are not useful for evaluating stenosis in the RCA proper before or after angioplasty, we specifically investigated the diagnostic value of the CFR measurements in the RCA (Table 2). Although the anatomic and functional improvements after PTCA were similar in the RCA and the LCA (distal CFR increase of 1.04±0.99 versus 1.14±0.97, P=.2442), DSVR in the RCA remained unchanged after PTCA, which confirmed the observation of Heller et al.²⁴ No physiologically relevant changes in blood pressure and heart rate were noted before versus after PTCA.

The Doppler signal was recorded for 15 minutes after the procedure. Cyclic flow variation, defined as gradual decline in flow over several minutes followed by a sudden restoration to higher values,²⁵ was observed in 4 patients. In 3 of them, the occurrence of cyclic flow was predictive of immediate complications (2 intracoronary thromboses and 1 acute closure), whereas none of the patients without cyclic flow variation showed acute closure during their hospital stay.

Predictive Values of CFR, MLD, and DS on Early and Late Recurrence of Symptoms and/or Ischemia, TLR, and Angiographic Restenosis
One hundred ninety-seven patients (88% of the eligible population) underwent a clinical evaluation and a bicycle stress test 4 weeks after PTCA: 162 patients (82%) were free of symptoms and ischemic events, whereas 35 patients (18%) either experienced typical chest pain (n=12 patients) or had an electrocardiographically positive exercise test (n=16 patients); 7 patients had both typical angina and a positive stress test.

At 6 months, 204 patients (91% of the eligible population) underwent a clinical evaluation and a bicycle stress test; 123 were free of angina and/or ischemia, whereas 81 (40%) either experienced angina pectoris (n=43) or had an electrocardiographically positive exercise test (n=21); 17 patients had both typical angina and a positive stress test.

Two hundred twenty-four patients (99.6% of the eligible population) were monitored for the occurrence of any adverse major cardiac event during the 6-month follow-up. No death or myocardial infarction occurred during this observational period. One hundred sixty-two patients had no TLR, whereas 62 underwent either a new percutaneous revascularization (n=58) or a bypass operation (n=4).

Two hundred two patients (90% of the eligible population) had an angiographic follow-up at 6 months; 130 had no restenosis, whereas 72 had a diameter stenosis 50%.

Patients with or without symptoms and/or ischemia 1 month after PTCA had similar angiographic measurements after PTCA. However, distal CFR after angioplasty was significantly lower in patients with early recurrence of ischemia (2.38±0.74) compared with the asymptomatic patients (2.82±0.95, P=.0034; see Table 3). Other indices based on flow velocity measurements, such as DSVR and P/D ratio, showed similar values in both groups and thus had no prognostic value. At 6-month follow-up, both morphological (DS, MLD) and functional (distal CFR) postprocedural measurements were significantly different between patients with and those without symptoms and/or ischemia. However, while angiographic measurements were not significantly different between patients with and those without TLR within 6 months, distal CFR was higher (2.80±0.95) in patients without TLR compared with those with TLR (2.50±0.77, P=.0137). Postprocedural DS was higher in patients with angiographic restenosis at 6 months than in those without (41±8% versus 35±8%, P=.0001).

View this table: [in this window] [in a new window]   Table 3. Angiographic and CFR Measurements After PTCA in the Groups With and Those Without Recurrence of Angina or Ischemia, TLR, and Angiographic Restenosis

Table 4 shows the results of logistic regression and ROC analyses. Postprocedural CFR appears to have modest prognostic value in predicting the incidence of symptoms and/or ischemia at 4 weeks (ROC area, 64%). The prognostic value in predicting late recurrence of symptoms and the need for reintervention on the target lesion was weaker (both ROC areas, 58%). The "optimal" prognostic cutoff for CFR is 2.5.

View this table: [in this window] [in a new window]   Table 4. Predictive Values of Coronary Flow Reserve and Diameter Stenosis

DS has a reasonable prognostic value in predicting angiographic restenosis (ROC area, 68%) and a weaker value in predicting recurrence at 6 months (ROC area, 60%). The "optimal" cutoff value for DS is 35%.

In addition, we performed a multivariate logistic regression analysis that demonstrated that DS% and CFR had significant independent prognostic values (see Table 4). Therefore we categorized our population into subgroups of patients: those with a DS either greater or smaller than 35% together with a CFR either higher or lower than 2.5. Four subgroups, each comprising 20% to 30% of the entire cohort, are in this way identified. The most favorable subset of patients is characterized by a DS 35% and a CFR >2.5 and consequently had the lowest incidence of early and late clinical recurrence, TLR, and restenosis (Fig 3). Conversely, the worst subgroup of patients has a DS >35% and a CFR 2.5 and is associated with the worst clinical and angiographic outcomes. The two remaining subgroups, with either CFR 2.5 or DS >35%, had intermediate outcomes. When the best subset of patients is compared with the three other pooled groups, then the early and late recurrence in the best group is 10% and 23% versus 19% (P=.149) and 47% (P=.005) in the other three groups, respectively. Similarly, the TLR rate and the restenosis rates in the best subgroup are 16% and 16% versus 34% (P=.02) and 41% (P=.002) in the other three, respectively.

View larger version (62K): [in this window] [in a new window]   Figure 3. Percent incidence of recurrence of symptoms and/or ischemia (AI), TLR, and angiographic restenosis (Rest) in the four groups identified by predefined residual diameter stenosis and distal coronary flow reserve after PTCA. Values are percentages. Group I, n=44, DS 35% and CFR >2.5; groups II+III+IV, n=158, DS >35% or CFR 2.5; group II, n=60, DS >35% and CFR >2.5; group III, n=42, DS 35% and CFR 2.5; and group IV, n=56, DS >35% and CFR 2.5. The percentage of events (1 month AI, 6 month AI, TLR, and rest, respectively), in patients with DS 35% or CFR >2.5 (combination of groups I, II, and III) is 15%, 39%, 26%, and 34%.

Relative Risk Analysis
The optimal prognostic cutoff criteria of the combined categorical variables were subsequently applied to establish the RR of early and late clinical and angiographic recurrence. Results of the RR analysis are summarized in Table 5. When the patients were divided into two groups, those that achieved either a "bad" anatomic (DS >35%) or functional (CFR 2.5) result had an approximately 2 times higher risk for short- and long-term events compared with the group that achieved "good" anatomic and functional results.

View this table: [in this window] [in a new window]   Table 5. Predictive Values of Coronary Flow Reserve, Diameter Stenosis, and Their Combination

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Findings of the Present Study
In this prospective but observational study, we have identified threshold values of DS and CFR that characterize a group of patients with good, intermediate, and bad clinical and angiographic outcomes.

From the RR analysis, it might be inferred that flow velocity parameters recorded at the time of the procedure are mainly prognostic indicators of early clinical recurrence, whereas DS and MLD measured after angioplasty are more predictive markers of angiographic restenosis defined in a categorical fashion. Clinical recurrence at 6 months and rate of reintervention, although associated with a small increase in RR (ranging from 1.2 to 1.5), are not predicted by anatomic (DS >35%) or functional (CFR 2.5) parameters individually recorded at the time of the procedure. The combination of these two parameters, however, was predictive of 6 months' recurrence of symptoms and TLR.

This apparent paradox illustrates the complexity and intricacies of the relationship between anatomy, function, and symptoms. Detailed analysis could not unravel the intricacies of these relationships, and only a few simple explanatory assumptions can be put forward in the interpretation of the results.

During balloon angioplasty, the inflation of the balloon will disrupt the morphological structure of the vessel wall and lumen, inducing dissections, plaque rupture, and so forth. These changes can impair the ability of any anatomic measure to assess the resulting lumen. Ultrasound analysis of post-PTCA results has repeatedly demonstrated how unreliable angiography is in assessing the anatomic benefit of balloon angioplasty. It might be assumed that flow reserve assessment in these cases of pseudo–angiographic success (tears and splits filled with contrast medium) will be abnormal, and the persistence of symptoms and ischemia at 1 month in these patients with incomplete dilatation might be predicted or at least consistent with an abnormal flow reserve measured immediately after the procedure. In the long term, these "pseudo–angiographic successes" with abnormal flow reserve will become "pseudo-restenosis," so that in these cases the long-term predictive value of procedural flow assessment will emerge. Since the risk for clinical recurrence is doubled in the subset of patients with a CFR 2.5 (24% versus 12% if CFR is >2.5), it appears justifiable to resort immediately to treatment other than balloon angioplasty. On the other hand, it is not surprising to see that the acute poor angiographic result (DS >35%), irrespective of its flow reserve assessment, is at long term intrinsically associated with a high risk of angiographic restenosis, on the basis of categorical criteria (DS 50%). It is more likely, for example, that a large-diameter stenosis after PTCA will gradually worsen over time and exceed an arbitrary threshold defining angiographic restenosis, whereas a lower residual diameter stenosis will have less chance of reaching this threshold.

Limitations of the Present Study
It should be emphasized that the present analysis is based on the "off-line" results of two independent core laboratories: the Doppler and the quantitative angiographic core labs of the coordinating center (see "Appendix"). Although the concordance of the on-line (catheterization lab) and off-line (core lab) analyses for both techniques has been investigated and validated (unpublished data), it is clear that a solely prospective trial using on-line measurements for decision making will establish the clinical value of combined Doppler and quantitative angiographic assessments.

To avoid confounding factors that might obscure the predictive value of Doppler measurements, we included a highly selected patient population (eg, single-vessel disease, no previous myocardial infarction). (This population was similar to, and therefore could be compared with, the Benestent I and II patients receiving either balloon angioplasty or stent implantation.) The application of these cutoff criteria (DS 35 and CFR >2.5) to patient populations different than that presented here should be undertaken cautiously; for example, preliminary data from other small single-vessel studies have suggested that CFR after stent deployment in patients with multivessel disease may be remarkably lower than that seen in patients with single-vessel disease.^{26 27 28} Several potential explanations for this phenomenon have been described in previous Doppler studies^{6 7 8 11} and include the presence of acute disturbance of flow regulation after angioplasty by the release of endothelin, thrombin, or microemboli,^{29 30 31} modifications in the hemodynamic conditions after PTCA, alterations of smooth muscle vasomotor tone due to mechanical trauma after PTCA, and chronic impairment of microvascular response.

Prior studies have reported inconsistent results in terms of post-PTCA CFR, with most patients showing improvement, although others demonstrated degradation or no change in their postinterventional CFR. One explanation that has been proposed to explain this variability is that the baseline flow velocity may be significantly larger after PTCA compared with before PTCA, thus blunting the calculated CFR ratio. In this patient cohort, the distal baseline APV increased by only 14% during the intervention (from 16.1±7.7 cm/s before PTCA to 18.4±8.5 cm/s after PTCA, P=.007).

Because some investigators have suggested that there may be a difference in phasic Doppler flow velocity indices in the RCA compared with the LCA, we examined the question of whether there might be a disparity in the predictive value of the CFR in the LCA versus the RCA by using a two-factor (TLR and LCA/RCA) ANOVA model. There was no significant difference in the CFR between the two vessels (P=.85), nor was there an interaction found between TLR and the vessel (P=.34).

In this report, we did not correct for individual changes in blood pressure and heart rate, which could have affected the CFR measurements, because these corrections did not improve at all the predictive value provided by the nonindexed version of the CFR. In the present study population, there were on average small but statistically significant changes in heart rate (-2 bpm) and blood pressure (-4 mm Hg) between the preprocedural and the postprocedural status of the patient, as indicated in Table 2. This absence of major fluctuations in blood pressure and heart rate is presumably the result of a highly standardized protocol mandating, for example, systematic intracoronary administration of nitrates before flow assessment and a 15-minute phase of watchful monitoring before performing flow assessment.

Similarly, we did not try to correct for other factors known to affect flow reserve such as age, hypertension, hypertrophy, or hypercholesterolemia. It will be the role of subsequent multivariate analyses to unravel the relative contribution of these factors to the change in CFR after PTCA.

A further limitation of this study is that it was observational and by design not blinded. Therefore at the time of recatheterization, the need for reintervention might have been driven by the result of angiographic ("oculostenotic" reflex) and Doppler ("audiostenotic" reflex) assessments and not related to symptomatic and ischemic conditions of the patients. This interpretation is unlikely because before his recatheterization, the patient had to undergo an exercise test to assess his freedom from angina and ischemia as an indication for either further reintervention or abstention of reintervention. Conversely, a sizable group of patients did not undergo a reintervention despite a DS 50% and/or CFR 2.5, suggesting that the main guidelines for reintervention were still the symptomatic and ischemic status of the patient (Fig 4).

View larger version (18K): [in this window] [in a new window]   Figure 4. Venn diagram: relationship between recurrence of symptoms at 6 months, angiographic restenosis, and TLR in the 190 patients in whom information on both recurrence of symptoms at 6 months and restenosis was available. Three patients out of the 62 TLR mentioned in Table 5 do not have information about restenosis (1 cinefilm lost) or recurrence (2 exercise tests not performed).

Clinical Implications
As a result of this study, the long-term prognosis of an individual can be stratified as follows: a patient with a DS 35% will have a 26% incidence of events at 6 months. A patient with a CFR >2.5 will have a 24% incidence of events, while a patient with a DS 35% and a CFR >2.5 will have the best long-term result with an event rate of 16%, a level of long-term success comparable to the best result obtained so far with a stent.³² The identification of a subgroup of patients with freedom from events of 84% at 6 months certainly has major clinical implications in an era of use and abuse of the stent, considering the current financial constraint that the medical community faces. Our results would suggest that 20% to 25% of the patients treated in the DEBATE trial did not need further therapy to achieve a clinical outcome and freedom from events similar to those observed after stent implantation. It must be pointed out that in this trial, no particular procedural or technical recommendation or guidance was advised to optimize the result of balloon angioplasty. The current percentage of acute procedural success (DS 35% and CFR >2.5) observed in this trial might be increased to 30% to 50% of patients if some type of Doppler and on-line angiographic guidance is used. Conversely, in a subgroup of patients with both poor anatomic and functional results, further therapy (ie, with stenting) must be contemplated in view of the highly predictable outcome of these patients. The cost-effectiveness of a therapeutic policy based on these guidelines is self-evident and certainly merits a prospective, randomized trial (DEBATE II). Coronary stenting has been shown to be associated with a larger lumen gain immediately after stenting and a reduced long-term restenosis.³³ Because stent implantation remains a technically demanding and expensive procedure, the use of intracoronary flow velocity measurements along with on-line quantitative angiography can represent a cost-effective way of selecting the patients who can benefit most from this intervention.

	Selected Abbreviations and Acronyms

 

CFR = coronary flow reserve DS = diameter stenosis DSVR = diastolic/systolic velocity ratio LAD = left anterior descending LCA = left coronary artery LCx = left circumflex MLD = minimum lumen diameter P/D = proximal/distal (velocity ratio) PTCA = percutaneous transluminal coronary angioplasty QCA = quantitative coronary angioplasty RCA = right coronary artery ROC = receiver operator characteristic RR = relative risk TLR = target lesion revascularization

	Footnotes

 
¹ The remaining investigators in the DEBATE Study Group are listed in the "Appendix."

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The following institutions and investigators participated in the DEBATE study. The number enrolled at each center is given in parentheses.

Academic Medical Center, Amsterdam, Netherlands: J. Piek, K. Koch (40); Clinique Universitaire de Mont-Godinne, Yvoir, Belgium: E. Schroeder, O. Gurné, P. Chenu (33); Universitair Ziekenhuis Antwerpen, Belgium: C. Vrints (30); Thoraxcenter Rotterdam, Netherlands: C. di Mario, R. Gil, P. Nierop, P.W. Serruys (28); Kardiologische Universitatsklinik Wien, Austria: P. Probst, G. Porenta (25); Onze Lieve Vrouwe Kliniek Aalst, Belgium: G. Heyndrickx, B. de Bruyne, W. Wijns (24); Clinique Universitaire St Luc, Brussels, Belgium: C. Hanet (20); Deutsches Herzzentrum Berlin, Germany: E. Fleck, E. Wellnhofer, H. Sauer (17); Universität Essen, Germany: R. Erbel, M. Haude, D. Baumgart (15); Ospedale di Circolo, Varese, Italy: E. Verna (13); Onassis Cardiac Surgery Center, Athens, Greece: V. Voudris, A. Manginas (12); CHU Henri Mondor, La Creteil, France: H. Geschwind (10); Universitätsklinik fur Innere Medizin Innsbrück, Austria: V. Mühlberger, N. Moes, G. Friedrich (9); Sahlgrenska Hospital Göteborg, Sweden: H. Emanuelsson (9); Ospedale Niguarda Ca'Granda, Milano, Italy: L. Campolo, G. Danzi (6); Academisch Ziekenhuis Groningen, Netherlands: P. den Heijer, H. Peels (6).

Steering Committee: P.W. Serruys (Chairman), H.J. Geschwind, C. di Mario, A. Ford, G.A. van Es.

Doppler Committee: J.J. Piek, V. Mühlberger, C. Vrints, B. de Bruyne, H. Emanuelsson.

Angiography Committee: P. Probst, G.B. Danzi, M. Haude.

Critical Event Committee: V. Voudris, E. Schroeder, G.R. Heyndrickx.

Coordinating center: Cardialysis BV, Rotterdam, Netherlands: Gerrit-Anne van Es, Linda Goderie, Ingrid de Zwart, Eric Boersma, Eline Montauban van Swijndregt.

Angiographic core laboratory: Cardialysis BV, Rotterdam, Netherlands: Diny Amo, Marcel van der Brand, Ellie van de Leur, Robert Gil.

Received March 7, 1997; revision received July 14, 1997; accepted July 21, 1997.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

1. Rensing BJ, Hermans WR, Vos J, Tijssen JG, Rutsch W, Danchin N, Heyndrickx GR, Mast EG, Wijns W, Serruys PW. Luminal narrowing after percutaneous transluminal coronary angioplasty: a study of clinical, procedural and lesional factors related to long-term angiographic outcome: Coronary Artery Restenosis Prevention on Repeated Thromboxane Antagonism (CARPORT) Study Group. Circulation.. 1993;88:975-985.[Abstract/Free Full Text]
   
2. Hermans WR, Rensing BJ, Foley DP, Deckers JW, Rutsch W, Emanuelsson H, Danchin N, Wijns W, Chappuis F, Serruys PW. Therapeutic dissection after successful coronary balloon angioplasty: no influence on restenosis or on clinical outcome in 693 patients: the MERCATOR study group (Multicenter European Research Trial with Cilazapril after Angioplasty to prevent Transluminal Coronary Obstruction and Restenosis). J Am Coll Cardiol.. 1992;20:767-780.[Abstract]
   
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6. Serruys PW, Juilliere Y, Zijlstra F, Beatt KJ, De Feyter PJ, Suryapranata H, Van den Brand M, Roelandt J. Coronary blood flow velocity during percutaneous transluminal coronary angioplasty as a guide for assessment of the functional result. Am J Cardiol.. 1988;61:253-259.[Medline] [Order article via Infotrieve]
   
7. Kern MJ, Deligonul U, Vandormael M, Labovitz A, Gudipati CV, Gabliani G, Bodet J, Shah Y, Kennedy HL. Impaired coronary vasodilator reserve in the immediate postcoronary angioplasty period: analysis of coronary artery flow velocity indexes and regional cardiac venous reflux. J Am Coll Cardiol.. 1989;13:860-872.[Abstract]
   
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9. Serruys PW, Zijlstra F, Laarman GJ, Reiber HHC, Beatt K, Roelandt J. A comparison of two methods to measure coronary flow reserve in the setting of coronary angioplasty: intracoronary blood flow velocity measurements with a Doppler catheter, and digital subtraction cineangiography. Eur Heart J.. 1989;10:725-736.[Abstract/Free Full Text]
   
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13. Serruys PW, Di Mario C, Meneveau N, de Jaegere P, Strikwerda S, de Feyter PJ, Emanuelsson H. Intracoronary pressure and flow velocity with sensor-tip guidewires: a new methodologic approach for assessment of coronary hemodynamics before and after coronary interventions. Am J Cardiol.. 1993;71:41D–53D.[Medline] [Order article via Infotrieve]
    
14. Di Mario C, Gil R, Sunamura M, Serruys PW. New concepts for interpretation of intracoronary velocity and pressure tracings. Br Heart J.. 1995;74:485-492.[Abstract/Free Full Text]
    
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18. Di Mario C, Haase J, Den Boer A, Reiber JH, Serruys PW. Edge detection versus densitometry in the quantitative assessment of stenosis phantoms: an in vivo comparison in porcine coronary arteries. Am Heart J.. 1992;124:1181-1189.[Medline] [Order article via Infotrieve]
    
19. Serruys PW, Foley DP, de Feyter PJ, eds. Quantitative Coronary Angiography in Clinical Practice. Dordrecht/Boston/London: Kluwer Academic Publishers; 1994.
    
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23. Rensing BJ, Hermans WRM, Deckers JW, de Feyter PJ, Serruys PW. Which angiographic variable best describes functional status 6 months after successful single-vessel coronary balloon angioplasty? J Am Coll Cardiol.. 1993;21:317-324.[Abstract]
    
24. Heller LI, Silver KH, Villegas BJ, Balcom SJ, Weiner BH. Blood flow velocity in the right coronary artery: assessment before and after angioplasty. J Am Coll Cardiol.. 1994;24:1012-1017.[Abstract]
    
25. Sunamura M, Di Mario C, Piek JJ, Schroeder E, Vrints C, Probst P, Heyndrickx GR, Fleck E, Serruys PW, on behalf of the DEBATE investigators group. Cyclic flow variations after angioplasty: a rare phenomenon predictive of immediate complications. Am Heart J.. 1996;131:843-848.[Medline] [Order article via Infotrieve]
    
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27. Joye JD, Campsey M, Soukas P, Farah T, Schulman D, Lasorda D. Coronary flow reserve after PTCA and intracoronary stenting: a physiologic endpoint of procedural success. J Invas Cardiol.. 1996;8:48. Abstract.
    
28. Haude M, Baumgart D, Caspari G, Erbel R. Does adjunct coronary stenting in comparison to balloon angioplasty has an impact on Doppler flow velocity parameters? Circulation. 1995;92 (Suppl I):I-547.
    
29. Marmur JD, Merlini PA, Sharma SK, De Silva R, Davies GJ, Maseri A. Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty. J Am Coll Cardiol.. 1995;24:1484-1491.
    
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31. Di Mario C, Gil R, Serruys PW. Long-term reproducibility of coronary flow velocity measurements in patients with coronary artery disease. Am J Cardiol.. 1995;75:1177-1180.[Medline] [Order article via Infotrieve]
    
32. Serruys PW, Emanuelsson H, van der Giessen W, Lunn AC, Kiemeney F, Macaya C, Rutsch W, Heyndrickx G, Suryapranata H, Legrand V, Goy JJ, Materne P, Bonnier H, Morice MC, Fajadet J, Belardi J, Colombo A, Garcia E, Ruygrok P, de Jaegere P, Morel MA, on behalf of the Benestent Study Group. Heparin-coated Palmaz-Schatz stents in human coronary arteries: early outcome of the Benestent-II pilot study. Circulation.. 1996;93:412-422.[Abstract/Free Full Text]
    
33. Serruys PW, De Jaegere PJ, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, Van den Heuvel P, Delcan J, Morel MA, for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med.. 1994;331:489-495.[Abstract/Free Full Text]
    

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