Objective. We sought to develop a prognostic lesion classification based on simple angiographic parameters, lesion length and reference diameter that predicts differential outcome in patients undergoing intracoronary radiation. Methods and Results. Three types of lesions were identified: Type A characterized by lesion length <= 30 mm, reference diameter > 2.5 mm to <= 4.0 mm (short lesion: “normal” diameter), Type B by lesion length <= 30 mm, reference diameter <= 2.5 mm or > 4 mm (short lesion: “extreme” diameter), and Type C by lesion length > 30 mm (long lesion). A total of 1,151 lesions (77.7% in-stent restenosis) in 1,098 consecutive patients undergoing brachytherapy were classified into these 3 lesion types. Overall, 79.9%, 10.3 % and 9.8 % patients met the criteria for Type A, B and C lesions. While the in-hospital major adverse cardiac event (MACE) rate was 1.4%, 3.6% and 3.8% (p = 0.026), the 6-month MACE rate was 16.1%, 22.5% and 32.1% (p < 0.001), the angiographic restenosis rate was 21.3%, 32.4% and 42.4% (p < 0.001), and the late thrombosis rate was 4.1%, 9.0% and 11.3%, (p < 0.001) in Type A, B and C lesions, respectively. Consequently, with increasing lesion severity, 3 risk groups with low, medium and high risk were defined. Multivariate analysis showed that Type B and C lesions were independent predictors of 6-month MACE (OR, 1.5 and 1.9, respectively). Conclusion. The proposed novel and easily applicable lesion classification effectively predicts early and medium term outcome, and may be used for appropriate therapeutic decision making in patients undergoing brachytherapy.

       Intracoronary radiation therapy, by virtue of its antiproliferative and favorable remodeling effects, reduces restenosis in both in-stent restenosis (ISR) and de novo lesions. While several large, randomized and non-randomised trials have demonstrated the efficacy of brachytherapy,^1–7 little is known about the lesion-specific characteristics that might determine the outcome of this modality. In this era of evidence-based medicine, this information may be important, specifically with respect to cost-effective resource utilization. Furthermore, with the advent of drug-eluting stents (DES), it has become imperative to further refine the indications of brachytherapy. Lesion length and reference vessel diameter are the two most commonly studied angiographic parameters to identify the results of conventional percutaneous coronary interventions (PCI).^8–13 Using these parameters, we sought to evolve a simple yet predictive lesion classification that could define the early- and medium-term outcomes after radiation in a mixed, unselected population of patients encountered in day-to-day clinical practice.

Methods
       Patient population. Between April 1999 and September 2000, RENO (REgistry NOvoste), the first large-scale (post-marketing surveillance) registry of brachytherapy applied in routine clinical practice, included 1,098 consecutive patients, with 1,151 lesions treated with the BetaCath^™ System (Novoste, Norcross, Georgia) in 46 European centers. The methodology and results of the registry are published elsewhere.⁵ Based on the lesion length and reference diameter, we divided the lesions into three morphologic types: Type A, lesion length <= 30 mm, reference diameter > 2.5 to <= 4.0 mm (short lesion = “normal” diameter), Type B, lesion length <= 30 mm, reference diameter <= 2.5 mm or > 4 mm, (short lesion = “extreme” diameter), and Type C, lesion length > 30 mm (long lesion)
       Rationale of lesion classification. A scattergram was constructed to study the impact of lesion length and reference diameter on the occurrence

Figure 1

Scattergram to study the impact of lesion length and reference diameter on the occurrence of 6-month MACE.

of major adverse cardiac events (MACE) in the study patients (Figure 1). The event points were not evenly distributed, and there were areas of higher concentration. To further define local risk areas, we superimposed a mosaic plot (that demonstrates local risks) upon this scattergram (Figure 2). The latter figure suggested that while the MACE risk was low where a majority of patients were situated (lesion length < 30 mm, vessel diameter > 2.5 mm to < 4 mm), three regions of elevated risk were identified, namely short lesions with very large vessel diameters, short lesions with very small vessel diameters, and long lesions. To rule out arbitrariness due to the choice of the smoothing method and chance effects that may have resulted from the relatively small sample sizes of the medium- and high-risk groups, this regional risk distribution was further studied using two different 3-D smoothing methods: the inverse squared distance smoothing, and the LOWESS smooth. The risk groups were confirmed by both methods. Based on this analysis, we divided the study population into lesion types A, B and C. The attempt was to evolve a lesion classification which could, based on common angiographic-morphologic correlates, prognosticate a lesion with respect to the outcome of brachytherapy.
       Brachytherapy procedure. Ethical committee approval, signed informed consent, pre-brachytherapy interventional procedure, and pre- and post-brachytherapy protocol were according to the practices prevalent at the individual participating centers. After a satisfactory acute angioplasty result, all lesions were treated with the BetaCath^™ System, a non-centering device, the details of which are given elsewhere.5 The prescribed dose, measured at 2 mm from the source axis for vessels <= 3.5 mm, > 3.5 to < 4 mm, and >= 4 mm, was 18.4 Gray (Gy), 23.0 Gy, and 25.3 Gy, respectively, when ISR was the indication for brachytherapy, and 16.1 Gy, 20.7 Gy, and 23.0 Gy, respectively for de novo and non-stented restenotic lesions. The nominal diameter of the largest angioplasty balloon used prior to

Figure 2

Mosaic plot superimposed upon the scattergram of Figure 1, giving 6-month MACE risk estimates depending on lesion length and reference diameter.

brachytherapy was considered to represent the reference diameter. A minimum of 90 days of combined antiplatelet therapy with aspirin and clopidogrel (or ticlopidine) was recommended after the procedure, but a longer antiplatelet administration was left at the discretion of the individual operators.
       Endpoints. The clinical endpoints were: 1) in-hospital any-cause death, myocardial infarction (MI), composite of death or MI, target vessel revascularization (TVR), and total MACE. A MACE comprised of one or several of death, MI or TVR; and 2) six-month follow-up, including in-hospital, any-cause death, MI, composite of death or MI, TVR, and total MACE. Myocardial infarction was defined as a documented creatine kinase rise of more than two times the normal in the post-intervention phase, and by the presence of at least two of the following: pain, rise in creatine kinase, or electrocardiographic changes after discharge. The angiographic endpoint was the 6-month angiographic binary restenosis (defined as 50% stenosis relative to the reference luminal diameter) rate. A surrogate composite endpoint for late target vessel thrombosis was defined as the occurrence of one or several of the following beyond the first 30 days following brachytherapy: target vessel-related cardiac death, acute MI in any location (only when MI was documented not to have occurred in the territory of the target vessel, was it not counted as part of the surrogate endpoint), and documented angiographic total occlusion within the irradiated segment. All reported events were reviewed by a Critical Events Committee.

Figure 3

Kaplan Meier curves to demonstrate the cumulative MACE rate in the three risk groups.

       Statistical analysis. Mosaic plot (a tile smooth based on an automatic contouring algorithm), inverse squared distance smoothing, and LOWESS smooth were calculated using SYSTAT 10.2 for Windows. Discrete variables are provided as counts and percentages (in brackets). Continuous variables are expressed as mean ± SD. Associations between lesion types and patients’ characteristics, procedural details, and clinical and angiographic endpoints were studied with Spearman’s rank correlation coefficient. A p-value of < 0.05 was considered statistically significant. Logistic regression models were applied in order to identify potential risk factors for six-month MACE. Variable selection from an initial set of 15 baseline variables was performed as unconditional maximum likelihood backward selection (p out = 0.05).

Results
       The demographic and clinical profile of the patients are summarized in Table 1. While the majority of patients (79.9%) had Type A lesions, 10.3% patients had Type B, and 9.8% patients had Type C lesions. Almost similar characteristics were present in the three groups, except that patients with Type A lesions had a higher incidence of hypertension and a lower incidence of smoking and multivessel disease. More LAD lesions were treated in the Type A group, as against a greater number of RCA lesions in the Type C patients. In all groups, ISR was the predominant indication for brachytherapy.
The procedural details are depicted in Table 2. While a majority of patients were treated with a 40 mm source train, the 60 mm source was introduced late in the registry, and only 17% of the patients with Type C lesions could be treated with this device. For the same reason, pullback was employed much more frequently, and the dwell time was greater in Type C lesions. Geographic miss was seen more often in Type B and C lesions. Technical success (90% of the planned radiation dose delivery to the target coronary segment and post-procedural residual stenosis < 50%) was more frequently realized in Type A lesions.
       The clinical and angiographic follow-up is described in Tables 3 and 4. Overall, brachytherapy was safe during the early phase, with infrequent events, though in-hospital clinical events were still higher in lesion Types B (p = 0.085, Type B versus Type A lesions) and C (p = 0.070, Type C versus Type A lesions). Not only the composite endpoint of MACE, but the individual component endpoints, i.e. death, MI, death or MI, and TVR increased with increasing lesion severity. The 6-month follow-up at 6.3 ± 2.4 months similarly revealed higher clinical event rates, with increasingly severe lesion types (p = 0.091, Type B versus Type A lesions; p < 0.001 Type C versus Type A lesions), driven mainly by TVR and death. The surrogate composite endpoint of late target vessel thrombosis was also higher in lesion Types B and C (p = 0.020, Type B versus Type A lesions; p = 0.001 Type C versus Type A lesions).Interestingly, this late target vessel thrombosis did not manifest acutely in a majority of instances, and was detected as a total occlusion at follow-up angiography after more than 30 days. Angiographic restenosis, both occlusive and non-occlusive, was also higher in the more severe lesions (p = 0.031, Type B versus Type A lesions; p < 0.001 Type C versus Type A lesions).
Factors predictive of MACE during the 6-month follow-up, derived from multivariate analysis, were Type B lesion (odds ratio, OR 1.49), Type C lesion (OR 1.87), age (OR 0.98/year), cutting balloon (OR 0.53), and new stent (OR 1.62). Diabetes, however, was not an independent predictor.
When the analysis was restricted to the ISR subgroup, the results were qualitatively similar to the overall population, with three well-defined risk lesion categories (Table 5).

Discussion
       The principal finding of our study is that not all lesions respond similarly to brachytherapy, and that by using simple angiographic variables, lesion length, and reference diameter, three well-defined risk lesion types can be identified, which allow precise prediction of the outcome after brachytherapy. The RENO was the first large multicenter registry of over 1,000 consecutive patients undergoing radiation. The large sample size and the unselected nature of patients (several exclusion criteria often used in randomized trials, such as long lesions, chronic total occlusions, saphenous vein graft lesions, multivessel procedures, etc., did not apply to this registry) offered us a unique opportunity to develop this risk stratification scheme applicable to “real world” clinical practice.
       Risk groups. Type A, short lesion, “normal” diameter: Low-risk group. It is a reassuring fact that most of the lesions routinely treated with brachytherapy had fairly good results. The Kaplan-Meier (KM) curves constructed for the cumulative MACE rate clearly revealed three risk groups (Figure 3). While the low-risk group had a better likelihood of MACE-free survival right from the beginning, there was a widening of curves with time. It transpires that the low-risk group is likely to fare better in the in-hospital phase, through the intermediate- and long-term course, and that the better prognosis will increasingly become evident with the passage of time. An overwhelming majority of patients had ISR as the presenting lesion, and despite this high-risk group, where conventional interventional strategies have a poor outcome, a 6-month MACE rate of 16% and an angiographic restenosis rate of 21% is encouraging. The results are at least not inferior to the preliminary data that have come forth with DES (sirolimus, paclitaxel) in ISR, where in a follow-up of 6 to12 months, the MACE rate is shown to be 29–80%, while the restenosis rate is 13–61.5%^14–16 (in one study, however, there were no MACE and only 4% restenosis at 12 months¹⁷). Thus, based on our data, the best results of brachytherapy would accrue in lesions up to 30 mm long, with a reference diameter of 2.5–4 mm. From the multivariate analysis, it seems that avoiding the procedure in unstable angina and shunning new stents, and a greater use of cutting balloons can further improve the results. While in the registry, the nominal diameter of the largest angioplasty balloon used prior to brachytherapy was considered to represent the reference diameter, in practice, this could be extrapolated as the reference vessel diameter.
       Type B, short lesion, extreme diameter: Medium-risk group. Vessels with a small diameter have poor short- and long- term outcomes after conventional PCI. Acute outcome is mainly affected by the higher incidence of dissections, occlusions and higher residual stenosis. Diabetes is commonly associated with smaller vessels and contributes to the higher restenosis rate. Moreover, as the absolute late loss is independent of the reference vessel size and the amount of lumen loss is equal in vessels larger or smaller, the remarkably high restenosis rate in small vessels is reflective of the higher relative loss.¹² These factors seem to play a role after brachytherapy as well. An unexpected finding in our study was the worsening of results in vessels larger than 4 mm. This might be related to the steeper depth-dose fall-off curve with radiation. While optimal dose delivery at the adventitia determines the antiproliferative response of brachytherapy,¹⁸ it is likely that in very large vessels, the adventitial irradiation might be inadequate.
       Type C, long lesion: High-risk group. Long lesions have a poor outcome after conventional PCI. While diabetes is commonly associated with long lesions, longer lesions with greater plaque burden provide an increased source of smooth muscle cells that proliferate to form neointima.^10,11 Attrition of efficacy has also been demonstrated in long lesions, after radiation and intravascular ultrasound analysis suggests that this is mainly due to increased intimal hyperplasia cross-sectional area and a greater variability in neointimal response along the length of the stent with focal areas of lower dose delivery to the adventitia.¹⁹ Whereas the results in the present study were worst in long lesions, it is evident that lesion length is the dominating factor compared to vessel diameter and that long lesions, irrespective of the vessel size, seem to fare badly. Notwithstanding this fact, a subanalysis of RENO data in long lesions (mean length 35.3 ± 17.9 mm) does show a significant reduction in angiographic and clinical results at 6 months, compared to placebo groups of WRIST and Long WRIST studies taken as the reference population.²⁰ The 6-month outcome in long lesions has been particularly good, with a 60 mm transfer device/radiation source length.²¹ These studies may, however, not reflect a composite picture, as the KM plot (Figure 3) suggests that there is a sharp increase in clinical events after 6 months, and the cumulative MACE estimate at 15 months is 60%, thus mandating a need for a long-term randomized follow-up before conclusions can be firmly drawn.

Conclusions
       A lesion-specific classification based on the simple and commonly used angiographic parameters, lesion length, and vessel diameter, can be employed to determine the early and intermediate outcomes in patients undergoing brachytherapy. The low-risk group with short lesions (<= 30 mm) and “normal” diameter (> 2.5 mm to <= 4 mm) is attended by the best results, while the medium, short lesions (<= 30 mm) and “extreme” diameter (<= 2.5 mm and > 4 mm), and the high-risk groups, long lesions (> 30 mm), have increasingly worse prognoses. The proposed classification can be exploited to identify the patients best responding to brachytherapy and thus aid in optimal resource utilization.
       Limitations. This is a retrospective analysis and is, therefore, subject to the limitations pertinent to this type of clinical investigation. A prospective trial is warranted to corroborate our results.

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