The Leipzig Prospective Drug-Eluting Balloon-Registry　– Outcome of 484 Consecutive Patients Treated for Coronary In-Stent Restenosis and De Novo Lesions Using Paclitaxel-Coated Balloons –

Abstract

Background: Drug-eluting balloons (DEB) are an alternative treatment of in-stent restenosis (ISR), but data regarding outcomes of DEB in de novo lesions are lacking.

Methods and Results: We investigated the effect of DEB on target lesion revascularization (TLR), procedural complications (coronary dissection/rupture, pericardial effusion, stent thrombosis, peri-interventional NSTEMI, stroke), major adverse cardiac and cerebrovascular events (all-cause mortality, myocardial infarction, TLR, stroke) in patients with ISR and de novo lesions in an all-comers setting. Between April 2009 and October 2013, 484 consecutive patients (mean age 68.4 years; 77.9% male) were enrolled in a prospective registry. TLR rate was 4.9% at 12 months and 8.7% at long-term follow-up of 2.3 years. Subgroup analysis confirmed a TLR rate of 8.9% after DEB treatment of ISR in bare-metal stents (21/235 lesions), 13.0% in drug-eluting stents (21/161 lesions) and 0% for de novo lesions (0/76 lesions). At long-term follow-up, all-cause mortality/cardiac mortality was 8.7% (42/484)/3.3% (16/484) and MACCE rate was 18.4% (89/484 patients), with no differences between DEB for ISR compared with de novo lesions.

Conclusions: DEB for ISR resulted in a low rate of TLR. Our data support DEB in ISR as an effective treatment option. DEB in small coronary vessels in our limited cohort appeared to be safe. Larger, randomized trials in small coronary vessels should be undertaken to verify the long-term results of the current trial. (Circ J 2016; 80: 379–386)

The introduction of drug-eluting stents (DES) significantly reduced the rates of restenosis and target lesion revascularization (TLR), because of inhibition of cellular proliferation as compared with bare-metal stents (BMS).¹ Despite advances in treatment, in-stent restenosis (ISR) still remains the primary concern after percutaneous coronary intervention (PCI) using DES^2–7 and is surprisingly high ranging from 3% to 20%, especially in an all-comers scenario.^8–11 As confirmed in angiographic and optical intravascular imaging studies, there are morphological differences in ISR in BMS and DES. ISR in BMS is characterized by homogeneous tissue rich in smooth muscle cells compared with the heterogeneous, less cellular tissue in ISR in DES.¹² Moreover, ISR in DES is associated with worse outcomes than with ISR in BMS.¹³ Currently, there is no clear consensus about the optimal management of ISR. Intracoronary stenting is still the preferred treatment in patients with ISR after DES or BMS implantation.^9,14–16 However, drug-eluting balloons (DEB) provide potential advantages:¹⁷ rapid release of high drug concentrations and homogeneous drug delivery to the vessel wall, absence of stent and polymer, reduced chronic inflammation and shorter duration of antiplatelet therapy. The recently published SeQuent Please World Wide Registry¹⁸ confirmed a low TLR rate of 5.2% at 9.4 months’ follow-up in patients treated with a DEB for BMS restenosis.

The ISAR-DESIRE 3 trial showed non-inferiority of the paclitaxel-eluting balloon to paclitaxel-eluting stents in terms of diameter stenosis (38.0% vs. 37.4%) at mid-term angiographic follow-up.¹⁹ However, to date only limited and conflicting data are available regarding the treatment of de novo lesions, especially in small vessels, by DEB.²⁰ Therefore, we aimed to investigate the effect of DEB on TLR, procedural complications and major adverse cardiac and cerebrovascular events (MACCE; composite of all-cause mortality, myocardial infarction (MI), TLR, stroke) at 1 year and long-term follow-up in patients with de novo lesions compared with those with ISR.

Methods

Patient Cohort

Consecutive patients who underwent PCI using paclitaxel-coated balloons were enrolled in this prospective, single-center registry. Informed consent for the coronary catheterization and PCI, including the follow-up interview, was given by all patients.

Patients were eligible for the registry if they were ≥18 years old and presented with typical symptoms of angina pectoris and/or evidence of coronary ischemia in a stress test. All patients underwent detailed assessment of medical history and cardiovascular risk factors as well as a physical examination. Hemodynamic unstable patients presenting in cardiogenic shock and patients with a history of stroke within the previous 3 months were excluded.

Coronary Catheterization and Patient Treatment

All patients received unfractionated heparin in a body weight-adjusted dose (100 IU/kg body weight) intravenously prior to DEB intervention, 500 mg of aspirin (if not already chronically administered) and clopidogrel with 600-mg loading dose in the catheterization laboratory for elective DEB. In patients with acute coronary syndrome, a dual antiplatelet therapy with ticagrelor, prasugrel or clopidogrel in combination with aspirin was administered at the discretion of the interventional cardiologist in accordance with current guidelines.²¹ For elective DEB, patients were treated with dual antiplatelet therapy (aspirin and clopidogrel) for 3 months for de novo lesions and for ISR in BMS. In patients undergoing DEB for ISR in DES, aspirin and clopidogrel were administered for 12 months after stent implantation, but for at least 4 more weeks according to current recommendations. The DEB intervention was performed by experienced interventional cardiologists in patients presenting with de novo coronary artery stenosis with lesions in small vessels (vessel diameter ≥2.5 mm) or ISR ≥50% based on coronary angiography. After predilation using a conventional balloon with a balloon to vessel ratio of 0.8–1.0, the paclitaxel-coated balloon (SeQuent Please, B. Braun Melsungen AG, Germany) exceeding the target lesion proximally and distally was applied and kept inflated for 30–60 s with a pressure of at least 8 atmospheres. In patients with residual stenosis after the DEB intervention, the decision whether to additionally treat the target lesion with a BMS or DES was left to the discretion of the interventional cardiologist. In case of a coronary dissection type>B, a coronary stent (BMS or DES) was implanted.

Clinical Endpoints and Definitions

The primary outcome of the study was the incidence of clinically driven TLR after DEB intervention at 12 months and long-term follow-up of 2.27±1.3 years. TLR was defined as any repeat PCI of the target lesion or bypass surgery of the target vessel because of restenosis of the target lesion. Secondary endpoints included periprocedural complications (coronary dissection, coronary rupture, pericardial effusion, stent thrombosis, peri-interventional NSTEMI and stroke) and MACCE (comprising the composite of all-cause mortality, MI, TLR, stroke) at 12 months and at long-term follow-up.

All deaths were considered cardiac unless a clear noncardiac course could be established. In case of any doubt, death was counted as cardiac. The diagnosis of MI was based on the development of new pathological Q-waves in more than 2 contiguous ECG leads or elevation of cardiac enzyme levels ≥ twice the upper limit of normal values according to the Academic Research Consortium.²² Peri-interventional MI was defined as an elevation of creatinine kinase isoenzyme level >3-fold the upper normal limit after the procedure during the index hospitalization.²²

Follow-up

Clinical follow-up was conducted via structured questionnaire by telephone interview, hospital charts or direct contact with the treating physician.

The 30-day follow-up was completed in all patients (100%). The clinical 12-month follow-up was completed in a total of 482/484 patients (99.6%). Clinical long-term follow-up was obtained after a mean time interval of 2.27±1.3 years after DEB intervention.

Statistical Analysis

Dichotomous variables are reported as numbers and proportions. Continuous parameters are presented as mean±standard deviation and interquartile range (IQR). Nonparametric variables were compared by Fisher’s exact test and ordered proportions by Armitage’s test for trend. Cox proportional hazards regression modeling was used to identify independent risk factors associated with TLR, mortality and MACCE. All tests were performed as 2-sided at significance level α=5%. All variables with a P-value <0.05 in univariable modeling entered the multivariable model. Statistical analyses were performed using SPSS 19.0 (SPSS Inc, Chicago, IL, USA). Time-to-event data and cumulative survival were characterized with the use of Kaplan-Meier curves.

Results

Patient Characteristics

Between April 2009, and October 2013, 484 consecutive patients who underwent DEB intervention were included in the registry. Baseline characteristics of the patient population are summarized in Table 1. Mean patient age was 68 years (range 39–91) and 377 (77.9%) were male. Most patients had multivessel coronary artery disease (74.2%). In patients with ISR, the time between initial stent implantation and DEB was 3.52±4.07 years (IQR: 0–17). 163 patients presented with acute coronary syndromes (33.7%), 75 patients (15.5%) had MI without ST-segment elevation and 17 patients (3.5%) with ST-segment elevation. In the majority of patients, the target lesion was in the left anterior descending coronary artery (30.2%), in 28.9% in the right coronary artery and in 22.7% in the circumflex coronary artery (Table 2).

Table 1. Baseline Clinical Characteristics of Patients With ISR and De Novo Lesions

Variable (n, %)	Patient cohort (n=484)	ISR (n=408)	De novo lesion (n=76)	P value
Age (years), median±SD	68.4±10.4	68.2±10.3	69.7±10.9	0.245
Male sex	377 (77.9)	317 (77.7)	60 (78.5)	0.881
BMI (kg/m2), median±SD	28.4±4.56	28.6±4.54	27.5±4.61	0.068
Cardiovascular risk factors, n (%)
Hypertension	474 (97.9)	401 (98.3)	73 (96.1)	0.197
Hyperlipoproteinemia	407 (84.1)	352 (86.3)	55 (72.4)	0.006
Current smoking	89 (18.4)	74 (18.1)	15 (19.7)	0.748
Diabetes mellitus	232 (47.9)	198 (48.5)	34 (44.7)	0.617
No. of diseased vessels
1	125 (25.8)	100 (24.5)	25 (32.9)	0.153
2	149 (30.8)	182 (44.6)	28 (36.8)	0.257
3	210 (43.4)	126 (30.9)	23 (30.3)	1.00
Left main	59 (12.2)	52 (68.4)	7 (9.2)	0.450
Acute coronary syndrome	163 (33.7)	122 (29.9)	41 (53.9)	<0.001
Unstable angina	71 (14.7)	59 (14.5)	12 (15.8)	0.726
NSTEMI	75 (15.5)	52 (12.7)	23 (30.3)	<0.001
STEMI	17 (3.5)	11 (2.7)	6 (7.9)	0.036

BMI, body mass index; ISR, in-stent resenosis; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

Table 2. TLs in Patients With ISR and De Novo Lesions

Target vessel (n, %)	Patient cohort (n=480)	ISR (n=408)	De novo lesion (n=76)	P value
Left anterior descending	149 (30.8)	136 (33.3)	13 (17.1)	0.003
Ramus diagonalis	33 (6.90)	18 (4.4)	15 (19.7)	0.007
Right coronary artery	143 (29.5)	130 (31.9)	13 (17.1)	0.013
Ramus circumflexus	110 (22.7)	83 (20.3)	27 (35.5)	0.007
Ramus intermedius	12 (2.5)	9 (2.2)	3 (3.9)	0.413
Left main	17 (3.5)	13 (3.2)	4 (5.3)	0.322
CABG	20 (4.1)	19 (4.7)	1 (1.3)	0.340

CABG, coronary artery bypass graft; ISR, in-stent resenosis; TL, target lesion.

Procedural Data

The main indication for DEB intervention was ISR (84.3%), whereas in 76 patients (15.7%) the DEB was applied for significant de novo lesions. Procedural data are displayed in Table 3. A total of 92 patients with ISR (19.0%) had undergone at least 1 previous intervention of the target lesion before the DEB intervention. In 40 patients (8.3%) more than 1 previous intervention of the target lesion was recorded. Whether or not to implant an additional stent was left to the discretion of the interventional cardiologist according to dissection of the vessel or residual stenosis. An additional stent implantation in the target lesion was in trend more often after DEB use for ISR compared with DEB use for de novo lesions (14.7% vs. 4.1%; odds ratio (OR) 0.58; confidence interval (CI) 0.32–1.03; P=0.078). In patients with de novo lesions the mean inflation pressure of the DEB was significantly lower than in patients with ISR. The mean length of the DEB was significantly shorter and the mean diameter of the DEB was significantly smaller in de novo lesions. The mean duration of in-hospital stay was 3.5 days (range 0–47 days) with no difference between the 2 groups.

Table 3. Procedural Data of Patients With ISR and De Novo Lesions

Variable (n, %)	Patient cohort (n=484)	ISR (n=408)	De novo lesions (n=76)	P value
Contrast media (ml)	168±69.9	166±69	181±72	0.086
Time from stent implantation to DEB (years)	3.52±4.07	3.52±4.07	–	–
Additional stent implantation in TL	81 (18.8)	71 (14.7)	20 (4.1)	0.078
PCI of other lesion(s)	157 (32.4)	120 (24.8)	37 (7.6)	0.001
Femoral/radial access	447 (92.4)/37 (7.6)	374 (77.3)/34 (7.0)	73 (15.1)/3 (0.6)	0.242
Mean inflation pressure (bars)	14.9±4.09	15.5±4.0	11.6±3.1	<0.001
Mean length of DEB (mm)	22.0±4.76	22.4±4.7	20.3±4.7	0.001
Mean diameter of DEB (mm)	3.05±0.38	3.12±0.35	2.68±0.32	<0.001

DEB, drug-eluting balloons; PCI, percutaneous coronary intervention. Other abbreviations as in Table 2.

Procedural Complications

The incidence of coronary dissection after DEB intervention was 9.1% (44 patients) with no difference between DEB in ISR and DEB in de novo lesions (relative risk (RR) 0.82, 95% CI 0.37–1.8, P=0.64). A coronary rupture after DEB was seen in a total of 4 patients (0.8%), of whom 1 patient developed a hemodynamic relevant pericardial effusion (0.2%). In 2 patients with coronary rupture, an immediate coronary angioplasty using conventional balloons, which were kept inflated for 15 min sealed off the leak. In the other 2 patients, a covered stent was successfully implanted. Of these 4 patients with coronary rupture, the DEB was performed in 1 patient for de novo lesions with an inflation pressure of 10 bar in a long-segment artery discontinuity of the RIVP (vessel diameter 2.5 mm), and in 3 patients for significant ISR with an inflation pressure of 10, 12, and 15 bar in strongly calcified vessels, respectively. We noted no statistical difference in regard to coronary rupture between patients with ISR and de novo lesions (RR 0.56, 95% CI 0.06–5.4, P=0.613). There was no evidence of stent thrombosis after DEB intervention during hospitalization or at 30-day follow-up. The incidence of peri-interventional NSTEMI and of peri-interventional stroke was 0.6% and 0.6% (3/484 patients with MI and 3/484 patients with stroke), respectively.

At 30 days, major bleeding after DEB was seen in 2 patients (0.4%); 1 patient presented with pericardial effusion detected on echocardiography under anticoagulation with aspirin, clopidogrel and dabigatran at day 12 after DEB intervention, which was successfully treated by pericardiocentesis; the 2nd patient was hospitalized after syncope of unclear origin and cranial computed tomography revealed intracerebral hemorrhage at day 30 after DEB intervention.

Clinically Driven TLR

TLR (the primary outcome) occurred in 8.7% (42/484 patients) after a mean follow-up of 2.27±1.3 years after DEB. The time-to-event curve for the primary objective is shown in Figure A. At 30 days, TLR occurred in 2 patients (0.4%). At 6 months, the rate of TLR was 2.4% (11/458 patients). Long-term event analysis using Kaplan-Meier estimates confirmed a TLR rate of 4.9±1.0% at 1 year, 8.2±1.0% at 2 years, and 12.9±2.0% at 3 years.

Figure.

(A) Time-to-event curve for target lesion revascularization, (B) long-term survival after DEB intervention and (C) freedom from MACCE after DEB intervention for up to 3 years after the procedure. DEB, drug-eluting balloon; MACCE, major adverse cardiac and cerebrovascular events.

The rate of TLR was 8.9% after DEB treatment of ISR in BMS (21/235 lesions), 13.0% for after DEB treatment of ISR in DES (21/161 lesions; RR 0.65, CI 0.35–1.24, P=0.195) and 0% for de novo lesions (0/76 lesions; P=0.001).

Predictors of TLR

Predictors of TLR are presented in Table 4. Treatment of ISR with DEB was significantly associated with the occurrence of TLR compared with DEB treatment of de novo lesions (P=0.001). In detail, TLR was strongly associated with patients undergoing the DEB intervention for significant ISR. To avoid statistical separation, ISR was not analyzed in univariable and multivariable regression models. Treatment of ISR in a coronary artery bypass graft (CABG) was associated with a higher rate of TLR as compared with treatment of de novo lesions with DEB (RR 6.60, 95% CI 2.47–17.6).

Table 4. Predictors of TLR in Univariate and Multivariate Logistic Regression Analysis

Baseline variables	Univariate		Stepwise multivariate
	OR (95% CI)	P value	OR (95% CI)	P value
Male sex	0.68 (0.34–1.39)	0.293	–	–
Age, years	1.02 (0.99–1.05)	0.185	–	–
BMI, kg/m2	0.96 (0.89–1.03)	0.281	–	–
Diabetes mellitus	1.50 (0.79–2.84)	0.214	–	–
ACS	0.51 (0.24–1.09)	0.084	0.43 (0.20–0.96)	0.040
ISR in BMS	0.81 (0.43–1.54)	0.523	–	–
ISR in CABG	6.60 (2.47–17.61)	<0.001	7.87 (2.85–21.77)	<0.001
Stent implantation TL	0.74 (0.32–1.72)	0.485	–	–

ACS, acute coronary syndrome; BMS, bare-metal stent; CI, confidence interval; OR, odds ratio; TLR, TL revascularization. Other abbreviations as in Tables 1,2,4.

The type of stent used (BMS vs. DES) did not affect the rate of TLR in long-term follow-up (9.8% vs. 12.0%, RR 0.80, 95% CI 0.42–1.53, P=0.50).

Multivariable modeling revealed ISR in CABG as an independent predictor for TLR (RR 7.87, 95% CI 2.85–21.77, P<0.001). Patient sex, age, diabetes and BMI were not associated with TLR after DEB treatment.

Mortality

No patient died during the interventional procedure. The overall 30-day mortality was 0.8% (4/484 patients, cardiac/noncardiac death 0.6/0.2%). After a follow-up of 2.27±1.3 years (0–5.4 years), 42 patients had died (all-cause mortality 8.7%, 16 patients (3.3%) from cardiac causes and 26 patients (5.4%) from noncardiac causes). A total of 26/449 patients died within 12 months (all-cause mortality 5.8%, cardiac mortality 2.2%/noncardiac-mortality 3.6%) after the DEB intervention.

Long-term survival analysis using Kaplan-Meier estimates showed a survival rate of 94.6±1.0% at 1 year, 91.7±1.4% at 2 years and 90.1±1.6% at 3 years, respectively. Mortality did not differ between the ISR group and de novo lesion group (P=0.547 by log-rank test; Figure B).

In univariable analysis, coronary multivessel disease, older age and NSTEMI at the time of DEB intervention were significant risk factors of mortality (Table 5). However, only older age could be identified as an independent predictor for mortality by stepwise multivariable regression (P<0.001). There was no difference between DEB for ISR or de novo lesion in regard to mortality at long-term follow-up (P=0.539 by log-rank test).

Table 5. Risk Factors of Mortality in Univariate Logistic Regression Analysis

Variable	OR (95% CI)	P value
Age (years)	1.11 (1.06–1.15)	<0.001
ACS	2.11 (1.12–4.0)	0.021
NSTEMI	3.54 (1.78–7.03)	<0.001
1-vessel disease	0.28 (0.10–0.80)	0.017
3-vessel disease	2.84 (1.42–5.67)	0.003
BMI (kg/m2)	0.93 (0.86–1.00)	0.081
TLR	0.99 (0.34–2.92)	0.984

Abbreviations as in Tables 1,4.

Clinical Outcomes in Long-Term Follow-up

MACCE occurred in 13.6% (53 patients) at 12 months after DEB intervention. After a mean follow-up of 2.27±1.3 years, a total of 98 events occurred in 89 patients (18.4%; Table 6B). Kaplan-Meier estimates showed freedom from MACE at 1 year in 89.0±1.4%, at 2 years in 83.2±1.9% and at 3 years in 76.2±2.6%, respectively (Figure C). Again, there was no difference with regard to MACCE between DEB for ISR and de novo lesions (P=0.323 by log-rank test).

Table 6. (A) Predictors of MACCE in Univariate and Multivariate Logistic Regression Analyses, (B) Clinical Outcomes of Patients With ISR and De Novo Lesions at 12 Months and in Long-Term Follow-up

(A) Variable	Univariate		Stepwise multivariate
	OR (95% CI)	P value	OR (95% CI)	P value
Age (years)	1.06 (1.03–1.08)	<0.001	1.05 (1.02–1.07)	0.001
ISR in CABG	4.95 (1.99–12.29)	0.001	3.59 (1.40–9.25)	0.008
NSTEMI	1.82 (1.03–3.24)	0.040	–	–
1-vessel disease	0.31 (0.16–0.63)	0.001	0.41 (0.19–0.90)	0.026
3-vessel disease	1.73 (1.09–2.76)	0.020	–	–
Hospitalization	1.07 (1.03–1.11)	0.002	1.05 (1.01–1.10)	0.013
(B) Clinical event	ISR (n=408)		De novo lesion (n=76)
TLR (n=42)
At 12 months	24		0
At 2.27±1.3 years	42		0
All-cause mortality (n=42)
At 12 months	20		6
At 2.27±1.3 years	35		7
MI (n=10)
At 12 months	4		2
At 2.27±1.3 years	7		3
Stroke (n=4)
At 12 months	4		0
At 2.27±1.3 years	–		–

MACCE , major adverse cardiac and cerebrovascular events; MI, myocardial infarction. Other abbreviations as in Tables 1,2,4.

Univariable modeling revealed a significant association between age, NSTEMI at index hospitalization, coronary multivessel disease and ISR in CABG and the occurrence of MACCE. In addition, longer hospitalization was associated with a higher rate of MACCE. Stepwise multiple Cox regression analysis confirmed older age, coronary multivessel disease, increased hospital stay and ISR in CABG as independent predictors of MACCE (Table 6A).

Discussion

This single-center, all-comers, real-world registry at a tertiary care facility describes our clinical experience and outcomes in patients undergoing DEB intervention. To the best of our knowledge, this is 1 of the largest single-center studies to date to assess hard clinical outcomes after DEB intervention.

The following major findings emerged from this study: (1) DEB is safe and effective, with an acceptably low rate of TLR (8.7%) at long-term follow-up; (2) TLR occurred only in patients after DEB for ISR, but not in those with de novo lesions; ISR in CABG was an independent predictor of TLR and MACE; and (4) long-term survival rates are similar to clinical outcomes after PCI using DES.

Incidence of TLR

In previous trials investigating the incidence of TLR after DEB angioplasty,²³ the rate of TLR was 9.2% at 12 months (2.4% for BMS-ISR and 17.1% for DES-ISR). In our large, single-center study of 484 patients, the incidence of TLR was even lower at 4.9% at 12 months after DEB using the SeQuent Please paclitaxel-coated balloon. Our TLR rate is in line with the previously published SeQuent Please World Wide registry¹⁸ reporting a TLR rate of 5.2% after 9.4 months. In contrast to the results of the SeQuent Please Registry, the rate of TLR did not differ between BMS-ISR and DES-ISR in our study. This finding might be partially explained by the relatively small number of patients with TLR in the present registry, even though the rate of TLR after DEB for ISR in BMS was slightly lower compared with DEB for ISR in DES (8.9% vs. 13%). However, until now adequately powered trials evaluating in a randomized fashion the effect of DEB in patients with de novo lesions have not been published.

Moreover, PCI with deployment of stents in significant lesions in small coronary arteries is limited by a high rate of TLR. However, our results demonstrate a highly significant lower occurrence of TLR in patients undergoing DEB for de novo lesions compared with ISR (P=0.001), whereas analysis of the SeQuent Please World Wide Registry did not demonstrate a difference between these groups, despite very low TLR rates in patients with de novo lesions at 9 months (1% with additional BMS implantation, 2.4% without additional BMS implantation). Again, this finding might be related to the small number of patients analyzed in this study undergoing DEB for de novo lesions. In 2010, Unverdorben et al²³ reported the results of a non-randomized cohort of 118 patients undergoing PCI of small coronary vessels using a paclitaxel-coated balloon. The trial showed a TLR rate of 12% at 12 months after the DEB intervention. Interestingly, in a 3-year follow-up, the rate of TLR was comparably low, with 4.9% in patients with DEB only and 28.1% in patients with DEB plus additional BMS deployment.²⁴ However, even though clinical data with a high level of evidence are still lacking, those previous findings as well as our results clearly support a DEB-only strategy in patients undergoing coronary intervention for significant de novo lesions in small coronary arteries.

The current study identified ISR in a CABG as an independent predictor of TLR and MACCE in multivariable Cox regression analysis. There are 2 possible explanations for this finding; first, the difference might be partially caused by the limited number of patients with ISR in a CABG included in this registry; second, there might be a different pathomechanism of ISR in a CABG as compared with ISR in a native coronary artery (accumulation of cholesterol plaque instead of neointimal hyperplasia?). However, to date no representative data exist reporting the incidence of TLR in patients undergoing DEB for ISR in CABG. Therefore, clinical studies are needed to investigate the outcome of patients after DEB for ISR in CABG in a randomized fashion.

MACCE

The investigators of the recently published DELUX registry²⁵ report a MACCE rate (composite of all-cause mortality, nonfatal MI and clinically driven TLR) of 15.1% at 12 months (11.6% for BMS-ISR, 20.6% for DES-ISR and 9.4% for de novo lesions) after PCI using the Pantera Lux paclitaxel-coated balloon. In our registry, the incidence of MACCE at 12 months was even lower at 13.6%, despite harder endpoint definition by the additional inclusion of the occurrence of stroke. Previous studies demonstrated a higher MACCE rate in DES-ISR after DEB compared with BMS-ISR treated with DEB.^25,26 However, we were unable to confirm such an association in our present study. In contrast, coronary 3-vessel disease and ISR in CABG were independent predictors of MACCE in follow-up.

The PEPCAD-DES study reported a significantly reduced MACE rate at 6 months in patients treated with a paclitaxel-coated balloon compared with uncoated balloon angioplasty (16.7% vs. 50%, P<0.001).²⁷ In a previous study reporting long-term clinical outcomes after DES implantation, the rate of MACE (defined as cardiovascular death, death of unknown cause, MI, stent thrombosis, TLR) was 29.7% for the Yukon stent, and 31.6% for the Taxus stent at 5 years.²⁸ Furthermore, the Investigators of the Syntax trial confirmed a MACCE rate (defined as the composite of all-cause mortality, stroke, MI, repeat revascularization) of 18.8% at 12 months and 37.3% at 5 years after PCI in patients with 3-vessel or left main coronary artery disease.^29,30 A possible reason for the lower incidence of MACCE at 12 months, as well as up to 4 years, in our study might be the inclusion of a significant portion of patients with 1- and 2-vessel coronary disease.

Interestingly, additional stent implantation after DEB did not result in a higher rate of TLR or MACCE in our follow-up. In consequence, DEB treatment in ISR and of de novo lesions in small vessels can be considered safe with reasonable clinical outcomes that are comparable with those after DES implantation.

Study Limitations

The main limitation of the current study is its observational nature. Because of its registry design, a selection bias cannot be ruled out. However, because of its all-comers nature, this present registry reflects a real-world clinical setting of unselected consecutive patients and experienced yet unselected interventional cardiologists.

Conclusions

This large, single-center, real-world registry of DEB confirmed a low rate of TLR in long-term follow-up. Our data support the DEB in ISR as an effective and safe treatment option with reasonable mortality and MACCE rates. DEB interventions in small coronary vessels in our limited cohort appear to be a safe treatment option. Larger, randomized trials with a DEB-only strategy in small coronary vessels should be undertaken to verify the long-term results of the current trial.

Funding

No sources of funding.

Disclosures

None of the authors has a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Acknowledgments

We thank Mrs Maren Redlich for help with data documentation.

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