Abstract
Objectives
To evaluate the impact of diabetes on the efficacy of drug-eluting balloon (DEB) as compared to paclitaxel-eluting stent (PES) for the reduction of restenosis in small vessels according to the presence of diabetes in patients enrolled in the BELLO (Balloon Elution and Late Loss Optimization) trial.
Background
Small vessel disease is common in diabetic patients but currently there are no available data regarding DEB in these patients.
Methods
In the BELLO trial, 182 patients with lesions in small vessels were randomized 1:1 to receive DEB or PES. In the current sub analysis, patients were stratified according to the presence of diabetes. The diabetic group consisted of 74 patients (DEB = 39, PES = 35) and the nondiabetic group of 108 patients (DEB = 51, PES = 57). Angiographic endpoints examined were in-stent/in-balloon and in-segment late loss and binary restenosis at 6 months. Clinical endpoints were major adverse cardiac events (MACE; death, myocardial infarction, target vessel revascularization) at 1 year.
Results
In-stent/in-balloon late loss was significantly less with DEB as compared to PES in both diabetic (0.05 ± 0.41 vs. 0.30 ± 0.51 mm, p = 0.033) and nondiabetic patients (0.10 ± 0.36 vs. 0.29 ± 0.40 mm, p = 0.015). In patients with diabetes, angiographic restenosis and in-segment late loss were significantly lower with DEB as compared to PES (respectively, 6.3% vs. 25.0%; p = 0.039 and −0.013 ± 0.39 vs. 0.25 ± 0.53; p = 0.023), with no differences noted in nondiabetic patients. The cumulative MACE rate at 1 year was similar between DEB and PES in both the diabetic (13.2% vs. 25%, p = 0.194) and nondiabetic groups (11.8% vs. 14.3%, p = 0.699).
Conclusions
Diabetes does not appear to have a negative impact on the efficacy of DEB in small vessels, which were associated with better angiographic outcomes at 6 months in this complex subgroup. Larger studies are needed to confirm these findings.
Highlights
- •
We evaluated the impact of diabetes on the efficacy of drug-eluting balloon (DEB) as compared to paclitaxel-eluting stent (PES) for the reduction of restenosis in small vessels according to the presence of diabetes in patients enrolled in the BELLO (Balloon Elution and Late Loss Optimization) trial.
- •
The diabetic group consisted of 74 patients (DEB = 39, PES = 35) and the nondiabetic group of 108 patients (DEB = 51, PES = 57).
- •
In patients with diabetes, angiographic restenosis and in-segment late loss was significantly lower with DEB as compared to PES (respectively, 6.3% vs. 25.0%; p = 0.039 and −0.013 ± 0.39 vs. 0.25 ± 0.53; p = 0.023), with no differences noted in nondiabetic patients. No difference in MACE were observed.
- •
Diabetes does not appear to have a negative impact on the efficacy of DEB in small vessels, which were associated with better angiographic outcomes at 6 months in this complex subgroup. Larger studies are needed to confirm these findings.
1
Introduction
Patients with diabetes mellitus have worse clinical outcomes after percutaneous coronary intervention (PCI) as compared with their nondiabetic counterparts . This has been ascribed to the smaller caliber of treated vessels, greater degree of underlying vascular inflammation, a pro-thrombotic milieu, and a greater incidence of associated cardiovascular risk factors such as chronic renal failure . Greater plaque burden and neointimal proliferation also contribute to a higher risk of restenosis after coronary stent deployment . Although drug-eluting stents (DES) reduce angiographic and clinical restenosis as compared to bare-metal stents (BMS) , the presence of diabetes remains a significant predictor of adverse outcomes . Drug-eluting balloons (DEB) can deliver antiproliferative agents to the vessel wall without the need for implantation and can thus offer a valuable treatment alternative in this patient cohort. There are no data currently available comparing DEB to DES in diabetic patients with small coronary vessel disease. We thus sought to investigate the efficacy of DEB as compared to paclitaxel-eluting stent (PES) in reducing angiographic restenosis in the diabetic and nondiabetic patients enrolled in the BELLO (Balloon Elution and Late Loss Optimization) trial .
2
Methods
The BELLO (Balloon Elution and Late Loss Optimization) trial was an investigator-initiated, prospective, multicenter, single-blinded, active-treatment controlled clinical trial in which 182 patients undergoing percutaneous revascularization of small coronary vessels (reference vessel diameter [RVD] <2.8 mm by visual estimation) were randomly assigned in a 1:1 ratio to treatment with: 1) IN.PACT Falcon paclitaxel DEB (Medtronic, Inc., Santa Rosa, California) dilation and provisional BMS; or 2) PES (Taxus Libertè, Boston Scientific, Boston, Massachusetts) implantation as per standard practice. A detailed study protocol was provided in the main publication .
Briefly, In the DEB arm, pre-dilation with a standard balloon was recommended in all lesions. The diameter and length of the DEB were selected with a balloon:artery ratio of 1:1 and 2.5 to 5 mm (per edge) longer, respectively, than the target lesion. DEB were inflated only once for 30 to 60 s at an inflation pressure approximately or slightly beyond nominal to achieve complete apposition of the balloon on the vessel wall, while trying to avoid edge dissection. Bailout provisional stenting with BMS was permitted in the DEB arm only in cases of a suboptimal result, defined as a persistent residual stenosis refractory to optimal balloon dilation or in cases of flow-limiting dissection. In cases of stenting, the protocol recommended using the shortest stent length to fully cover the residual stenosis or seal the dissection and recommended that the stent be deployed entirely within the area treated with DEB to avoid geographic miss. In the PES arm, stent implantation was performed as per standard practice and post-dilation per operator’s discretion.
The protocol recommended that patients receive aspirin indefinitely and daily clopidogrel (or ticlopidine, if required) for a minimum of: 1) 30 days in case of treatment with only DEB; 2) 3 months in case of provisional BMS after DEB; and 3) 12 months after DES implantation. Protocol-specified angiographic follow-up was scheduled at 6 months after the procedure for all patients unless necessary at an earlier time for clinical reasons.
2.1
Quantitative coronary angiographic measurements
Coronary angiograms were analyzed offline using a validated edge detection system (CMS, version 5.2, Medis Medical Imaging Systems BV, Leiden, the Netherlands) by an expert operator at an independent core laboratory (Mediolanum Cardio Research, Milan, Italy). Minimal lumen diameter (MLD), RVD, and percent diameter stenosis were measured at baseline, post-procedure, and follow-up. All angiographic parameters were calculated both in-stent and in segment (stent and 5 mm proximal and distal). Late lumen loss was defined as the difference between the MLD immediately after the procedure and at 6-month follow-up. Net lumen gain was defined as the difference between the MLD at follow-up and at baseline. Binary angiographic restenosis was defined as diameter stenosis >50% by quantitative coronary angiography within a previously stented segment (stent and 5 mm proximal and distal) at the follow-up angiogram. The pattern of restenosis at follow-up was categorized according to the Mehran classification .
2.2
Study endpoints and definitions
Angiographic endpoints examined were in-stent/in-balloon and in-segment late loss and binary restenosis at 6 months. Clinical endpoints were major adverse cardiac events (MACE; death, myocardial infarction, target vessel revascularization) at 1 year. Other endpoints included target lesion revascularization (TLR), binary restenosis, device success, and procedural success. TVR was defined as any repeat revascularization of the target vessel, and TLR was defined as any repeat revascularization within the stented or DEB-treated segment. Periprocedural MI was defined as an elevation of cardiac biomarkers (troponin or creatine kinase-myocardial band) >3 times the upper limit of normal. Nonprocedural acute MI was defined as an elevation of troponin above the upper range limit in combination with at least one of the following: ischemic symptoms, ECG changes indicative of new ischemia, development of new pathological Q waves on ECG, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality . Stent thrombosis was classified according to the Academic Research Consortium definition . Patients were recognized as having DM if they had a previous diagnosis of DM at admission with chronic use of oral hypoglycemic agents and/or any extended-release insulin or diet therapy .
2.3
Statistical analysis
Categorical data are reported as counts and percentage, and were compared using chi-square test. Continuous parameters are reported as mean ± standard deviation and were compared using Student’s t test. Selected baseline characteristics, angiographic data and clinical outcomes were compared between treatment groups and between the presence or absence of diabetes mellitus. Results were considered significant for p values ≤0.05. All analyses were performed using SPSS version 19.0.
2
Methods
The BELLO (Balloon Elution and Late Loss Optimization) trial was an investigator-initiated, prospective, multicenter, single-blinded, active-treatment controlled clinical trial in which 182 patients undergoing percutaneous revascularization of small coronary vessels (reference vessel diameter [RVD] <2.8 mm by visual estimation) were randomly assigned in a 1:1 ratio to treatment with: 1) IN.PACT Falcon paclitaxel DEB (Medtronic, Inc., Santa Rosa, California) dilation and provisional BMS; or 2) PES (Taxus Libertè, Boston Scientific, Boston, Massachusetts) implantation as per standard practice. A detailed study protocol was provided in the main publication .
Briefly, In the DEB arm, pre-dilation with a standard balloon was recommended in all lesions. The diameter and length of the DEB were selected with a balloon:artery ratio of 1:1 and 2.5 to 5 mm (per edge) longer, respectively, than the target lesion. DEB were inflated only once for 30 to 60 s at an inflation pressure approximately or slightly beyond nominal to achieve complete apposition of the balloon on the vessel wall, while trying to avoid edge dissection. Bailout provisional stenting with BMS was permitted in the DEB arm only in cases of a suboptimal result, defined as a persistent residual stenosis refractory to optimal balloon dilation or in cases of flow-limiting dissection. In cases of stenting, the protocol recommended using the shortest stent length to fully cover the residual stenosis or seal the dissection and recommended that the stent be deployed entirely within the area treated with DEB to avoid geographic miss. In the PES arm, stent implantation was performed as per standard practice and post-dilation per operator’s discretion.
The protocol recommended that patients receive aspirin indefinitely and daily clopidogrel (or ticlopidine, if required) for a minimum of: 1) 30 days in case of treatment with only DEB; 2) 3 months in case of provisional BMS after DEB; and 3) 12 months after DES implantation. Protocol-specified angiographic follow-up was scheduled at 6 months after the procedure for all patients unless necessary at an earlier time for clinical reasons.
2.1
Quantitative coronary angiographic measurements
Coronary angiograms were analyzed offline using a validated edge detection system (CMS, version 5.2, Medis Medical Imaging Systems BV, Leiden, the Netherlands) by an expert operator at an independent core laboratory (Mediolanum Cardio Research, Milan, Italy). Minimal lumen diameter (MLD), RVD, and percent diameter stenosis were measured at baseline, post-procedure, and follow-up. All angiographic parameters were calculated both in-stent and in segment (stent and 5 mm proximal and distal). Late lumen loss was defined as the difference between the MLD immediately after the procedure and at 6-month follow-up. Net lumen gain was defined as the difference between the MLD at follow-up and at baseline. Binary angiographic restenosis was defined as diameter stenosis >50% by quantitative coronary angiography within a previously stented segment (stent and 5 mm proximal and distal) at the follow-up angiogram. The pattern of restenosis at follow-up was categorized according to the Mehran classification .
2.2
Study endpoints and definitions
Angiographic endpoints examined were in-stent/in-balloon and in-segment late loss and binary restenosis at 6 months. Clinical endpoints were major adverse cardiac events (MACE; death, myocardial infarction, target vessel revascularization) at 1 year. Other endpoints included target lesion revascularization (TLR), binary restenosis, device success, and procedural success. TVR was defined as any repeat revascularization of the target vessel, and TLR was defined as any repeat revascularization within the stented or DEB-treated segment. Periprocedural MI was defined as an elevation of cardiac biomarkers (troponin or creatine kinase-myocardial band) >3 times the upper limit of normal. Nonprocedural acute MI was defined as an elevation of troponin above the upper range limit in combination with at least one of the following: ischemic symptoms, ECG changes indicative of new ischemia, development of new pathological Q waves on ECG, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality . Stent thrombosis was classified according to the Academic Research Consortium definition . Patients were recognized as having DM if they had a previous diagnosis of DM at admission with chronic use of oral hypoglycemic agents and/or any extended-release insulin or diet therapy .
2.3
Statistical analysis
Categorical data are reported as counts and percentage, and were compared using chi-square test. Continuous parameters are reported as mean ± standard deviation and were compared using Student’s t test. Selected baseline characteristics, angiographic data and clinical outcomes were compared between treatment groups and between the presence or absence of diabetes mellitus. Results were considered significant for p values ≤0.05. All analyses were performed using SPSS version 19.0.
3
Results
3.1
Baseline and procedural characteristics
A total of 182 patients were enrolled in the BELLO trial. Seventy-four (40.7%) had a diagnosis of diabetes mellitus whereas 108 (59.3%) had no documented history of the disease. In the diabetic cohort, 39 patients were treated with DEB (42 lesions) and 35 with PES (37 lesions). In patients without diabetes, 51 (52 lesions) were treated with DEB and 57 with PES (60 lesions). Although, baseline patient and procedural characteristics were broadly similar between the different groups some small differences were noted between the diabetic and nondiabetic patients ( Table 1 ). More specifically, patients with diabetes were more frequently treated for hypertension (87.8% vs. 75.7%; p = 0.042) and had less family history of coronary artery disease (14.9% vs. 32.8; p = 0.007). Importantly, however, there were no significant differences in the baseline characteristics of patients who were treated with DEB or PES irrespective of the presence of diabetes. Procedural characteristics are shown in Table 2 . Predilation was performed almost routinely in the DEB group, whereas direct stenting was performed in 17.2% of the lesions in the PES group. Bailout BMS was required in 20.2% of lesions, with stent implantation being within the DEB treated zone in all cases. With regards to baseline angiographic characteristics ( Table 3 ) these were similar between the different groups apart from the fact that slightly smaller vessels were treated with DEB as compared to PES especially in the nondiabetic patients (nondiabetic cohort; 2.15 ± 0.29 mm vs. 2.26 ± 0.25 mm, p = 0.026, diabetic cohort; 2.15 ± 0.24 mm vs. 2.24 ± 0.20, p = 0.069).
| Diabetic patients | Nondiabetic patients | ||||||
|---|---|---|---|---|---|---|---|
| DEB | PES | p | DEB | PES | p | p values diabetes vs nondiabetes | |
| Patients | 39 | 35 | 51 | 57 | |||
| Age, y | 66 ± 8 | 70 ± 8 | 0.072 | 64 ± 8 | 64 ± 9 | 0.726 | |
| Men | 32 (84.2) | 28 (77.8) | 0.480 | 39 (76.5) | 43 (76.8) | 0.969 | 0.475 |
| Insulin-treated diabetes | 16 (42.1) | 9 (25.0) | 0.120 | – | – | – | |
| Hypertension | 31 (81.6) | 34 (94.4) | 0.091 | 40 (78.4) | 41 (73.2) | 0.530 | 0.042 |
| Dyslipidemia | 30 (78.9) | 28 (77.8) | 0.903 | 40 (78.4) | 45 (80.4) | 0.806 | 0.863 |
| Previous or current smokers | 14 (36.8) | 17 (47.2) | 0.366 | 24 (47.1) | 27 (48.2) | 0.905 | 0.443 |
| Previous MI | 18 (47.4) | 11 (30.6) | 0.257 | 28 (55) | 22 (39) | 0.394 | 0.425 |
| Previous PCI | 25 (65.8) | 19 (41.7) | 0.031 | 27 (52.9) | 24 (42.9) | 0.297 | 0.398 |
| Previous CABG | 4 (10.5) | 4 (16.7) | 0.440 | 5 (9.8) | 6 (10.7) | 0.877 | 0.504 |
| Familyhistory of CAD | 6 (15.8) | 5 (13.9) | 0.818 | 17 (33.3) | 18 (32.1) | 0.896 | 0.007 |
| Unstable angina | 10 (26.3) | 8 (22.2) | 0.682 | 12 (23.5) | 12 (21.4) | 0.795 | 0.767 |
| Multivesseldisease | 23 (60.5) | 22 (62.9) | 0.8384 | 32 (62.7) | 34 (60.7) | 0.829 | 0.996 |
| Lesions | 42 | 37 | 52 | 60 | |||
| Target vessel | |||||||
| Left anteriordiscending | 5 (11.9) | 5 (13.9) | 0.794 | 5 (9.6) | 8 (12.1) | 0.666 | 0.504 |
| Diagonal | 6 (14.3) | 3 (8.3) | 0.416 | 10 (19.2) | 6 (9.1) | 0.110 | 0.419 |
| Left circumflex | 6 (14.3) | 6 (16.7) | 0.771 | 4 (7.7) | 12 (18.2) | 0.098 | 0.683 |
| Obtuse marginal/ramus | 11 (26.2) | 11 (30.6) | 0.669 | 14 (26.9) | 19 (28.8) | 0.823 | 0.742 |
| Right coronary artery | 4 (9.5) | 2 (5.6) | 0.512 | 4 (7.7) | 6 (9.1) | 0.787 | 0.535 |
| PDA/PL | 10 (23.8) | 9 (25.0) | 0.903 | 15 (28.8) | 15 (22.7) | 0.449 | 0.889 |
| Target lesion | |||||||
| Reference vessel diameter, mm ⁎ | 2.4 ± 0.4 | 2.5 ± 0.2 | 0.091 | 2.4 ± 0.3 | 2.4 ± 0.5 | 0.2991 | 0.866 |
| Lesion length, mm ⁎ | 15.3 ± 7 | 13.9 ± 5 | 0.338 | 15.5 ± 6 | 14.7 ± 6 | 0.427 | 0.647 |
| Diameterstenosis, % ⁎ | 83 ± 10 | 84 ± 8 | 0.537 | 81 ± 9 | 83 ± 9 | 0.427 | 0.252 |
| AHA type B2/C lesion | 25 (59.5) | 14 (38.9) | 0.147 | 21 (40.4) | 33 (50.0) | 0.426 | 0.925 |
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