Abstract
Background
Drug-eluting stents with biodegradable polymer might be particularly useful in diabetic patients who are at increased risk for target lesion/target vessel revascularization. We therefore aimed at assessing the safety and performance of a biodegradable polymer sirolimus-eluting stent (BP-SES) in combination with comprehensive optimal medical therapy following coronary interventions.
Methods
This prospective, multicenter registry was conducted at six centers in Israel. Aside of stent treatment, we aimed for an LDL-C level < 70 mg/dl; at one and six months post-intervention a diabetic consultancy was required, and follow-up data were collected at six and twelve months. The primary outcome measure was target vessel failure, a composite of cardiac death, target-vessel myocardial infarction and clinically driven target vessel revascularization. Secondary outcomes were target lesion failure, its individual components, and stent thrombosis.
Results
From August 2013 until May 2014, 120 diabetic patients with 158 lesions were treated with a BP-SES. Mean age was 63.9 ± 9.2 years, 27.5% were insulin dependent, 28.3% had a history of myocardial infarction, and 47.5% had prior coronary interventions. By visual estimation, lesions were 3.0 ± 0.5 mm in diameter and 15.2 ± 7.4 mm long; mean stent diameter and length were 3.0 ± 0.5 mm and 19.2 ± 6.8 mm. Target vessel failure and target lesion failure at 12 months occurred in seven (6.4% [95% CI: 3.1–13.0]) and four patients (3.5% [95% CI: 1.3–9.2]), respectively, and definite stent thrombosis in one patient (1.0% [95% CI: 0.1–7.0]).
Conclusion
Treatment with a BP-SES demonstrated excellent target-vessel and target-lesion revascularization rates in a high-risk diabetic patient population undergoing catheter-based revascularization followed by intensified medical care.
Annotated table of contents
In 120 high-risk diabetic patients with coronary artery stenosis, treatment with the Orsiro sirolimus-eluting stent with biodegradable polymer and comprehensive antidiabetic therapy resulted in excellent clinical outcomes. Target vessel revascularization occurred in 6.4% of patients and target lesion revascularization in 3.5%.
1
Introduction
The development of drug-eluting stents (DES) significantly reduced the rate of restenosis compared to bare-metal stents, but suboptimal polymer compatibility, local drug toxicity, delayed stent endothelialization and associated very late stent thrombosis remain an area of concern . Hybrid DESs with biodegradable polymers are one of the novel technologies which were developed to address these concerns. They provide temporary drug exposure with subsequent degradation of the polymer, leaving a bare-metal stent in the vessel. Randomized controlled trials comparing biodegradable polymer DES with permanent polymer DES have indicated superiority in regard to stent thrombosis at long-term follow-up . Therefore, biodegradable polymer DES might be particularly useful in diabetic patients who are at increased risk for target lesion/target vessel revascularization (TLR/TVR) and stent thrombosis .
Further, comprehensive antidiabetic therapy has shown to reduce the risk of cardiovascular events . Nevertheless, despite a high compliance with guideline-guided medical therapy, diabetic patients still show higher rates of target lesion failure compared to non-diabetics .
The BIOFLOW-III Satellite was designed to follow a “holistic approach” with comprehensive medical therapy to treat diabetes via diabetic consult performed by endocrinologist and high dose statins to reduce low-density lipoprotein-cholesterol (LDL-C) to ≤70 mg/dl in addition to coronary stenting with the Orsiro biodegradable polymer sirolimus-eluting stent (BP-SES). This stent uses poly- l -lactidic acid (PLLA) as biodegradable polymer from which sirolimus is eluted. It has proven to be non-inferior to contemporary everolimus-eluting stents at one year in randomized trials and to be safe and effective in all-comer populations .
2
Materials and methods
2.1
Study design and patient population
The BIOFLOW-III Diabetic Satellite is a prospective, national, multicenter registry that evaluates the safety and performance of the Orsiro BP-SES in combination with comprehensive diabetic care in patients requiring coronary revascularization. Patients were eligible, if they had diabetes mellitus type 1 or 2 and one of the following criteria: (a) stable angina CCS class ≥II and evidence of myocardial ischemia, (b) silent ischemia and a large (e.g., >10%) myocardial territory at risk, (c) unstable angina, and (d) non-ST-elevation myocardial infarction (NSTEMI). Main exclusion criteria were: left main disease, complex bifurcations, thrombus, Syntax score ≥ 33, chronic total occlusion or ST elevation acute myocardial infarction (STEMI). The protocol did not restrict vessel size. A full list of inclusion and exclusion criteria is available at ClinicalTrials.gov , NCT01895712 .
At six sites in Israel, 120 patients were enrolled. The procedure was performed according to standard of care at the study centers. The diabetic therapy targeted an LDL-C value ≤70 mg/dl as recommended by the European Society of Cardiology (ESC) guidelines . Dual antiplatelet therapy (DAPT) was recommended for 12 months post-procedure in patients with acute coronary syndrome (ACS) and for a minimum of six months in elective percutaneous coronary interventions (PCI). Data were collected at baseline/intervention, and at 6- and 12-month follow-up. At one and six months, a diabetic consultancy to optimize diabetic control was required and the patients were seen by endocrinologists specialized in diabetes care. Furthermore, hemoglobin A1c (HbA1c), fasting glucose and LDL were assessed.
The registry was conducted according to the Declaration of Helsinki and ISO14155:2011 and approved by the regional ethical review board affiliated with each participating center. All patients provided informed consent. To ensure data quality, the first two patients at each study site and every eights patient thereafter were fully source document verified, furthermore all patient informed consent forms and all serious adverse events were reviewed. A clinical events physician adjudicated all adverse device effects, serious adverse events and serious adverse device effects. No core laboratory was used and lesion parameters are based on visual estimates.
2.2
Study device
The Orsiro stent (Biotronik AG, Bülach, Switzerland) has been previously described . In brief, it consists of a balloon expandable stent pre-mounted on a rapid exchange delivery system. The underlying bare metal stent is the PRO-Kinetic Energy stent, which is made of cobalt chromium and is completely covered by a thin layer of amorphous silicon carbide. The polymer compound used as a carrier material for supply and release of sirolimus is poly- l -lactic acid (PLLA), which is highly biocompatible. The absorption process occurs via hydrolysis, producing lactic acid which degrades via the Krebs cycle .
2.3
Study outcomes
The primary outcome measure was target vessel failure (TVF), a composite of cardiac death, target-vessel myocardial infarction, and clinically driven TVR at 12 months. Secondary outcomes were target lesion failure (TLF), a composite of cardiac death, target-vessel myocardial infarction, and clinically driven TLR, its individual components, all-cause mortality, and definite/probable stent thrombosis. Cardiac death, TVR, TLR and stent thrombosis were defined according to the Academic Research Consortium (ARC) criteria , and myocardial infarction was defined according to the ESC/ACC/AHA/WHF task force universal definition and on the basis of the 2010 ARC extended historical definition . Device success was defined as successful delivery and deployment of the investigational stent at the intended target lesions and successful withdrawal of the stent delivery system with attainment of a final residual stenosis <30% by visual estimate. Procedure success was defined as device success without the occurrence of any major adverse cardiac event during the hospital stay.
2.4
Statistical analysis
Statistical analyses were performed based on available data. Data are presented using descriptive statistical methods. Numerical variables are presented as the mean ± standard deviation. Categorical variables are presented as absolute and relative frequencies. When appropriate, 95% confidence intervals were calculated. Survival estimates were calculated using Kaplan–Meier method and for comparison between subgroups the log-rank test was used. All statistical analyses were carried out using SAS 9.3 (SAS Institute Inc. Cary, NC, USA).
2
Materials and methods
2.1
Study design and patient population
The BIOFLOW-III Diabetic Satellite is a prospective, national, multicenter registry that evaluates the safety and performance of the Orsiro BP-SES in combination with comprehensive diabetic care in patients requiring coronary revascularization. Patients were eligible, if they had diabetes mellitus type 1 or 2 and one of the following criteria: (a) stable angina CCS class ≥II and evidence of myocardial ischemia, (b) silent ischemia and a large (e.g., >10%) myocardial territory at risk, (c) unstable angina, and (d) non-ST-elevation myocardial infarction (NSTEMI). Main exclusion criteria were: left main disease, complex bifurcations, thrombus, Syntax score ≥ 33, chronic total occlusion or ST elevation acute myocardial infarction (STEMI). The protocol did not restrict vessel size. A full list of inclusion and exclusion criteria is available at ClinicalTrials.gov , NCT01895712 .
At six sites in Israel, 120 patients were enrolled. The procedure was performed according to standard of care at the study centers. The diabetic therapy targeted an LDL-C value ≤70 mg/dl as recommended by the European Society of Cardiology (ESC) guidelines . Dual antiplatelet therapy (DAPT) was recommended for 12 months post-procedure in patients with acute coronary syndrome (ACS) and for a minimum of six months in elective percutaneous coronary interventions (PCI). Data were collected at baseline/intervention, and at 6- and 12-month follow-up. At one and six months, a diabetic consultancy to optimize diabetic control was required and the patients were seen by endocrinologists specialized in diabetes care. Furthermore, hemoglobin A1c (HbA1c), fasting glucose and LDL were assessed.
The registry was conducted according to the Declaration of Helsinki and ISO14155:2011 and approved by the regional ethical review board affiliated with each participating center. All patients provided informed consent. To ensure data quality, the first two patients at each study site and every eights patient thereafter were fully source document verified, furthermore all patient informed consent forms and all serious adverse events were reviewed. A clinical events physician adjudicated all adverse device effects, serious adverse events and serious adverse device effects. No core laboratory was used and lesion parameters are based on visual estimates.
2.2
Study device
The Orsiro stent (Biotronik AG, Bülach, Switzerland) has been previously described . In brief, it consists of a balloon expandable stent pre-mounted on a rapid exchange delivery system. The underlying bare metal stent is the PRO-Kinetic Energy stent, which is made of cobalt chromium and is completely covered by a thin layer of amorphous silicon carbide. The polymer compound used as a carrier material for supply and release of sirolimus is poly- l -lactic acid (PLLA), which is highly biocompatible. The absorption process occurs via hydrolysis, producing lactic acid which degrades via the Krebs cycle .
2.3
Study outcomes
The primary outcome measure was target vessel failure (TVF), a composite of cardiac death, target-vessel myocardial infarction, and clinically driven TVR at 12 months. Secondary outcomes were target lesion failure (TLF), a composite of cardiac death, target-vessel myocardial infarction, and clinically driven TLR, its individual components, all-cause mortality, and definite/probable stent thrombosis. Cardiac death, TVR, TLR and stent thrombosis were defined according to the Academic Research Consortium (ARC) criteria , and myocardial infarction was defined according to the ESC/ACC/AHA/WHF task force universal definition and on the basis of the 2010 ARC extended historical definition . Device success was defined as successful delivery and deployment of the investigational stent at the intended target lesions and successful withdrawal of the stent delivery system with attainment of a final residual stenosis <30% by visual estimate. Procedure success was defined as device success without the occurrence of any major adverse cardiac event during the hospital stay.
2.4
Statistical analysis
Statistical analyses were performed based on available data. Data are presented using descriptive statistical methods. Numerical variables are presented as the mean ± standard deviation. Categorical variables are presented as absolute and relative frequencies. When appropriate, 95% confidence intervals were calculated. Survival estimates were calculated using Kaplan–Meier method and for comparison between subgroups the log-rank test was used. All statistical analyses were carried out using SAS 9.3 (SAS Institute Inc. Cary, NC, USA).
3
Results
From August 2013 until May 2014, 120 consecutive diabetic patients with 158 lesions were enrolled at 6 sites in Israel ( Fig. 1 ). One quarter of patients were insulin-dependent ( n = 33, 27.5%), had a history of myocardial infarction ( n = 42, 28.3%), or had more than one lesion per subject ( n = 35, 29.2%) ( Table 1 ). Lesions had a reference vessel diameter from 2.0 to 4.0 mm with an average 3.0 ± 0.5 mm and were 15.2 ± 7.4 mm long. A thrombus was present in 6.3% of the lesions, and 19% were moderate or severely calcified ( Table 2 ).
| n = 120 | |
|---|---|
| Age [years] | 63.9 ± 9.2 |
| Male | 100 (83.3) |
| Hypertension | 98 (81.7) |
| Hypercholesteremia | 112 (93.3) |
| Smoker | 75 (62.5) |
| Thereof current smoker | 29 (38.7) |
| Diabetes mellitus | |
| Insulin dependent | 33 (27.5) |
| Non-insulin dependent | 87 (72.5) |
| Renal disease | 5 (4.2) |
| Hepatic disease | 5 (4.2) |
| History of MI | 34 (28.3) |
| Congestive heart failure | 4 (3.3) |
| History of stroke or TIA | 7 (5.8) |
| Cancer | 13 (10.8) |
| Previous coronary interv. | 57 (47.5) |
| Thereof more than one | 25 (43.9) |
| Lesions per subject | |
| 1 | 85 (70.8) |
| 2 | 32 (26.7) |
| 3 | 3 (2.5) |
| 4 | 0 (0.0) |
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