München, Germany
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Objectives This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. Background The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. Methods The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N = 1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n = 857) or durable polymer sirolimus-eluting stents (SES) (n = 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. Results At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, p for superiority = 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n = 5 [0.7%] vs. n = 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n = 3 of 749 vs. n = 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p = 0.005). Conclusions The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220) © 2013 by the American College of Cardiology Foundation.


Serruys P.W.,Erasmus Medical Center | Silber S.,Kardiologische Praxis und Praxisklinik | Garg S.,Erasmus Medical Center | Van Geuns R.J.,Erasmus Medical Center | And 21 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. METHODS: In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. RESULTS: At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P = 0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (±SD) of in-stent stenosis (21.65±14.42% for zotarolimus vs. 19.76±14.64% for everolimus, P = 0.04 for noninferiority). In-stent late lumen loss was 0.27±0.43 mm in the zotarolimus-stent group versus 0.19±0.40 mm in the everolimusstent group (P = 0.08). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. Copyright © 2010 Massachusetts Medical Society. All rights reserved.


Stefanini G.G.,University of Bern | Serruys P.W.,Erasmus Medical Center | Silber S.,Kardiologische Praxis und Praxisklinik | Khattab A.A.,University of Bern | And 18 more authors.
Journal of the American College of Cardiology | Year: 2011

Objectives: The aim of this study was to investigate the impact of patient and lesion complexity on outcomes with newer-generation zotarolimus-eluting stents (ZES) and everolimus-eluting stents (EES). Background: Clinical and angiographic outcomes of newer-generation stents have not been described among complex patients. Methods: Patients enrolled in the RESOLUTE All Comers trial (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) were stratified into "complex" and "simple." Results: Of 2,292 patients, 1,520 (66.3%) were complex and treated with ZES (n = 764) or EES (n = 756). Event rates were higher among complex patients, and results did not differ between ZES and EES, regardless of complexity. At 1 year, target lesion failure was 8.9% in ZES- and 9.7% in EES-treated complex patients (p = 0.66) and 6.8% in ZES- and 5.7% in EES-treated simple patients (p = 0.55). Rates of cardiac death (1.3% vs. 2.2%, p = 0.24), target-vessel myocardial infarction (4.3% vs. 4.4%, p = 0.90), and clinically indicated target lesion revascularization (4.4% vs. 4.0%, p = 0.80) were similar for both stent types among complex patients. Definite or probable stent thrombosis occurred in 20 (1.3%) complex patients with no difference between ZES (1.7%) and EES (0.9%, p = 0.26). Angiographic follow-up showed similar results for ZES and EES in terms of in-stent percentage diameter stenosis (22.2 ± 15.4% vs. 21.4 ± 15.8%, p = 0.67) and in-segment binary restenosis (6.6% vs. 8.0%, p = 0.82) in the complex group. Conclusions: In this all-comers randomized trial, major adverse cardiovascular events were more frequent among complex than simple patients. The newer-generation ZES and EES proved to be safe and effective, regardless of complexity, with similar clinical and angiographic outcomes for both stent types through 1 year. (RESOLUTE-III All Comers Trial: A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention; NCT00617084) © 2011 American College of Cardiology Foundation.


Stefanini G.G.,University of Bern | Kalesan B.,University of Bern | Serruys P.W.,Erasmus University Rotterdam | Heg D.,University of Bern | And 16 more authors.
The Lancet | Year: 2011

Background: The effectiveness of durable polymer drug-eluting stents comes at the expense of delayed arterial healing and subsequent late adverse events such as stent thrombosis (ST). We report the 4 year follow-up of an assessment of biodegradable polymer-based drug-eluting stents, which aim to improve safety by avoiding the persistent inflammatory stimulus of durable polymers. We did a multicentre, assessor-masked, non-inferiority trial. Between Nov 27, 2006, and May 18, 2007, patients aged 18 years or older with coronary artery disease were randomly allocated with a computer-generated sequence to receive either biodegradable polymer biolimus-eluting stents (BES) or durable polymer sirolimus-eluting stents (SES; 1:1 ratio). The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation (TVR); patients were followed-up for 4 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389220. 1707 patients with 2472 lesions were randomly allocated to receive either biodegradable polymer BES (857 patients, 1257 lesions) or durable polymer SES (850 patients, 1215 lesions). At 4 years, biodegradable polymer BES were non-inferior to durable polymer SES for the primary endpoint: 160 (18·7) patients versus 192 (22·6) patients (rate ratios [RR] 0·81, 95 CI 0·66-1·00, p for non-inferiority <0·0001, p for superiority=0·050). The RR of definite ST was 0·62 (0·35-1·08, p=0·09), which was largely attributable to a lower risk of very late definite ST between years 1 and 4 in the BES group than in the SES group (RR 0·20, 95 CI 0·06-0·67, p=0·004). Conversely, the RR of definite ST during the first year was 0·99 (0·51-1·95; p=0·98) and the test for interaction between RR of definite ST and time was positive (p interaction=0·017). We recorded an interaction with time for events associated with ST but not for other events. For primary endpoint events associated with ST, the RR was 0·86 (0·41-1·80) during the first year and 0·17 (0·04-0·78) during subsequent years (p interaction=0·049). Biodegradable polymer BES are non-inferior to durable polymer SES and, by reducing the risk of cardiac events associated with very late ST, might improve long-term clinical outcomes for up to 4 years compared with durable polymer SES. Biosensors Europe SA, Switzerland. © 2011 Elsevier Ltd.


Klauss V.,Ludwig Maximilians University of Munich | Serruys P.W.,Erasmus University Rotterdam | Pilgrim T.,University of Bern | Buszman P.,Medical University of Silesia, Katowice | And 13 more authors.
JACC: Cardiovascular Interventions | Year: 2011

Objectives: This study sought to investigate safety and efficacy of biolimus-eluting stents (BES) with biodegradable polymer as compared with sirolimus-eluting stents (SES) with durable polymer through 2 years of follow-up. Background: BES with a biodegradable polymer provide similar efficacy and safety as SES with a durable polymer at 9 months. Clinical outcomes beyond the period of biodegradation of the polymer used for drug release and after discontinuation of dual antiplatelet therapy are of particular interest. Methods: A total of 1,707 patients were randomized to unrestricted use of BES (n = 857) or SES (n = 850) in an all-comers patient population. Results: At 2 years, BES remained noninferior compared with SES for the primary endpoint, which was a composite of cardiac death, myocardial infarction, or clinically indicated target vessel revascularization (BES 12.8% vs. SES 15.2%, hazard ratio [HR]: 0.84, 95% confidence interval [CI]: 0.65 to 1.08, p noninferiority < 0.0001, p superiority = 0.18). Rates of cardiac death (3.2% vs. 3.9%, HR: 0.81, 95% CI: 0.49 to 1.35, p = 0.42), myocardial infarction (6.3% vs. 5.6%, HR: 1.12, 95% CI: 0.76 to 1.65, p = 0.56), and clinically indicated target vessel revascularization (7.5% vs. 8.6%, HR: 0.86, 95% CI: 0.62 to 1.20, p = 0.38) were similar for BES and SES. The rate of definite stent thrombosis through 2 years was 2.2% for BES and 2.5% for SES (p = 0.73). For the period between 1 and 2 years, event rates for definite stent thrombosis were 0.2% for BES and 0.5% for SES (p = 0.42). After discontinuation of dual antiplatelet therapy, no very late definite stent thrombosis occurred in the BES group. Conclusions: At 2 years of follow-up, the unrestricted use of BES with a biodegradable polymer maintained a similar safety and efficacy profile as SES with a durable polymer. (Limus Eluted From a Durable Versus Erodable Stent Coating [LEADERS]; NCT00389220) © 2011 American College of Cardiology Foundation.


Wykrzykowska J.J.,Erasmus Medical Center | Garg S.,Erasmus Medical Center | Girasis C.,Erasmus Medical Center | De Vries T.,Cardialysis B.V. | And 15 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: We aimed to assess the predictive value of the SYNTAX score (SXscore) for major adverse cardiac events in the all-comers population of the LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial. Background: The SXscore has been shown to be an effective predictor of clinical outcomes in patients with multivessel disease undergoing percutaneous coronary intervention. Methods: The SXscore was prospectively collected in 1,397 of the 1,707 patients enrolled in the LEADERS trial (patients after surgical revascularization were excluded). Post hoc analysis was performed by stratifying clinical outcomes at 1-year follow-up, according to 1 of 3 SXscore tertiles. Results: The 1,397 patients were divided into tertiles based on the SXscore in the following fashion: SXscore ≤8 (SXlow) (n = 464), SXscore >8 and ≤16 (SXmid) (n = 472), and SXscore >16 (SXhigh) (n = 461). At 1-year follow-up, there was a significantly lower number of patients with major cardiac event-free survival in the highest tertile of SXscore (SXlow = 92.2%, SXmid = 91.1%, and SXhigh = 84.6%; p < 0.001). Death occurred in 1.5% of SXlow patients, 2.1% of SXmid patients, and 5.6% of SXhigh patients (hazard ratio [HR]: 1.97, 95% confidence interval [CI]: 1.29 to 3.01; p = 0.002). The myocardial infarction rate tended to be higher in the SXhigh group. Target vessel revascularization was 11.3% in the SXhigh group compared with 6.3% and 7.8% in the SXlow and SXmid groups, respectively (HR: 1.38, 95% CI: 1.1 to 1.75; p = 0.006). Composite of cardiac death, myocardial infarction, and clinically indicated target vessel revascularization was 7.8%, 8.9%, and 15.4% in the SXlow, SXmid, and SXhigh groups, respectively (HR: 1.47, 95% CI: 1.19 to 1.81; p < 0.001). Conclusions: The SXscore, when applied to an all-comers patient population treated with drug-eluting stents, may allow prospective risk stratification of patients undergoing percutaneous coronary intervention. (LEADERS Trial Limus Eluted From A Durable Versus ERodable Stent Coating; NCT00389220). © 2010 American College of Cardiology Foundation.


Faerber G.,Friedrich - Schiller University of Jena | Schleger S.,Hospital Bogenhausen | Diab M.,Friedrich - Schiller University of Jena | Breuer M.,Friedrich - Schiller University of Jena | And 3 more authors.
Journal of Interventional Cardiology | Year: 2014

Transcatheter aortic valve implantation (TAVI) has become an established procedure for patients with aortic valve stenosis and significant comorbidities. One option offered by this technique is the implantation of a transcatheter valve inside a surgically implanted bioprosthesis. Many reports address the feasibility but also the pitfalls of these valve-in-valve (VIV) procedures. Review articles provide tables listing which valve sizes are appropriate based on the size of the initially implanted bioprosthesis. However, we previously argued that the hemodynamic performance of a prosthetic tissue valve is in large part a result of the dimensions of the bioprosthesis in relation to the patient's aortic outflow dimensions. Thus, the decision if a VIV TAVI procedure is likely to be associated with a favorable hemodynamic result cannot safely be made by looking at premade sizing tables that do not include patient dimensions and do not inquire about the primary cause for bioprosthetic valve stenosis. Prosthesis-patient mismatch (PPM) may therefore be more frequent than expected after conventional aortic valve replacement. Importantly, it may be masked by a potentially flawed method assessing its relevance. Such PPM may therefore impact significantly on hemodynamic outcome after VIV TAVI. Fifteen percent of currently published VIV procedures show only a minimal reduction of pressure gradients. We will address potential pitfalls in the current determination of PPM, outline the missing links for reliable determination of PPM, and present a simplified algorithm to guide decision making for VIV TAVI. (J Interven Cardiol 2014;27:287-292) © 2014, Wiley Periodicals, Inc.


Iwen K.A.,University of Lübeck | Wenzel E.T.,University of Lübeck | Ott V.,University of Lübeck | Perwitz N.,University of Lübeck | And 5 more authors.
Metabolism: Clinical and Experimental | Year: 2011

Adipose tissue function and sympathetic nervous system (SNS) activity are tightly interconnected. Adipose tissue is densely innervated by the SNS. Adipokines secreted by adipose tissue are implicated in maintaining energy homeostasis, the control of blood pressure, immune system function, hemostasis, and atherosclerosis. Little is known about a direct effect of SNS activation on influencing adipose tissue endocrine function in humans. In 10 lean, healthy male volunteers, SNS was activated by whole-body exposure to cold for 2 hours; a group of 10 subjects served as controls. Vital parameters were evaluated, plasma adipokine levels were measured, and adipokine gene expression in subcutaneous abdominal adipose tissue was determined. Cold exposure caused an increase in cold sensation and a drop in body temperature and heart rate. Norepinephrine, but not epinephrine, plasma levels were elevated. Adiponectin plasma concentrations were acutely and significantly decreased. There was a trend of increased monocyte chemoattractant protein-1 plasma concentrations. Interleukin-6 and leptin levels increased and decreased, respectively, in both groups. Vascular endothelial growth factor plasma levels were unaffected. Subcutaneous adipokine gene expression was unchanged. Cold exposure caused SNS activation and differentially influenced adipokine secretion. Adiponectin levels were acutely reduced, whereas monocyte chemoattractant protein-1 concentrations tended to increase. No specific changes in leptin and IL-6 concentrations were detectable. The observed alterations appeared to be posttranscriptional because adipokine gene expression was found to be unaltered. © 2011 Elsevier Inc. All rights reserved.


Juchem G.,Ludwig Maximilians University of Munich | Weiss D.R.,Friedrich - Alexander - University, Erlangen - Nuremberg | Gansera B.,Hospital Bogenhausen | Kemkes B.M.,Hospital Bogenhausen | And 2 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

The frequently observed deendothelialization of venous coronary bypass grafts prepared using standard methods exposes subendothelial prothrombotic cells to blood components, thus endangering patients by inducing acute thromboembolic infarction or long-term proliferative stenosis. Our aim was to gain deeper histological and physiological insight into these relations. An intricate network of subendothelial cells, characterized by histological features specific for true pericytes, was detected even in healthy vessels and forms, coupled to the luminal endothelium, a second leaflet of the macrovascular intima. These cells, and particularly those in the venous intima, express enormous concentrations of tissue factor and can recruit additional amounts of up to the 25-fold concentration within 1 h during preincubation with serum (intimal pericytes of venous origin activate 30.71 ± 4.07 pmol coagulation factor x·min-1·10-6 cells; n = 15). Moreover, decoupled from the endothelium, they proliferate rapidly (generation time, 15 ± 2.1 h, n = 8). Central regions of atherosclerotic plaques, as well as of those of restenosed areas of coronary vein grafts, consist almost completely of these cells. In stark contrast with the prothrombogenicity of the intimal pericytes, intact luminal endothelium recruits high concentrations of thrombomodulin (CD 141) specifically within its intercellular junctions, activates Protein C rapidly (42 ± 5.1 pmol/min·106 venous endothelial cells at thrombin saturation; n = 15), can thus actively prevent coagulatory processes, and never expresses histologically detectable and functionally active tissue factor. Given this strongly prothrombotic potential of the intimal pericytes and their overshooting growth behavior in endothelium-denuded vascular regions, they may play important roles in the development of atherosclerosis, thrombosis, and saphenous vein graft disease. Copyright © 2010 American Physiological Society.


PubMed | Ludwig Maximilians University of Munich, TU Munich, Barmherzige Bruder Hospital and Hospital Bogenhausen
Type: Journal Article | Journal: International archives of occupational and environmental health | Year: 2016

The aim of this pilot study was to evaluate surface contamination by platinum drugs in the environment of patients in ICUs and wards treated by hyperthermic intraperitoneal chemotherapy (HIPEC).The monitoring included 12 HIPEC treatments from four hospitals during the following 3days after perfusion. A total of 33 urine and 33 drainage fluids from HIPEC patients and 160 wipe samples from several surfaces (urine/drainage bags, floors, gloves) were taken during the study period.In urine, the highest platinum concentrations were measured on the first day after perfusion. Median platinum concentrations were 1260ng/ml for patients after cisplatin perfusion and 11,000ng/ml for oxaliplatin treatment. Concentrations decreased until day three to 413ng/ml cisplatin and 529ng/ml oxaliplatin, respectively. In drainage liquids, platinum concentrations were generally lower. Platinum concentrations from surfaces of bags and floors ranged from 0.01 to 439pg/cm(2) (median: urine bag 2.77pg/cm(2), drainage bag 0.22pg/cm(2), floor left 0.14pg/cm(2), floor right 0.24pg/cm(2)), with the highest contamination found on the outer surface of the urine bags. Samples from nurses protective gloves ranged between 0.03 and 12pg/cm(2) (median: 0.2pg/cm(2)).High platinum-drug concentrations in urine and drainage liquids are the main source of contamination. Therefore, safe handling of these liquids is the best way to avoid cross-contamination on surfaces in wards and ICUs. Our results show that it is possible to take care of HIPEC patients without high contaminations during the first 3days.

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