Mounir W.Z. Basalus

Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial

BACKGROUND Third-generation, permanent-polymer-based drug-eluting stents with novel, flexible designs might be more easily delivered than previous generations of stents in complex coronary lesions, but might be less longitudinally stable. We aimed to assess the safety and efficacy in all-comer patients of two third-generation stents that are often used clinically, but that have not yet been compared, and one of which has not previously been assessed in a randomised trial. METHODS In this investigator-initiated, single-blind, multicentre, randomised, two-arm, non-inferiority trial, patients aged 18 years and older who required a percutaneous coronary intervention with implantation of a drug-eluting stent were recruited from four study sites in the Netherlands. We randomly assigned patients by independently managed computer-generated allocation sequences in a 1:1 ratio to receive either cobalt-chromium-based zotarolimus-eluting stents (Resolute Integrity, Medtronic, Santa Rosa, CA, USA) or platinum-chromium-based everolimus-eluting stents (Promus Element, Boston Scientific, Natick, MA, USA). Patients and analysts were masked to the allocated stent, but treating clinicians were not. The primary endpoint of target-vessel failure was a composite of safety (cardiac death or target-vessel-related myocardial infarction) and efficacy (target-vessel revascularisation) at 12 months, analysed by intention to treat (with a non-inferiority margin of 3·6%). This trial is registered with ClinicalTrials.gov, number NCT01331707. FINDINGS Between Nov 25, 2010, and May 24, 2012, 1811 eligible all-comer patients, with 2371 target lesions, were enrolled in the study. 370 (20%) patients presented with ST-elevation myocardial infarction and 447 (25%) with non-ST-elevation myocardial infarction. 906 patients were assigned to receive zotarolimus-eluting stents and 905 to receive everolimus-eluting stents. Ease of stent delivery was shown by very low numbers of patients requiring treatment other than their assigned study treatment (six [1%] in the zotarolimus-eluting stent group vs five [1%] in the everolimus-eluting stent group; p=0·22). 12-month follow-up results were available for 1810 patients (one patient in the zotarolimus-eluting stent group withdrew consent). The primary endpoint was met by 55 (6%) of 905 patients in the zotarolimus-eluting stent group and 47 (5%) of 905 in the everolimus-eluting stent group. The zotarolimus-eluting stent was non-inferior to the everolimus-eluting stent (absolute risk difference 0·88%, 95% CI -1·24% to 3·01%; upper limit of one-sided 95% CI 2·69%; non-inferiority p=0·006). We noted no significant between-group differences in individual components of the primary endpoint. Definite stent thrombosis occurred in three (0·3%) patients in the zotarolimus-eluting stent group and six (0·7%) patients in the everolimus-eluting stent group (p=0·34). Longitudinal stent deformation was seen only in the everolimus-eluting stent group (nine [1·0%] of 905 vs 0 of 906, p=0·002; nine of 1591 [0·6%] everolimus-eluting stents implanted became deformed), but was not associated with any adverse events. INTERPRETATION Both stents were similarly efficacious and safe, and provided excellent clinical outcomes, especially in view of the large number of patients who presented with acute myocardial infarctions. FUNDING Boston Scientific, Medtronic.

Scanning electron microscopic assessment of the biodegradable coating on expanded biolimus-eluting stents

AIMS Biodegradable coatings on drug-eluting stents (DES) may help to avoid adverse long-term effects of DES such as late/very late stent thrombosis which is partly attributed to durable polymers. As the post-expansion morphology of biodegradable coatings is greatly unknown, we investigated the polylactic acid coating on biolimus-eluting BioMatrix stents. METHODS AND RESULTS Scanning electron microscopy (SEM) was used to carefully examine five 3.5mm stents following expansion at 6-14atm (maximum 7% overstretch). SEM examination demonstrated only mild cracks of the coating after stent expansion at 6 atm. An increase in expansion pressure, associated with mild stent overstretch, resulted in more severe cracks. Lifting of the coating together with few sites of partial detachment of fragments was noticed after stent expansion in water at 14atm; these irregularities further increased after aggressive oversized partial postdilatation with a 5.0mm non-compliant balloon with additional secondary cracks. CONCLUSIONS SEM assessment suggests a relatively low elasticity of the biodegradable coating on BioMatrix stents. At nominal pressure, stents showed predominantly mild cracks of the coating, while cracks increased after slight overstretch. Aggressive overexpansion of the stent, such as sometimes required in left main bifurcation stenting, worsened cracks and led to some detachment of fragments of the coating in vitro.

DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity (DUTCH PEERS): Rationale and study design of a randomized multicenter trial in a Dutch all-comers population

BACKGROUND Drug-eluting stents (DES) are increasingly used for the treatment of coronary artery disease. An optimized DES performance is desirable to successfully treat various challenging coronary lesions in a broad population of patients. In response to this demand, third-generation DES with an improved deliverability were developed. Promus Element (Boston Scientific, Natick, MA) and Resolute Integrity (Medtronic Vascular, Santa Rosa, CA) are 2 novel third-generation DES for which limited clinical data are available. Accordingly, we designed the current multicenter study to investigate in an all-comers population whether the clinical outcome is similar after stenting with Promus Element versus Resolute Integrity. METHODS DUTCH PEERS is a multicenter, prospective, single-blinded, randomized trial in a Dutch all-comers population. Patients with all clinical syndromes who require percutaneous coronary interventions with DES implantation are eligible. In these patients, the type of DES implanted will be randomized in a 1:1 ratio between Resolute Integrity versus Promus Element. The trial is powered based on a noninferiority hypothesis. For each stent arm, 894 patients will be enrolled, resulting in a total study population of 1,788 patients. The primary end point is the incidence of target vessel failure at 1-year follow-up. SUMMARY DUTCH PEERS is the first randomized multicenter trial with a head-to-head comparison of Promus Element and Resolute Integrity to investigate the safety and efficacy of these third-generation DES.

Scanning electron microscopic assessment of coating irregularities and their precursors in unexpanded durable polymer-based drug-eluting stents

Objectives: To assess and quantify coating irregularities on unexpanded and expanded durable polymer‐based drug‐eluting stents (DES) to gain insights into the origin of coating irregularities. Background: Previous scanning electron microscopy (SEM) studies in various expanded DES revealed differences in frequency and size of coating irregularities between DES types and specific distribution patterns, however, the origin of these irregularities is unclear. Methods: We assessed at bench side a total of 1,200 SEM images obtained in 30 DES samples (15 expanded and 15 unexpanded) of Cypher Select Plus, Taxus Liberté, Endeavor, Xience V, and resolute. Results: For most coating irregularities seen on expanded DES (72%; 23/32), a matching irregularity (n = 18/23) and/or its precursor (n = 11/23) was observed in unexpanded DES. Unexpanded Cypher select showed (small) crater lesions and cracks together with precursors of “peeling.” On unexpanded Taxus Liberté, thinning of polymer, small bare metal areas, wrinkles, and one precursor type were found. Unexpanded endeavor showed cracks, small bare metal areas, crater lesions, and precursors of the latter. Unexpanded Xience V and resolute mainly revealed crater lesions and their precursors. On unexpanded versus expanded DES, there was no difference in measured frequency of coating irregularities and precursors (P = ns) with the exception of more bare metal areas on expanded Taxus Liberte (P = 0.01). Conclusions: Most coating irregularities, or the potential to develop them, are inherent to the unexpanded DES. Important determinants of the formation of coating irregularities may be the stent geometry and the physical properties of the coating, while stent‐balloon interaction plays no major role.

Polymer coatings on drug-eluting stents: Samson’s hair and Achilles’ heel?

Drug-eluting stents (DES) minimise the risk of in-stent restenosis by means of controlled, local delivery of antiproliferative drugs from a thin layer of coating applied to a rigid stent backbone. In this respect, polymer coatings have proven largely indispensable for the control of drug release kinetics and the optimisation of DES efficacy. Investigation of polymer-free stent platforms has typically yielded comparatively lower levels of neointimal suppression by virtue of rapid drug dissociation in the initial hours and days after stent implantation 1 . Indeed, all of the currently available FDA-approved DES devices control drug release by use of durable polymer coatings 2,3

Comparison of Frequency of Periprocedural Myocardial Infarction in Patients With and Without Diabetes Mellitus to Those With Previously Unknown but Elevated Glycated Hemoglobin Levels (from the TWENTE Trial)

In patients without a history of diabetes mellitus, increased levels of glycated hemoglobin (HbA1c) are associated with higher cardiovascular risk. The relation between undetected diabetes and clinical outcome after percutaneous coronary intervention is unknown. To investigate whether these patients may have an increased risk of periprocedural myocardial infarction (PMI), the most frequent adverse event after percutaneous coronary intervention, we assessed patients of the TWENTE trial (a randomized, controlled, second-generation drug-eluting stent trial) in whom HbA1c data were available. Patients were classified as known diabetics or patients without a history of diabetes who were subdivided into undetected diabetics (HbA1c ≥6.5%) and nondiabetics (HbA1c <6.5%). Systematic measurement of cardiac biomarkers and electrocardiographic assessment were performed. One-year clinical outcome was also compared. Of 626 patients, 44 (7%) were undetected diabetics, 181 (29%) were known diabetics, and 401 (64%) were nondiabetics. In undetected diabetics the PMI rate was higher than in nondiabetics (13.6% vs 3.7%, p = 0.01) and known diabetics (13.6% vs 6.1%, p = 0.11). Multivariate analysis adjusting for covariates confirmed a significantly higher PMI risk in undetected diabetics compared to nondiabetics (odds ratio 6.13, 95% confidence interval 2.07 to 18.13, p = 0.001) and known diabetics (odds ratio 3.73, 95% confidence interval 1.17 to 11.89, p = 0.03). After 1 year, target vessel MI rate was significantly higher in undetected diabetics (p = 0.02) than in nondiabetics, which was related mainly to differences in PMI. Target vessel failure was numerically larger in unknown diabetics than in nondiabetics, but this difference did not reach statistical significance (13.6% vs 8.0%, p = 0.25). In conclusion, undetected diabetics were shown to have an increased risk of PMI.

Five-year outcome after implantation of zotarolimus- and everolimus-eluting stents in randomized trial participants and nonenrolled eligible patients : A secondary analysis of a randomized clinical trial

Importance Long-term follow-up after a clinical trial of 2 often-used, newer-generation drug-eluting stents (DESs) in a broad patient population is of interest. Comprehensive long-term outcome of eligible nonenrolled patients has never been reported. Objective To assess 5-year safety and efficacy of 2 newer-generation DESs in randomized participants with non–ST-elevation acute coronary syndromes or stable angina and to evaluate long-term outcomes of nonenrolled eligible patients treated with the same DESs. Design, Setting, and Participants The TWENTE (Real-World Endeavor Resolute vs Xience V Drug-Eluting Stent Study in Twente) trial is an investigator-initiated, patient-blinded, randomized, comparative DES trial that enrolled patients from June 18, 2008, to August 26, 2010. Most patients had non–ST-elevation acute coronary syndromes and complex lesions. Of all 1709 eligible patients, 1391 (81.4%) were treated in the TWENTE trial with zotarolimus-eluting (ZES, n = 697) or everolimus-eluting (EES, n = 694) cobalt-chromium stents. The remaining 318 eligible patients (18.6%) were not enrolled but underwent nonrandomized treatment with the same DESs. Data were analyzed from August 26, 2015, to October 11, 2016. Event rates (percentages) were derived from log-rank analysis and may differ from straightforward calculation (nominator/denominator). The 5-year follow-up of the TWENTE participants was prespecified in the trial protocol; that of the nonenrolled participants was ad hoc. Main Outcomes and Measures Target vessel failure (TVF), a composite of cardiac death, target vessel–related myocardial infarction, or target vessel revascularization. Results Of 1709 eligible participants, 1233 (72.1%) were men, 476 (27.9%) were women, and mean (SD) age was 64.6 (10.6) years. Among the 1370 of 1391 TWENTE trial participants (98.5% follow-up), TVF was similar between those in the ZES (16.1%) and EES (18.1%) groups (P = .36). Stent thrombosis rates were low: definite (7 of 697 [1.0%] vs 4 of 694 [0.6%]; P = .37) and occurred after more than 1 year in 3 (0.4%) with ZES vs 4 (0.6%) with EES (P = .69). The 318 nonenrolled eligible patients (308 patients [96.9%] of whom were followed up) were older and had more advanced disease than trial participants. Their TVF rate was higher than that of trial participants (71 of 318 [23.3%] vs 233 of 1391 [17.1%]; P = .02), which partly reflects a difference in cardiac mortality (23 of 318 [7.7%] vs 60 of 1391 [4.5%]; P = .03). Similar 5-year rates were found for myocardial infarction (91 of 1391 [6.7%] vs 22 of 318 [7.2%]; P = .80) and target vessel revascularization (129 of 1391 [9.7%] vs 34 of 318 [11.4%]; P = .36) between trial participants and nonenrolled eligible patients. In all eligible patients (ie, trial participants plus nonenrolled eligible patients), the TVF rate was only slightly higher than in trial participants only (18.3% vs 17.1%). Conclusions and Relevance Long-term outcome data from nonenrolled eligible patients support the validity of the TWENTE trial findings and present, with the trial, a strong case for the long-term safety and efficacy of the newer-generation DESs used. Trial Registration clinicaltrials.gov Identifier: NCT01066650

Incidence of periprocedural myocardial infarction following stent implantation: Comparison between first- and second-generation drug-eluting stents

Background: First‐ and second‐generation drug‐eluting stents (DES) differ in coating materials, which may influence the incidence of periprocedural myocardial infarction (PMI). Objective: To compare the incidence of PMI between first‐ and second‐generation DES, using the current Academic Research Consortium (ARC) definition of PMI. Methods: We assessed 800 patients treated with first‐ (Taxus Liberté or Endeavor) or second‐generation DES (Xience V or Resolute). Each DES group consisted of 200 consecutive patients, who were treated during the transition from first‐ to second‐generation DES. Routine peri‐interventional assessment of cardiac biomarkers was performed to compare the incidence of PMI between DES groups according to the updated definition by the ARC: 2x upper reference limit of creatine kinase (CK), confirmed by CK‐MB elevation. Results: In 800 patients, a total of 1,522 DES (363 Taxus; 385 Endeavor; 382 Xience V; 392 Resolute) were implanted to treat 1,232 lesions. Patient characteristics did not differ between groups. In patients receiving second‐generation DES, more multivessel percutaneous coronary interventions were performed (P = 0.01). The overall incidence of PMI was 4.75%. Between first‐ and second‐generation DES, there was no significant difference in PMI (5.5% vs. 4.0%; P = 0.29). In a multivariate analysis, only the total number of stents implanted (P < 0.001) and presentation with acute coronary syndrome (P = 0.02) were independent predictors of PMI. Conclusion: Using the revised ARC definition, we found no significant difference in PMI between first‐ and second‐generation DES. Overall, PMI occurred in 4.75%, which is 58% lower than with use of the historical PMI definition.

TWENTE Study: The Real-World Endeavor Resolute Versus Xience V Drug-Eluting Stent Study in Twente: study design, rationale and objectives

Background. New-generation drug-eluting stents (DES) may solve several problems encountered with first-generation DES, but there is a lack of prospective head-to-head comparisons between new-generation DES. In addition, the outcome of regulatory trials may not perfectly reflect the outcome in ‘real world’ patients.Objectives. To compare the efficacy and safety of two new-generation DES in a ‘real world’ patient population.Methods. A prospective, randomised, single-blinded clinical trial to evaluate clinical outcome after Endeavor Resolute vs. Xience V stent implantation. The primary endpoint is target vessel failure at one-year follow-up. In addition, the study comprises a two-year and an open-label five-year follow-up. (Neth Heart J 2010;18:360-4.)

Clinical outcome of patients with implantation of second‐generation drug‐eluting stents in the right coronary ostium: Insights from 2‐year follow‐up of the TWENTE trial

The aim of the present study was to assess the impact on clinical outcome of right coronary artery (RCA) ostial coverage with second‐generation drug‐eluting stents (DES).