Martin G. Stoel

Functional recovery after acute myocardial infarction: comparison between angiography, electrocardiography, and cardiovascular magnetic resonance measures of microvascular injury.

OBJECTIVES We examined the relation between angiographic, electrocardiographic, and gadolinium-enhanced cardiovascular magnetic resonance (CMR) characteristics of microvascular obstruction (MVO), and their predictive value on functional recovery after acute myocardial infarction (AMI). BACKGROUND Microvascular obstruction on CMR has been shown to predict left ventricular (LV) remodeling, but it is not well known how it compares with commonly used criteria of microvascular injury, and earlier reports have produced conflicting results on the significance and extent of MVO. METHODS Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade (MBG), and ST-segment resolution were assessed in 60 patients with AMI treated with primary stenting. Cardiovascular magnetic resonance was performed between 2 and 9 days after revascularization to determine early MVO on first-pass perfusion imaging, late MVO on late gadolinium-enhanced imaging, and infarct size and transmural extent. Cine imaging was used to determine LV volumes and global and regional function at baseline and 4-month follow-up. RESULTS Early and late MVO were both related to incomplete ST-segment resolution (p = 0.002 and p = 0.01, respectively), but not to TIMI flow grade and MBG. Of all angiographic, electrocardiographic, and CMR variables, late MVO was the strongest parameter to predict changes in end-diastolic volume (beta = 0.53; p = 0.001), end-systolic volume (beta = 8.67; p = 0.001), and ejection fraction (beta = 3.94; p = 0.006) at follow-up. Regional analysis showed that late MVO had incremental diagnostic value to transmural extent of infarction (odds ratio: 0.18; p < 0.0001). CONCLUSIONS In patients after revascularized AMI, late MVO proved a more powerful predictor of global and regional functional recovery than all of the other characteristics, including transmural extent of infarction.

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.

High dose adenosine for suboptimal myocardial reperfusion after primary PCI: A randomized placebo-controlled pilot study

Objectives: This study was designed to investigate the influence of high dose intracoronary adenosine on persistent ST‐segment elevation after primary percutaneous coronary intervention (PCI). Background: After successful PCI for acute myocardial infarction 40–50% of patients show persistent ST‐segment elevation indicating suboptimal myocardial reperfusion. Adenosine has been studied to ameliorate reperfusion and is frequently used in a variety of doses, but there are no prospective studies to support its use for treatment of suboptimal reperfusion. Methods: We conducted a blinded, randomized, and placebo‐controlled study with high dose intracoronary adenosine in 51 patients with <70% ST‐segment resolution (STRes) after successful primary PCI. All patients were treated with stents and abciximab. Results: Immediately after adenosine, significantly more patients showed optimal (>70%) STRes compared with placebo (33% versus 9%, P < 0.05). Mean STRes was higher after adenosine (35.4% versus 23.0%, P < 0.05). In addition, TIMI frame count was significant lower (15.7 versus 30.2, P < 0.005), Myocardial Blush Grade was higher (2.7 versus 2.0, P < 0.05) and resistance index was lower in the adenosine group (0.70 versus 1.31 mm Hg per ml/min, P < 0.005). Conclusions: Intracoronary adenosine accelerates recovery of microvascular perfusion in case of persistent ST segment elevation after primary PCI.

Clinical Events and Patient-Reported Chest Pain in All-Comers Treated With Resolute Integrity and Promus Element Stents : 2-Year Follow-Up of the DUTCH PEERS (DUrable Polymer-Based STent CHallenge of Promus ElemEnt Versus ReSolute Integrity) Randomized Trial (TWENTE II)

OBJECTIVES This study assessed clinical events and patient-reported chest pain 2 years after treatment of all-comers with Resolute Integrity zotarolimus-eluting stents (Medtronic Vascular, Santa Rosa, California) and Promus Element everolimus-eluting stents (Boston Scientific, Natick, Massachusetts). BACKGROUND For both drug-eluting stents (DES), no all-comer outcome data from >12 months of follow-up have been published. Although there is increasing interest in patient-reported chest pain following stenting, data with novel DES are scarce. METHODS The DUTCH PEERS multicenter trial (TWENTE II) (DUrable Polymer-Based STent CHallenge of Promus ElemEnt Versus ReSolute Integrity) Randomized Trial [TWENTE II]) randomized 1,811 all-comer patients to treatment with 1 type of DES. Monitoring and event adjudication were performed by independent contract research organizations. RESULTS The 2-year follow-up of 1,810 patients (99.9%) was available. The primary composite endpoint target vessel failure occurred in 8.6% and 7.8% of patients treated with zotarolimus- and everolimus-eluting stents, respectively (p = 0.55). Rates of components of target vessel failure were: cardiac death (2.4% vs. 1.9%, p = 0.42); target vessel-related myocardial infarction (2.4% vs. 1.8%, p = 0.33); clinically-indicated target vessel revascularization (4.6% vs. 4.9%, p = 0.83). At 1- and 2-year follow-up, >80% of patients were free from chest pain (no between-stent difference). In addition, >87% of patients were either free from chest pain or experienced pain only at maximal physical exertion, but not during normal daily activities. Patients with chest pain after 12 months at no more than moderate physical effort had a higher risk of target vessel revascularization during the following year (hazard ratio: 1.89 [95% confidence interval: 1.05 to 3.39], p = 0.03). CONCLUSIONS During the second year of follow-up, the incidence of adverse clinical endpoints remained similar and low for both DES. The vast majority of patients were free from chest pain.

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.

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.)

Impact of severe lesion calcification on clinical outcome of patients with stable angina, treated with newer generation permanent polymer-coated drug-eluting stents: A patient-level pooled analysis from TWENTE and DUTCH PEERS (TWENTE II)

BACKGROUND The outcome of percutaneous coronary intervention with newer generation permanent polymer-coated drug-eluting stents (DES) in patients with severely calcified lesions is greatly unknown. We assessed the impact of severe lesion calcification on clinical outcome in patients with stable angina who underwent percutaneous coronary intervention with newer generation DES. METHODS TWENTE and DUTCH PEERS randomized trials enrolled 1423 patients with stable angina, who were categorized into patients with versus without severe target lesion calcification. A patient-level pooled analysis assessed clinical outcome, including target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization (TVR). RESULTS Patients with severe calcification (n = 342) were older (66.6 ± 9.1 vs 64.2 ± 9.8 years, P < .001) and had more diabetes (25.7% vs 20.4%, P = .04) than other patients (n = 1081). Patients with calcified lesions had higher rates of TVF (16.4% vs 9.8%, pLogrank = .001), cardiac death (4.4% vs 1.5%, P = .03), target vessel myocardial infarction (7.6% vs 3.4%, P = .001), and definite stent thrombosis (1.8% vs 0.4%, P = .02). Multivariate analysis demonstrated that severe calcification was an independent risk factor of 2-year TVF (HR 1.42, 95% CI: 1.02-1.99, pLogrank = .04); landmark analysis showed that this was based on a difference during the first year (periprocedural: 5.8% vs. 3.1%, pLogrank = .02; first year: 7.5% vs. 3.8%, pLogrank = .007; second year: 4.1% vs. 3.3%, pLogrank = .54). CONCLUSION In patients with stable angina, severe target lesion calcification is associated with an increased risk of adverse cardiovascular events following treatment with newer generation permanent polymer-coated DES. This increase in risk is restricted to the first year of follow-up, which is an encouraging finding.