Hans W. Louwerenburg

Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction

Background—ENTIRE-TIMI 23 evaluated enoxaparin with full-dose tenecteplase (TNK) and half-dose TNK plus abciximab. Methods and Results—Patients (n=483) with ST-elevation MI presenting <6 hours from symptom onset were randomized to full-dose TNK and either unfractionated heparin (UFH) (bolus 60 U/kg; infusion 12 U/kg per hour) or enoxaparin (1.0 mg/kg subcutaneously every 12 hours±initial 30 mg intravenous bolus), or half-dose TNK plus abciximab and either UFH (bolus 40 U/kg; infusion 7 U/kg per hour) or enoxaparin (0.3 to 0.75 mg/kg subcutaneously every 12 hours±initial intravenous bolus of 30 mg). With full-dose TNK and UFH, the rate of TIMI 3 flow at 60 minutes was 52% and was 48% to 51% with enoxaparin. Using combination therapy, the rate of TIMI 3 flow was 48% with UFH and 47% to 58% with enoxaparin. The rate of TIMI 3 flow among all UFH patients was 50% and was 51% among enoxaparin patients. Through 30 days, death/recurrent MI occurred in the full-dose TNK group in 15.9% of patients with UFH and 4.4% with enoxaparin (P =0.005). In the combination therapy group, the rates were 6.5% with UFH and 5.5% with enoxaparin. The rate of major hemorrhage with full-dose TNK was 2.4% with UFH and 1.9% with enoxaparin; with combination therapy, it was 5.2% using UFH and 8.5% with enoxaparin. Conclusions—Enoxaparin is associated with similar TIMI 3 flow rates as UFH at an early time point while exhibiting advantages over UFH with respect to ischemic events through 30 days. These findings with enoxaparin are achieved with a similar risk of major hemorrhage.

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.

Dose escalation trial of the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST elevation MI: Results of the TIMI 31 trial

Background: Currently available fibrinolytic agents are limited by their ability to restore normal blood flow in only half of patients, the risk of reocclusion, and the risk of intracranial hemorrhage. The genetically engineered agent BB-10153 is activated by thrombin, not plasminogen activator enzymes, which limits its activity to the site of thrombus which may in turn reduce the risk of systemic bleeding. BB-10153 also has a relatively long half-life of 3–4 hours, which may also limit the potential for early reocclusion [1, 2].Methods: The study was a phase II, open-label, multi-center, dose escalation, single-dose administration study to determine the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of BB-10153 in ST segment elevation MI (STEMI). STEMI patients (n = 50) received a single dose of BB-10153 at one of six dose levels (1.0, 2.0, 3.0, 5.0, 7.5 and 10 mg/kg). The primary endpoint was TIMI flow grade (TFG) 3 at 60 minutes following the intravenous bolus of BB-10153.Results: Mean area under the curve for drug concentration ranged from 48.0 μg⋅h/mL in the 1 mg/kg dose group to 788.6 μg⋅h/mL in the 10 mg/kg dose group. Likewise, mean Cmax generally increased with dose over the entire dose range, from 4.9 μg/mL in the 1 mg/kg dose group to 139.6 μg/mL in the 10 mg/kg dose group. The mean apparent terminal half-life (t1/2) was 4.4 hours (range 2.2 to 7.6 hours). Few patients in the 1–3 mg/kg dosage groups achieved TFG 3 on the one-hour post-dose angiogram (4/20, 20%), and no patients achieved complete ST segment resolution. The 5, 7.5 and 10 mg/kg doses were associated with similar rates of TIMI grade 3 flow of approximately three per seven patients. Pooling TFG 3 data from the 5, 7.5 and 10 mg/kg groups yielded a TIMI grade 3 flow rate of 34% (n = 10/29; range 29–43%). No patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study. One patient experienced recurrent angina and developed recurrent myocardial ischemia requiring urgent revascularization. Three patients sustained TIMI major bleeding events (one in 1 mg/kg group, two in 7.5 mg/kg group), six patients sustained TIMI minor bleeds (one in the 2, 3, 7.5 and 10 mg/kg groups, two in the 5 mg/kg group), twp patients sustained TIMI minimal bleeds (one in each of the 2 and 10 mg/kg groups) and no patients sustained intracranial hemorrhage (ICH).Conclusion: In a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29–43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.Condensed abstractIn a dose escalation study of a single intravenous bolus, the novel fibrinolytic agent, BB-10153 was associated with a rise in the mean area under the curve and Cmax for drug concentration over the dose range 1 to 10 mg/kg. Higher doses were associated with a range of TIMI grade 3 flow of 29–43%, and no patients experienced 30-day death, recurrent acute MI, cardiogenic shock, stroke or anaphylaxis during the study.

Impact of previous coronary artery bypass surgery on clinical outcome after percutaneous interventions with second generation drug-eluting stents in TWENTE trial and Non-Enrolled TWENTE registry

BACKGROUND Patients with previous coronary artery bypass grafting (CABG) who underwent percutaneous coronary intervention (PCI) have an increased repeat revascularization rate, but data on contemporary second-generation drug-eluting stents (DES) are scarce. METHODS We evaluated 1-year clinical outcome following secondary revascularization by PCI in patients of the TWENTE trial and non-enrolled TWENTE registry, and compared patients with previous CABG versus patients without previous CABG. RESULTS Of all 1709 consecutive patients, 202 (11.8%) had previously undergone CABG (on average 11.2±8.5 years ago). CABG patients were older (68.5±9.4 years vs. 64.1±10.7 years, P<0.001) and more often had diabetes (28.7% vs. 20.9%, P=0.01) and previous PCI (40.1% vs. 19.8%, P<0.001) compared to patients without previous CABG. Nevertheless, a higher target vessel revascularization (TVR) rate following PCI in the CABG patients (9.4% vs. 2.3%, P<0.001) was the only significant difference in clinical outcome at 1-year follow-up (available for 99.6%). Among CABG patients, the TVR rate was significantly higher in patients treated for graft lesions (n=65; 95.4% in vein grafts) than in patients treated for native coronary lesions only (n=137) (18.5% vs. 5.1%, P=0.002). Among 1638 patients with PCI of native coronary lesions only, there was only a non-significant difference in TVR between patients with previous CABG versus patients without previous CABG (5.1% vs. 2.3%, P=0.08). CONCLUSIONS Patients with previous CABG showed a favorable safety profile after PCI with second-generation DES. Nevertheless, their TVR rate was still much higher, driven by more repeat revascularizations after PCI of degenerated vein grafts. In native coronary lesions, there was no such difference.

thrombus aspiration in a series of patients with stable or unstable angina pectoris and lesion-site thrombus formation

Background. In acute myocardial infarction, thrombus aspiration prior to percutaneous coronary interventions (PCI) is often beneficial, but this approach has never been studied in patients without acute myocardial infarction. The aim of this retrospective study is to shed light on that topic based on our initial experience with manual thrombus aspiration in patients with stable or unstable angina pectoris and angiographic evidence of lesion-site thrombus. Methods. We assessed the feasibility (thrombus aspiration without predilatation) of this approach; in addition, we determined angiographic coronary flow and myocardial blush grade. Results. During 33 months in which a total of 4725 PCI were performed in our centre, manual thrombus aspiration was attempted in 14 patients with stable or unstable angina pectoris with angiographic evidence of thrombus. In nine of these 14 patients, the aspiration catheter could be advanced into the lesion without predilatation; in eight patients visible thrombus was obtained. The corrected TIMI frame count improved during the entire interventional procedure (21.1±11.2 vs. 12.8±5.9 frames; p=0.015). Myocardial blush grade, which overall improved during PCI (p<0.001), tended to show greater improvement in patients in whom thrombus aspiration could be achieved (1.6±0.9 vs. 0.7±0.5; p=0.06). Conclusions. Preliminary evidence suggests that manual thrombus aspiration may occasionally be considered in selected patients without acute myocardial infarction but with angiographic evidence of lesion-site thrombus. Nevertheless, prospective studies are required to clearly define the role of this approach in clinical practice. (Neth Heart J 2010;18:423-9.)