Jochen Wöhrle

ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting

BACKGROUND In patients receiving aspirin, the optimal duration of clopidogrel therapy after drug-eluting stent (DES) implantation remains unclear. METHODS This multicentre, randomized, double-blind, placebo-controlled trial tested the hypothesis that in patients undergoing DES implantation, 6 months of clopidogrel is non-inferior to 12 months in terms of clinical outcomes. At 6 months after DES implantation, patients on clopidogrel were randomly assigned to either a 6-month period of placebo or an additional 6-month period of clopidogrel. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, and thrombolysis in myocardial infarction major bleeding at 9 months after randomization. RESULTS Owing to slow recruitment and low event rates, the trial was stopped prematurely after enrolment of 4005 of 6000 planned patients. Of 4000 patients included in the final analysis, 1997 received 6 months of clopidogrel and 2003 received 12 months. The primary endpoint occurred in 29 patients (1.5%) assigned to 6 months of clopidogrel and 32 patients (1.6%) assigned to 12 months, observed difference -0.1%, upper limit of one-sided 95% confidence interval (CI) 0.5%, limit of non-inferiority 2%, Pfor noninferiority <0.001. Stent thrombosis was observed in five patients (0.3%) assigned to 6 months of clopidogrel and three patients (0.2%) assigned to 12 months; hazard ratio (HR) 1.66, 95% CI: 0.40-6.96, P = 0.49. Thrombolysis in myocardial infarction major bleeding was observed in 4 patients (0.2%) assigned to 6 months clopidogrel and 5 patients (0.3%) assigned to 12 months; HR 0.80, 95% CI: 0.21-2.98, P = 0.74. CONCLUSIONS In the present trial, characterized by low event rates, we did not observe a significant difference in net clinical outcome between 6 and 12 months of clopidogrel therapy after DES implantation. However, the results of the trial must be considered in view of its premature termination and lower than expected event rates. The trial is registered with ClinicalTrials.gov, Identifier: NCT00661206.

A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drug-eluting stent restenosis: the PEPCAD-DES study.

OBJECTIVES This study sought to define the impact of paclitaxel-coated balloon angioplasty for treatment of drug-eluting stent restenosis compared with uncoated balloon angioplasty alone. BACKGROUND Drug-coated balloon angioplasty is associated with favorable results for treatment of bare-metal stent restenosis. METHODS In this prospective, single-blind, multicenter, randomized trial, the authors randomly assigned 110 patients with drug-eluting stent restenoses located in a native coronary artery to paclitaxel-coated balloon angioplasty or uncoated balloon angioplasty. Dual antiplatelet therapy was prescribed for 6 months. Angiographic follow-up was scheduled at 6 months. The primary endpoint was late lumen loss. The secondary clinical endpoint was a composite of cardiac death, myocardial infarction attributed to the target vessel, or target lesion revascularization. RESULTS There was no difference in patient baseline characteristics or procedural results. Angiographic follow-up rate was 91%. Treatment with paclitaxel-coated balloon was superior to balloon angioplasty alone with a late loss of 0.43 ± 0.61 mm versus 1.03 ± 0.77 mm (p < 0.001), respectively. Restenosis rate was significantly reduced from 58.1% to 17.2% (p < 0.001), and the composite clinical endpoint was significantly reduced from 50.0% to 16.7% (p < 0.001), respectively. CONCLUSIONS Paclitaxel-coated balloon angioplasty is superior to balloon angioplasty alone for treatment of drug-eluting stent restenosis. (PEPCAD DES-Treatment of DES-In-Stent Restenosis With SeQuent® Please Paclitaxel Eluting PTCA Catheter [PEPCAD-DES]; NCT00998439).

Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial.

BACKGROUND Intracoronary administration of an abciximab bolus during a primary percutaneous coronary intervention results in a high local drug concentration, improved perfusion, and reduction of infarct size compared with intravenous bolus application. However, the safety and efficacy of intracoronary versus standard intravenous bolus application in patients with ST-elevation myocardial infarction (STEMI) undergoing this intervention has not been tested in a large-scale clinical trial. METHODS The AIDA STEMI trial was a randomised, open-label, multicentre trial. Patients presenting with STEMI in the previous 12 h with no contraindications for abciximab were randomly assigned in a 1:1 ratio by a central web-based randomisation system to intracoronary versus intravenous abciximab bolus (0·25 mg/kg bodyweight) during percutaneous coronary intervention with a subsequent 12 h intravenous infusion 0·125 μg/kg per min (maximum 10 μg/min). The primary endpoint was a composite of all-cause mortality, recurrent infarction, or new congestive heart failure within 90 days of randomisation. Secondary endpoints were the time to occurrence of the primary endpoint, each individual component of that endpoint, early ST-segment resolution, thrombolysis in myocardial infarction (TIMI) flow grade, and enzymatic infarct size. A masked central committee adjudicated the primary outcome and its components. Treatment allocation was not concealed from patients and investigators. This trial is registered with ClinicalTrials.gov, NCT00712101. FINDINGS Between July, 2008, and April, 2011, 2065 patients were randomly assigned intracoronary abciximab (n=1032) or intravenous abciximab (n=1033). Intracoronary, as compared with intravenous abciximab, resulted in a similar rate of the primary composite clinical endpoint at 90 days in 1876 analysable patients (7·0%vs 7·6%; odds ratio [OR] 0·91; 95% CI 0·64-1·28; p=0·58). The incidence of death (4·5%vs 3·6%; 1·24; 0·78-1·97; p=0·36) and reinfarction (1·8%vs 1·8%; 1·0; 0·51-1·96; p=0·99) did not differ between the treatment groups, whereas less patients in the intracoronary group had new congestive heart failure (2·4%vs 4·1%; 0·57; 0·33-0·97; p=0·04). None of the secondary endpoints or safety measures differed significantly between groups. INTERPRETATION In patients with STEMI undergoing primary percutaneous coronary intervention, intracoronary as compared to intravenous abciximab did not result in a difference in the combined endpoint of death, reinfarction, or congestive heart failure. Since intracoronary abciximab bolus administration is safe and might be related to reduced rates of congestive heart failure the intracoronary route might be preferred if abciximab is indicated. FUNDING Lilly, Germany. University of Leipzig-Heart Centre. University of Leipzig, Clinical Trial Centre Leipzig, supported by the Federal Ministry of Education and Research (BMBF).

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient Data

RATIONALE The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy. OBJECTIVE We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252). METHODS AND RESULTS The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63-1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, -0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters. CONCLUSIONS This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.

Pioglitazone Reduces Neointima Volume After Coronary Stent Implantation A Randomized, Placebo-Controlled, Double-Blind Trial in Nondiabetic Patients

Background— Restenosis requiring reintervention limits the long-term success after coronary stent implantation. Thiazolidinediones, like pioglitazone or rosiglitazone, are oral antidiabetic drugs with additional antirestenotic properties. In a randomized, placebo-controlled, double-blind trial, we examined the effect of 6-month pioglitazone therapy on neointima volume after coronary stenting in nondiabetic coronary artery disease patients. Methods and Results— Fifty nondiabetic patients after coronary stent implantation were randomly assigned to pioglitazone (30 mg daily; pio) or placebo (control) treatment in addition to standard therapy, and neointima volume was assessed by intravascular ultrasound at the 6-month follow-up. Both groups were comparable with regard to baseline characteristics, angiographic lesion morphology, target vessel, and length of the stented segment. In addition, there were no statistical differences in minimal lumen diameter before and after intervention, as well as reference diameter after stent implantation. In this study population of nondiabetic patients, pio treatment did not significantly change fasting blood glucose, fasting insulin, or glycosylated hemoglobin levels, as well as lipid parameters. In contrast, pio treatment significantly reduced neointima volume within the stented segment, with 2.3±1.1 mm3/mm in the pio group versus 3.1±1.6 mm3/mm in controls (P=0.04). Total plaque volume (adventitia-lumen area) was significantly lower at follow-up in the pio group (11.2±3.2 mm3/mm) compared with controls (13.2±4.2 mm3/mm; P=0.04). Moreover, the binary restenosis rate was 3.4% in the pio group versus 32.3% in controls (P<0.01). Conclusions— Thus, 6-month treatment with pio significantly reduced neointima volume after coronary stent implantation in nondiabetic patients. These data bolster the hypothesis that antidiabetic thiazolidinediones, in addition to their metabolic effects, exhibit direct antirestenotic effects in the vasculature.

Reduction of Major Adverse Cardiac Events With Intracoronary Compared With Intravenous Bolus Application of Abciximab in Patients With Acute Myocardial Infarction or Unstable Angina Undergoing Coronary Angioplasty

Background—In patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty, abciximab reduces major adverse cardiac events (MACE). Clinical trials have studied intravenous administration only. Intracoronary bolus application of abciximab causes very high local drug concentrations and may be more effective. We studied whether intracoronary bolus administration of abciximab is associated with a reduced MACE rate compared with the standard intravenous bolus application. Methods and Results—We stratified 403 consecutive patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty according to the type of application of abciximab. A 20-mg bolus of abciximab was given intravenously in 109 patients and intracoronarily in 294 patients. There were no differences between the groups with regard to diabetes mellitus, cardiogenic shock, successful intervention, or preprocedural and postprocedural TIMI flow. At 30 days, the incidence of MACE (death, myocardial infarction, urgent revascularization) was significantly lower in the patients with intracoronary compared with intravenous administration of abciximab (10.2% versus 20.2%;P <0.008), which was independent from stenting in multivariate analysis. The effect was most pronounced in patients with preprocedural TIMI 0/1 flow (MACE: intracoronary 11.8% versus intravenous 27.5%, P <0.002; n=273). Conclusions—In patients with acute myocardial infarction or unstable angina undergoing emergency coronary angioplasty, intracoronary bolus application of abciximab is associated with a reduction of MACE compared with the standard intravenous bolus application of abciximab. Prospective, randomized trials are warranted to further assess intracoronary application of abciximab.

A randomized trial of elective stenting after balloon recanalization of chronic total occlusions

OBJECTIVES The aim of this study was to assess the role of Wiktor stent implantation after recanalization of chronic total coronary occlusions with regard to the clinical and angiographic outcome after six months. BACKGROUND Beside the common use of stents in clinical practice, the number of stent indications proven by randomized trials is still limited. METHODS Eighty-five patients with a thrombolysis in myocardial infarction grade 0 chronic coronary occlusion were examined. After standard balloon angioplasty, the patients were randomly assigned to stent implantation, or percutaneous transluminal coronary angioplasty (PTCA) alone (no further intervention). Quantitative coronary angiography was performed at baseline and after six months. RESULTS The minimal lumen diameter did not differ immediately after recanalization (stent group 1.61 +/- 0.30 mm vs. PTCA group 1.65 +/- 0.36 mm), and increased after stent implantation to 2.51 +/- 0.41 mm. After six months, the stent group still had a significantly greater lumen (1.57 +/- 0.59 vs. 1.06 +/- 0.90 mm; p < 0.01) and a significantly lower restenosis and reocclusion rate (32% and 3%) compared with the PTCA group (64% and 24%); restenosis analysis according to treatment was 72% (PTCA) versus 29% (stent, p < 0.01). Late loss was equal in both groups. At follow-up, the stent patients had a better angina class (p < 0.01), and fewer cardiac events (p < 0.03). A meta-analysis including this trial and three other controlled trials with the Palmaz-Schatz stent showed concordant results. CONCLUSIONS Stent implantation after reopening of a chronic total occlusion provides a better angiographic result, corresponding to a better clinical outcome with fewer recurrence of symptoms and reinterventions after six months.

SeQuent Please World Wide Registry : Clinical Results of SeQuent Please Paclitaxel-Coated Balloon Angioplasty in a Large-Scale, Prospective Registry Study

OBJECTIVES This study sought to assess the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in an international, multicenter, prospective, large-scale registry study. BACKGROUND In small randomized trials, PCB angioplasty was superior to uncoated balloon angioplasty for treatment of bare-metal stent (BMS) and drug-eluting stent (DES) restenosis. METHODS Patients treated with SeQuent Please PCBs were included. The primary outcome measure was the clinically driven target lesion revascularization (TLR) rate at 9 months. RESULTS At 75 centers, 2,095 patients with 2,234 lesions were included. The TLR rate was 5.2% after 9.4 months. Definite vessel thrombosis occurred in 0.1%. PCB angioplasty was performed in 1,523 patients (72.7%) with DES or BMS restenosis and 572 patients (27.3%) with de novo lesions. The TLR rate was significantly lower in patients with PCB angioplasty for BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p < 0.001). The TLR rate did not differ for PCB angioplasty of paclitaxel-eluting stent and non-paclitaxel-eluting sten restenosis (8.3% vs. 10.8%, p = 0.46). In de novo lesions (small vessels), the TLR rate was low and did not differ between PCB angioplasty with and without additional BMS implantation (p = 0.31). CONCLUSIONS PCB angioplasty in an all-comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES.

Impact of In-Hospital Major Bleeding on Late Clinical Outcomes After Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction: The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial

OBJECTIVES We aimed to investigate the long-term prognosis of patients with in-hospital major bleeding (IHMB). BACKGROUND The effect of IHMB on the long-term prognosis of patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction is unknown. METHODS Primary PCI was performed in 3,345 (92.9%) of 3,602 patients in the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial; in-hospital protocol-defined non-coronary artery bypass graft-related major bleeding developed in 231 (6.9%). We examined medication use at discharge, mortality, and major adverse cardiovascular events (composite of death, reinfarction, stroke, or ischemic target vessel revascularization) at 3-year follow-up in patients with and without IHMB. RESULTS At 3-year follow-up, patients with IHMB had higher mortality (24.6% vs. 5.4%, p < 0.0001) and major adverse cardiovascular events (40.3% vs. 20.5%, p < 0.0001). The deleterious effect of major bleeding was observed within 1 month, between 1 month and 1 year, and between 1 and 3 years. IHMB was an independent predictor of mortality (hazard ratio: 2.80; 95% confidence interval: 1.89 to 4.16, p < 0.0001) at 3-year follow up. CONCLUSIONS Patients with IHMB after primary PCI have significantly increased 3-year rates of morbidity and mortality. Further investigation is warranted to understand the mechanisms underlying this relationship and to further improve outcomes in patients with ST-segment myocardial infarction. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).

Results of Intracoronary Stem Cell Therapy After Acute Myocardial Infarction

To assess the effect of autologous bone-marrow cell (BMC) therapy in patients with acute myocardial infarction in a rigorous double-blind, randomized, placebo-controlled trial. Patients with reperfusion >6 hours after symptom onset were randomly assigned in a 2:1 ratio to receive intracoronary BMC or placebo therapy 5 to 7 days after symptom onset. The patients were stratified according to age, acute myocardial infarction localization, and left ventricular (LV) function. Rigorous double-blinding was ensured using autologous erythrocytes for the placebo preparation that was visually indistinguishable from the active treatment. Serial cardiac magnetic resonance imaging studies were performed before study therapy and after 1, 3, and 6 months. The primary end point was the difference in the LV ejection fraction from baseline to 6 months. The secondary end points included changes in the LV end-diastolic and end-systolic volume indexes and infarct size. A total of 42 patients were enrolled (29 in the BMC group and 13 in the placebo group) in the integrated pilot phase. A mean of 381 x 10(6) mononuclear BMCs were administered. The baseline clinical and cardiac magnetic resonance imaging parameters did not differ. Compared to baseline, the difference in LV ejection fraction for the placebo group versus BMC group was 1.7 +/- 6.4% versus -0.9 +/- 5.5% at 1 month, 3.1 +/- 6.0% versus 1.9 +/- 4.3% at 3 months, and 5.7 +/- 8.4% versus 1.8 +/- 5.3% at 6 months (primary end point; not significant). No difference was found in the secondary end points between the 2 groups, including changes in infarct size or LV end-diastolic and end-systolic volume indexes. In conclusion, in this rigorous double-blind, randomized, placebo-controlled trial, we did not observe an evidence for a positive effect for intracoronary BMC versus placebo therapy with respect to LV ejection fraction, LV volume indexes, or infarct size.