Albert Schömig

Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction.

BACKGROUND Identification of high-risk patients after acute myocardial infarction is essential for successful prophylactic therapy. The predictive accuracy of currently used risk predictors is modest even when several factors are combined. Thus, establishment of a new powerful method for risk prediction independent of the available stratifiers is of considerable practical value. METHODS The study investigated fluctuations of sinus-rhythm cycle length after a single ventricular premature beat recorded in Holter electrocardiograms, and characterised the fluctuations (termed heart-rate turbulence) by two numerical parameters, termed turbulence onset and slope. The method was developed on a population of 100 patients with coronary heart disease and blindly applied to the population of the Multicentre Post-Infarction Program (MPIP; 577 survivors of acute infarction, 75 deaths during a median follow-up of 22 months) and to the placebo population of the European Myocardial Amiodarone Trial (EMIAT; 614 survivors of acute myocardial infarction, 87 deaths during median follow-up of 21 months). Multivariate risk stratification was done with the new parameters and conventional risk factors. FINDINGS One of the new parameters (turbulence slope) was the most powerful stratifier of follow-up mortality in EMIAT and the second most powerful stratifier in MPIP: MPIP risk ratio 3.5 (95% CI 2.2-5.5, p<0.0001), EMIAT risk ratio 2.7 (1.8-4.2, p<0.0001). In the multivariate analysis, low left-ventricular ejection fraction and turbulence slope were the only independent variables for mortality prediction in MPIP (p<0.001), whereas in EMIAT, five variables were independent mortality predictors: abnormal turbulence onset, abnormal turbulence slope, history of previous infarction, low left-ventricular ejection fraction, and high mean heart rate (p<0.001). In both MPIP and EMIAT, the combination of abnormal onset and slope was the most powerful multivariate risk stratifier: MPIP risk ratio 3.2 (1.7-6.0, p<0.0001), EMIAT risk ratio 3.2 (1.8-5.6, p<0.0001). INTERPRETATION The absence of the heart rate turbulence after ventricular premature beats is a very potent postinfarction risk stratifier that is independent of other known risk factors and which is stronger than other presently available risk predictors.

Predictive Factors of Restenosis After Coronary Stent Placement

OBJECTIVES The objective of this study was to identify clinical, lesional and procedural factors that can predict restenosis after coronary stent placement. BACKGROUND Coronary stent placement reduces the restenosis rate compared with that after percutaneous transluminal coronary angioplasty (PTCA). However, restenosis remains an unresolved issue, and identification of its predictive factors may allow further insight into the underlying process. METHODS All patients with successful coronary stent placement were eligible for this study unless they had had a major adverse cardiac event during the 1st 30 days after the procedure. Of the 1,349 eligible patients (1,753 lesions), follow-up angiography at 6 months was performed in 80.4% (1,084 patients, 1,399 lesions). Demographic, clinical, lesional and procedural data were prospectively recorded and analyzed for any predictive power for the occurrence of late restenosis after stenting. Restenosis was evaluated by using three outcomes at follow-up: binary restenosis as a diameter stenosis > or =50%, late lumen loss as lumen diameter reduction and target lesion revascularization (TLR) as any repeat PTCA or coronary artery bypass surgery involving the stented lesion. RESULTS Multivariate analysis demonstrated that diabetes mellitus, placement of multiple stents and minimal lumen diameter (MLD) immediately after stenting were the strongest predictors of restenosis. Diabetes increased the risk of binary restenosis with an odds ratio (OR) [95% confidence interval] of 1.86 [1.56 to 2.16] and the risk of TLR with an OR of 1.45 [1.11 to 1.80]. Multiple stents increased the risk of binary restenosis with an OR of 1.81 [1.55 to 2.06] and that of TLR with an OR of 1.94 [1.66 to 2.22]. An MLD <3 mm at the end of the procedure augmented the risk of binary restenosis with an OR of 1.81 [1.55 to 2.06] and that of TLR with an OR of 2.05 [1.77 to 2.34]. Classification and regression tree analysis demonstrated that the incidence of restenosis may be as low as 16% for a lesion without any of these risk factors and as high as 59% for a lesion with a combination of these risk factors. CONCLUSIONS Diabetes, multiple stents and smaller final MLD are strong predictors of restenosis after coronary stent placement. Achieving an optimal result with a minimal number of stents during the procedure may significantly reduce this risk even in patients with adverse clinical characteristics such as diabetes.

Absorption, Metabolization, and Antiplatelet Effects of 300-, 600-, and 900-mg Loading Doses of Clopidogrel Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial

Background— For patients undergoing percutaneous coronary intervention, the administration of a clopidogrel loading dose ranging from 300 to 600 mg is currently recommended. It is unknown, though, whether loading doses higher than 600 mg exert additional suppression of platelet function. Methods and Results— Sixty patients with suspected or documented coronary artery disease admitted to our hospital for coronary angiography were included in this trial. They were allocated to 1 of 3 clopidogrel loading doses (300, 600, or 900 mg) in a double-blinded, randomized manner. Plasma concentrations of the active thiol metabolite, unchanged clopidogrel, and the inactive carboxyl metabolite of clopidogrel were determined before and serially after drug administration. Optical aggregometry was performed before and 4 hours after administration of clopidogrel. Loading with 600 mg resulted in higher plasma concentrations of the active metabolite, clopidogrel, and the carboxyl metabolite compared with loading with 300 mg (P≤0.03) and lower values for adenosine diphosphate-induced (5 and 20 &mgr;mol/L) platelet aggregation 4 hours after drug administration (P=0.01 and 0.004). With administration of 900 mg, no further increase in plasma concentrations of active metabolite and clopidogrel (P≥0.38) and no further suppression of adenosine diphosphate-induced (5 and 20 &mgr;mol/L) platelet aggregation 4 hours after drug administration was achieved when compared with administration of 600 mg (P=0.59 and 0.39). Conclusions— Single doses of clopidogrel higher than 600 mg are not associated with an additional significant suppression of platelet function because of limited clopidogrel absorption.

Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.

OBJECTIVES The aim of this prospective trial was to assess whether platelet reactivity to clopidogrel assessed with multiple electrode platelet aggregometry (MEA) correlates with the risk of early drug-eluting stent thrombosis (ST). BACKGROUND Studies using light transmission aggregometry (LTA) have shown that insufficient suppression of platelet reactivity to adenosine diphosphate (ADP) after clopidogrel treatment is associated with an increased risk of adverse cardiovascular events after percutaneous coronary intervention (PCI). However, LTA is time- and labor-intensive and inconvenient for the routine. A point-of-care assay with similar predictive power would be of great value. METHODS Between February 2007 and April 2008, a total of 1,608 consecutive patients with coronary artery disease and planned drug-eluting stent implantation were enrolled. Before PCI, all patients received 600 mg clopidogrel. Blood was obtained directly before PCI. The ADP-induced platelet aggregation was assessed in whole blood with MEA on a Multiplate analyzer (Dynabyte, Munich, Germany). The primary end point was definite ST at 30 days. RESULTS The upper quintile of patients according to MEA measurements (n = 323) was defined as clopidogrel low responders. Compared with normal responders (n = 1,285), low responders had a significantly higher risk of definite ST within 30 days (2.2% vs. 0.2%; odds ratio [OR]: 9.4; 95% confidence interval [CI]: 3.1 to 28.4; p < 0.0001). Mortality rates were 1.2% in low versus 0.4% in normal responders (OR: 3.2; 95% CI: 0.9 to 11.1; p = 0.07). The composite of death or ST was higher in low versus normal responders (3.1% vs. 0.6%; OR: 5.1; 95% CI: 2.2 to 11.6; p < 0.001). CONCLUSIONS Low response to clopidogrel assessed with MEA is significantly associated with an increased risk of ST. Further studies are warranted to evaluate the ability of MEA to guide antiplatelet therapy in patients undergoing PCI.

Effect of Glycoprotein IIb/IIIa Receptor Blockade on Recovery of Coronary Flow and Left Ventricular Function After the Placement of Coronary-Artery Stents in Acute Myocardial Infarction

BACKGROUND Apart from its established effects on vessel patency after percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor blockade by abciximab may improve myocardial perfusion by inhibition of the interaction of platelets and platelet aggregates with the microvasculature. We investigated the effect of abciximab with stent placement in acute myocardial infarction. METHODS AND RESULTS In a prospective randomized trial, patients undergoing stenting in acute myocardial infarction within 48 hours after onset of symptoms were randomly assigned to receive either standard-dose heparin or abciximab plus low-dose heparin. Immediately after the procedure and at 14-day angiographic follow-up, we assessed flow velocity in the recanalized vessel with the Doppler wire and regional wall motion by the centerline method. End points were changes in papaverine-induced peak flow velocities and in wall motion indices. We assigned 98 patients to standard heparin and 102 to abciximab. We obtained 152 paired flow measurements and 151 paired left ventricular function studies. Residual stenoses of the treated lesions did not differ between the 2 groups. Improvement of peak flow velocity (mean [95% CI]: 18.1 cm/s [13.6 to 22.6 cm/s], n=80, versus 10.4 cm/s [5.4 to 15.4 cm/s], n=72, P=0.024) and wall motion index (0.44 SD/chord [0.29 to 0.59 SD/chord], n=79 versus 0. 15 SD/chord [0.00 to 0.30 SD/chord], n=72, P=0.007) was significantly greater in patients assigned to abciximab than in those on heparin alone. At follow-up, the abciximab group had a higher global left ventricular ejection fraction than the heparin group (62% [59% to 65%] versus 56% [53% to 59%], P=0.003). CONCLUSIONS Abciximab had important effects beyond the maintenance of large-vessel patency. It improved the recovery of microvascular perfusion and concomitantly enhanced the recovery of contractile function in the area at risk.

Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement

OBJECTIVES The objectives of this study were to analyze the clinical and angiographic outcome of diabetic patients with successful coronary stent placement and to compare these results with those achieved after stenting in nondiabetic patients. BACKGROUND The outcome of diabetic patients treated with stent placement due to coronary artery disease has not been assessed comprehensively. METHODS This study analyzes a consecutive series of patients with successful stent placement comprising 715 patients with diabetes and 2,839 patients without diabetes. Clinical one year follow-up and angiographic control at 6 months were part of the protocol. Death, myocardial infarction and target lesion revascularization were considered as adverse events. An automated edge detection system was used for the angiographic assessment. The primary clinical endpoint was event-free survival at one year. The primary angiographic endpoint was restenosis rate at 6 months (> or = 50% diameter stenosis). RESULTS Event-free survival was significantly lower in diabetic than in nondiabetic patients (73.1 vs. 78.5%, p < 0.001). Survival free of myocardial infarction was also significantly reduced in the diabetic group (89.9 vs. 94.4% in nondiabetics, p < 0.001). The incidence of both restenosis (37.5 vs. 28.3%, p < 0.001) and stent vessel occlusion (5.3 vs. 3.4%, p = 0.037) was significantly higher in diabetic patients. Diabetes was identified as an independent risk factor for adverse clinical events and restenosis in multivariate analyses. CONCLUSIONS Patients with diabetes mellitus have a less favorable clinical outcome at one year after successful stent placement as compared to the nondiabetic patients. The clinical follow-up was characterized by a higher incidence of death, myocardial infarction and reinterventions. Diabetic patients also demonstrated an increased risk for restenosis.

Cardiac Release of Cytokines and Inflammatory Responses in Acute Myocardial Infarction

BACKGROUND In animal models of myocardial infarction (MI), inflammatory responses compromise microcirculation during reperfusion and restrict functional recovery. To investigate cardiac inflammatory responses in patients with acute MI, we examined the cardiac release of cytokines, the expression on neutrophils of the beta 2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and the cardiac release of thrombomodulin as a marker of endothelial injury. METHODS AND RESULTS In 12 patients with acute anterior MI, blood samples were obtained from the coronary sinus and from the aorta immediately before and after recanalization of the coronary occlusion by balloon angioplasty. Twelve patients undergoing elective balloon angioplasty served as control subjects. Plasma concentrations of interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor-alpha, and thrombomodulin were determined by immunoassay, and surface expression of CD11b and CD62L was assessed by flow cytometry. Differences in coronary sinus and arterial blood were found in IL-6 before (median, 6.3 ng/L, P = .01) and after (13.4 ng/L, P = .002) recanalization and in IL-8 after recanalization (10.7 ng/L, P = .02). The cardiac release of both cytokines significantly (P < or = .03) increased with reperfusion. Cytokine release after reperfusion was associated with significant transcardiac gradients in surface expression on neutrophils of CD11b (10.1 mean channel of fluorescence intensity [mean fl], P = .01) and CD62L (-87 mean fl, P = .007) and with a thrombomodulin release (4.5 micrograms/L, P = .004). Transcardiac gradients in IL-1 beta and tumor necrosis factor-alpha were not found. None of the changes found in MI were detectable in the control group. CONCLUSIONS As evidence of cardiac inflammatory responses in reperfused acute MI, the study demonstrates cardiac neutrophil activation with signs of endothelial injury and a release of the proinflammatory cytokines IL-8 and IL-6. These findings may assist in the design of pharmacological interventions aimed at reducing microvascular reperfusion injury.

Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement

Background— The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C19*17 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. The aim of this study was to assess the impact of CYP2C19*17 on ADP-induced platelet aggregation, the risk of bleeding, and stent thrombosis in clopidogrel-treated patients undergoing percutaneous coronary intervention. Methods and Results— The study population included 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotypes were determined with a TaqMan assay. ADP-induced platelet aggregation was assessed on a Multiplate analyzer. The primary clinical safety end point was the 30-day incidence of bleeding defined according to Thrombolysis in Myocardial Infarction criteria, and the primary clinical efficacy end point was the 30-day incidence of stent thrombosis. For both heterozygous (*wt/*17; n=546) and homozygous (*17/*17; n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (*wt/*wt; n=902; P=0.039 and P=0.008, respectively). CYP2C19*17 allele carriage was significantly associated with an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients (P=0.01, &khgr;2 test for trend). Multivariate analysis confirmed the independent association of CYP2C19*17 allele carriage with platelet aggregation values (P<0.001) and the occurrence of bleeding (P=0.006). No significant influence of CYP2C19*17 on the occurrence of stent thrombosis was found (P=0.79). Conclusions— CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.

Vessel Size and Long-Term Outcome After Coronary Stent Placement

BACKGROUND The role of coronary stenting in the treatment of patients with small vessels is not well defined. The purpose of this study was to investigate the influence of vessel size on long-term clinical and angiographic outcome after coronary stent placement. METHODS AND RESULTS The study comprised 2602 patients with successful stent implantation for symptomatic coronary artery disease. Patients were subdivided into 3 equally sized groups (tertiles) according to vessel size, with respective ranges of <2.8, 2.8 to 3.2, and >3.2 mm. Event-free survival at 1 year was 69.5% in the group with smaller vessels, 77.5% in the second group, and 81% in the group with larger vessels (P<0.001). Late lumen loss was similar between the 3 groups (1.12+/-0.73, 1.12+/-0.79, and 1.09+/-0. 88 mm, respectively). Angiographic restenosis rate was significantly higher in the small-vessel group (38.6%, 28.4%, and 20.4% in groups 1, 2, and 3, respectively; P<0.001). The analysis identified subgroups with different risk for restenosis even among patients with small vessels. Within this group, the restenosis rate may be as low as 29.6% in patients without additional risk factors and as high as 53.5% in patients with diabetes and complex lesions. CONCLUSIONS Patients with small vessels present a higher risk for an adverse outcome after coronary stent placement because of a higher incidence of restenosis. However, the unusually high risk for restenosis is confined to those patients with small vessels who have concomitant risk factors such as diabetes and complex lesions.

Freedom From Atrial Tachyarrhythmias After Catheter Ablation of Atrial Fibrillation A Randomized Comparison Between 2 Current Ablation Strategies

Background—Data on the comparative value of the circumferential pulmonary vein and the segmental pulmonary vein ablation for interventional treatment of atrial fibrillation are limited. We hypothesized that the circumferential pulmonary vein ablation approach was superior to the segmental pulmonary vein ablation approach. Methods and Results—One hundred patients with highly symptomatic atrial fibrillation were randomly assigned to undergo either circumferential (n=50) or segmental pulmonary vein ablation (n=50). Freedom from atrial tachyarrhythmias in a 7-day Holter monitoring at 6 months was the primary end point. Secondary end points were freedom of arrhythmia-related symptoms and a composite of pericardial tamponade, thromboembolic complications, and pulmonary vein stenosis (safety end point). On the basis of the results of the 7-day Holter monitoring at 6 months, 21 patients (42%) after circumferential pulmonary vein ablation and 33 patients (66%) after segmental pulmonary vein ablation (P=0.02) were free of atrial tachyarrhythmia episodes. During the 6-month follow-up period, 27 patients (54%) after circumferential pulmonary vein ablation and 41 patients (82%) after segmental pulmonary vein ablation remained free of arrhythmia-related symptoms (P<0.01). No significant difference was found in the safety end point (6 versus 7 events; P=0.77) in the circumferential versus segmental pulmonary vein ablation group, respectively. Conclusions—This study demonstrates no superiority of the circumferential pulmonary vein ablation over segmental pulmonary vein ablation for treatment of atrial fibrillation in terms of efficacy and safety.