Christian Valina

Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.

OBJECTIVES The aim of this study was to evaluate the relative impact of demographic and clinical variables versus the cytochrome P450 2C19 (CYP2C19) polymorphism on antiplatelet effects of clopidogrel. BACKGROUND Platelet responses to clopidogrel show a marked interindividual variability with substantial impact on clinical outcome. Several demographic and clinical characteristics as well as a polymorphism of CYP2C19 have been described as predictors for a low response to clopidogrel. METHODS This analysis enrolled 760 patients undergoing elective coronary stent implantation after loading with 600 mg of clopidogrel. Residual platelet aggregation was determined by optical aggregometry (adenosine diphosphate 5 micromol/l) before discharge. We analyzed the predictive value of the CYP2C19*2 polymorphism and baseline variables for an insufficient antiplatelet response by multivariable regression analysis and classification and regression trees analysis and determined the proportion responsible for the antiplatelet response of these predictors by multivariable linear regression analysis. RESULTS Major independent predictors for an insufficient antiplatelet response to clopidogrel were CYP2C19*2 carrier status (odds ratio [OR]: 2.74; 95% confidence interval [CI]: 1.93 to 3.90) together with age (OR: 1.03; 95% CI: 1.01 to 1.05), diabetes mellitus (OR: 1.75; 95% CI: 1.19 to 2.56), and body mass index (OR: 1.06; 95% CI: 1.02 to 1.11). The classification and regression trees analysis demonstrated that CYP2C19*2 carrier status followed by diabetes mellitus was the best discriminator between a sufficient and an insufficient antiplatelet response to clopidogrel. The full linear regression model including all these parameters could only explain 11.5% of the antiplatelet response (5.2% by CYP2C19*2 carrier status alone). CONCLUSIONS Thus, our study does not suggest that, in patients critically dependent on adequate platelet inhibition, genotyping alone or in combination with clinical factors can replace phenotyping of platelet function. (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).

Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial

BACKGROUND The best way to manage restenosis in patients who have previously received a drug-eluting stent is unknown. We investigated the efficacy of paclitaxel-eluting balloons (PEB), paclitaxel-eluting stents (PES), and balloon angioplasty in these patients. METHODS In this randomised, open-label trial, we enrolled patients older than 18 years with restenosis of at least 50% after implantation of any limus-eluting stent at three centres in Germany between Aug 3, 2009, and Oct 27, 2011. Patients were randomly assigned (1:1:1; stratified according to centre) to receive PEB, PES, or balloon angioplasty alone by means of sealed, opaque envelopes containing a computer-generated sequence. Patients and investigators were not masked to treatment allocation, but events and angiograms were assessed by individuals who were masked. The primary endpoint was diameter stenosis at follow-up angiography at 6-8 months. Primary analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00987324. FINDINGS We enrolled 402 patients, of whom 137 (34%) were assigned to PEB, 131 (33%) to PES, and 134 (33%) to balloon angioplasty. Follow-up angiography at 6-8 months was available for 338 (84%) patients. PEB was non-inferior to PES in terms of diameter stenosis (38·0% [SD 21·5] vs 37·4% [21·8]; difference 0·6%, one-sided 95% CI 4·9%; p(non-inferiority)=0·007; non-inferiority margin of 7%). Findings were consistent in per-protocol analysis (p(non-inferiority)=0·011). PEB and PES were superior to balloon angioplasty alone (54·1% [25·0]; p(superiority)<0·0001 for both comparisons). Frequency of death, myocardial infarction, or target lesion thrombosis did not differ between groups. INTERPRETATION By obviating the need for additional stent implantation, PEB could be a useful treatment for patients with restenosis after implantation of a drug-eluting stent. FUNDING Deutsches Herzzentrum.

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.

Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency

Contrast media can lead to renal impairment that results in longer hospitalization and increased mortality. Adenosine is a crucial mediator of contrast-induced nephropathy (CIN; an increase in serum creatinine of >or=0.5 mg/dl within 48 hours). Therefore, it was the purpose of our study to investigate whether the adenosine antagonist theophylline reduces the incidence of CIN after coronary angiography. We also characterized risk factors for CIN after coronary angiography. One hundred patients with serum creatinine concentrations of >or=1.3 mg/dl randomly received 200 mg IV theophylline or placebo 30 minutes before coronary angiography (amount of contrast medium >or=100 ml). Patients who received theophylline and the controls were comparable with regard to baseline creatinine levels (means +/- SD) (1.65 +/- 0.41 vs 1.72 +/- 0.69 mg/dl) and the amount of contrast medium received (235 +/- 89 vs 261 +/- 139 ml). Theophylline significantly reduced the incidence of CIN (4% vs 20%, p = 0.0138). With placebo, creatinine significantly increased at 12 (1.82 +/- 0.79 mg/dl, p = 0.0057), 24 (1.90 +/- 0.86 mg/dl, p = 0.0001), and 48 hours (1.90 +/- 0.89 mg/dl, p = 0.0007) after administration of contrast medium. With pretreatment with theophylline, mean creatinine only increased 24 hours after contrast medium administration (1.70 +/- 0.40 mg/dl, p = 0.029), but was stable 12 hours (1.65 +/- 0.43 mg/dl, p = 0.99) and 48 hours after contrast medium administration (1.65 +/- 0.41 mg/dl, p = 0.99). The following parameters were significantly associated with contrast-induced renal impairment: Cigarroa quotient >5 (contrast medium [milliters] x serum creatinine/body weight [kg]), elevated troponin T, >300 ml of contrast medium, and emergency angiography. In conclusion, theophylline reduces the incidence of CIN in patients with chronic renal insufficiency undergoing coronary angiography. It should be used especially in patients receiving large amounts of contrast medium, and in patients with a Cigarroa quotient of >5 and/or elevated troponin T levels.

Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement.

Background— Recently published data indicate that the paraoxonase-1 (PON1) Q192R genotype—and not as previously shown activity of cytochrome P450 (CYP) 2C19—is the major determinant of metabolic bioactivation of clopidogrel and thereby variability of antiplatelet effect of clopidogrel. We sought to investigate whether the PON1 Q192R gene polymorphism affects platelet reactivity in patients undergoing elective coronary stent placement. Methods and Results— The study included 760 consecutive patients undergoing elective coronary stent placement after loading with clopidogrel 600 mg. Platelet function was assessed by adenosine diphosphate-induced (ADP 5 and 20 &mgr;mol/L) platelet aggregation and by flow-cytometric analysis of platelet surface protein expression before clopidogrel, at the time of coronary stent placement, and before discharge after coronary stent placement. PON1 Q192R genotype [NM_000446.5:c.575A>G single nucleotide polymorphism (rs662)] was analyzed by TaqMan polymerase chain reaction. Residual platelet aggregation (ADP 5 &mgr;mol/L) at predischarge was 8.0% (3.0% to 17.0%) [median (interquartile range)] in PON1 QQ192 patients (n=384), 8.0% (3.0% to 15.0%) in PON1 QR192 (n=304), and 11.0% (3.0% to 18.0%) in PON1 RR192 (n=72; P=0.603). By multivariable linear regression, residual platelet aggregation was not associated with PON1 QQ192/QR192 (partial &eegr;2<0.001, P=0.728) but with CYP2C19*2 loss-of-function allele (partial &eegr;2=0.045, P<0.001) as well as any CYP2C19*17 gain-of-function allele (partial &eegr;2=0.012, P=0.004). All other platelet assays also showed no significant association between PON1 Q192R genotype and antiplatelet effect of clopidogrel. The 1-year incidence of death and myocardial infarction did not differ between PON1 Q192R genotypes. Conclusions— On-treatment platelet reactivity in patients undergoing coronary stent placement after loading with clopidogrel 600 mg was not associated with PON1 Q192R genotype. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00457236.

ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention.

AIMS Although a 140 U/kg dose of unfractionated heparin (UFH) was comparable with bivalirudin in terms of net clinical outcome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, it was associated with a higher risk of bleeding. We designed this study to assess whether a reduction in the UFH dose from 140 to 100 U/kg is associated with improved net clinical outcome. METHODS AND RESULTS A total of 2505 biomarker negative patients undergoing percutaneous coronary intervention (PCI) after clopidogrel pre-treatment received a single bolus of 100 U/kg UFH. The primary endpoint was net clinical outcome-a quadruple endpoint of death, myocardial infarction, urgent target-vessel revascularization within 30 days, or in-hospital REPLACE 2 defined major bleeding. The primary comparison was with the historical UFH group of ISAR-REACT 3 (2281 patients). In a second analysis, we checked for non-inferiority against the historical bivalirudin arm of ISAR-REACT 3 (2289 patients). The incidence of the primary endpoint was 7.3% in the lower UFH dose group compared with 8.7% in the higher UFH dose group [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.67-1.00; P = 0.045]. The incidence of major bleeding was 3.6% in the lower UFH dose group and 4.6% in the higher UFH dose group (HR 0.79; 95% CI 0.59-1.05; P = 0.11). The lower UFH dose met the criterion of non-inferiority compared with bivalirudin (P < 0.001). CONCLUSION In biomarker negative patients undergoing PCI after clopidogrel loading, a reduced dose of 100 U/kg UFH provided net clinical benefit compared with the historical control of 140 U/kg UFH in the ISAR-REACT 3 trial. The benefit was mostly driven by reduction in bleeding. CLINICAL TRIAL REGISTRATION INFORMATION URL www.clinicaltrials.gov; Unique identifier NCT00735280.

Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium

Abstract Background Stent thrombosis (ST) is a rare but serious complication following percutaneous coronary intervention. Analysis of thrombus composition from patients undergoing catheter thrombectomy may provide important insights into the pathological processes leading to thrombus formation. We performed a large-scale multicentre study to evaluate thrombus specimens in patients with ST across Europe. Methods Patients presenting with ST and undergoing thrombus aspiration were eligible for inclusion. Thrombus collection was performed according to a standardized protocol and specimens were analysed histologically at a core laboratory. Serial tissue cross sections were stained with haematoxylin–eosin (H&E), Carstairs and Luna. Immunohistochemistry was performed to identify leukocyte subsets, prothrombotic neutrophil extracellular traps (NETs), erythrocytes, platelets, and fibrinogen. Results Overall 253 thrombus specimens were analysed; 79 (31.2%) from patients presenting with early ST, 174 (68.8%) from late ST; 79 (31.2%) were from bare metal stents, 166 (65.6%) from drug-eluting stents, 8 (3.2%) were from stents of unknown type. Thrombus specimens displayed heterogeneous morphology with platelet-rich thrombus and fibrin/fibrinogen fragments most abundant; mean platelet coverage was 57% of thrombus area. Leukocyte infiltrations were hallmarks of both early and late ST (early: 2260 ± 1550 per mm2 vs. late: 2485 ± 1778 per mm2; P = 0.44); neutrophils represented the most prominent subset (early: 1364 ± 923 per mm2 vs. late: 1428 ± 1023 per mm2; P = 0.81). Leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction. Neutrophil extracellular traps were observed in 23% of samples. Eosinophils were present in all stent types, with higher numbers in patients with late ST in sirolimus-and everolimus-eluting stents. Conclusion In a large-scale study of histological thrombus analysis from patients presenting with ST, thrombus specimens displayed heterogeneous morphology. Recruitment of leukocytes, particularly neutrophils, appears to be a hallmark of ST. The presence of NETs supports their pathophysiological relevance. Eosinophil recruitment suggests an allergic component to the process of ST.

Longitudinal compression of the platinum-chromium everolimus-eluting stent during coronary implantation: predisposing mechanical properties, incidence, and predictors in a large patient cohort.

Objectives: To assess the longitudinal compression behavior of platinum‐chromium everolimus‐eluting stents, evaluate frequency of inadvertent longitudinal compression during percutaneous intervention, and define patient‐ and lesion‐related predictors of this complication. Background: Platinum‐chromium stents of Element family have unique design features to improve flexibility that may, however, impair longitudinal stability. Incidence of longitudinal stent compression during implantation and predictors for this complication are not well understood. Methods: Five contemporary stent platforms were longitudinally compressed in a bench test experiment, and spring constant, yield force, and ultimate strength were calculated from force‐strain curves. We also evaluated all coronary cases treated with an Element stent from January 1, 2010, to October 31, 2011, for documented longitudinal compression. We compared baseline characteristics and periprocedural data between patients with and without longitudinal stent compression and assessed predictors for this event by multiple logistic regression models. Results: Yield force and ultimate strength were significantly lower for the Element compared with all other tested stents. In 20 patients (1.4%) and 20 lesions (0.7%) from 1,392 cases with 2,839 atherosclerotic lesions longitudinal stent compression was reported. Ostial segments, number of stents, and the presence of a bifurcation were significant predictors (adjusted odds ratios [95% confidence intervals]: 8.33 [3.30–21.28], 1.57 [1.01–2.45], 3.57 [1.36–9.35], respectively). Conclusion: The Element stent exhibits the lowest overall longitudinal strength compared with four contemporary platforms. Longitudinal compression of the Element stent is a rare complication and occurs more frequently in ostial or bifurcation lesions and with multiple stents.

High-sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease☆ , ☆☆

BACKGROUND In stable patients with unknown coronary anatomy, higher levels of cardiac troponin are associated with an increased risk of cardiovascular events. It was supposed that this association might be explained by the ability of cardiac troponin to detect minor myocardial necrosis which might be caused by subclinical coronary atherosclerosis. Thus, this analysis tested if the predictive value of high-sensitivity troponin T (hsTnT) in stable patients is dependent of the presence or absence of angiographically documented coronary heart disease. METHODS Stable patients undergoing elective coronary angiography were enrolled (n=2046). HsTnT was determined before diagnostic procedures. The patients were followed for up to seven years. Primary endpoint was all-cause mortality or non-fatal myocardial infarction. All endpoints were adjudicated by independent physicians. Results were adjusted to a clinical model including independent clinical predictors of the primary endpoint. RESULTS Out of the 2046 patients enrolled, 1236 (60%) had a diagnosis of obstructive coronary heart disease. HsTnT predicted independently the primary endpoint (adjusted HR 1.33, 95%-CI 1.21-1.46, P<0.001). The use of hsTnT in addition to the clinical model significantly improved discrimination (c-statistic: 0.751 to 0.773, P<0.001) as well as reclassification of the primary endpoint (NRI=0.362, P<0.001). This significant improvement persisted across various subsets and was independent of the presence of clinically detectable coronary heart disease and other variables. CONCLUSION The use of hsTnT in addition to clinical variables significantly improves discrimination and reclassification of patients with respect to all-cause mortality or non-fatal myocardial infarction irrespective of the presence of clinically detectable coronary heart disease. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (Identifier: NCT00457236).

Randomized Comparison of Different Thienopyridine Loading Strategies in Patients Undergoing Elective Coronary Intervention: The ExcelsiorLOAD Trial.

OBJECTIVES This randomized trial investigated to what extent loading with prasugrel can provide a more rapid peri-interventional antiplatelet effect than clopidogrel 600 mg. BACKGROUND Effective platelet inhibition at the start of a percutaneous coronary intervention (PCI) reduces the risk of ischemic complications. With clopidogrel administered immediately before a PCI, effective platelet inhibition is delayed by 2 h. Prasugrel has the potential of shortening this period. METHODS We randomly assigned 300 P2Y12 receptor blocker-naive patients undergoing an elective PCI to loading with clopidogrel 600 mg, prasugrel 30 mg, or prasugrel 60 mg immediately before the PCI. Platelet function was assessed serially by impedance aggregometry. The primary endpoint was the proportion of patients with high on-treatment platelet reactivity at 60 min after loading defined as ≥468 aggregation units × minute (Multiplate Analyzer, Roche Diagnostics, Mannheim, Germany). RESULTS The 3 groups were well balanced with respect to clinical and angiographic characteristics. At 60 min, 33% of the patients assigned to prasugrel 60 mg, 37% of patients assigned to prasugrel 30 mg, but 55% of those assigned to clopidogrel had high on-treatment platelet reactivity (p < 0.001). At any time point starting from 30 min, prasugrel 60 mg achieved significantly lower platelet reactivity than clopidogrel. Platelet reactivity at 60 min after prasugrel was not significantly different from that at 120 min after clopidogrel (p = 0.18). Prasugrel 30 mg had an intermediate effect. The 30-day incidence of bleeding events was not different among the 3 groups. CONCLUSIONS From 30 min onward, prasugrel 60 mg achieved a stronger platelet inhibition than clopidogrel loading in stable patients undergoing a PCI. Compared with clopidogrel, prasugrel 60 mg was associated with a twice as fast onset of platelet inhibition. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate-Advanced Loading Strategies [ExcelsiorLOAD]; DRKS00006102).