In patients undergoing percutaneous coronary intervention (PCI), a link between bleeding and excess mortality has been demonstrated. A potential association of platelet response to clopidogrel and ...bleeding has not been well established yet.
The aim of the present study was to assess the impact of clopidogrel responsiveness on the risk of bleeding in clopidogrel-treated patients undergoing PCI.
Patients (n=2533) undergoing PCI after pretreatment with 600 mg of clopidogrel were enrolled in this study. Blood was obtained directly before PCI. Adenosine-diphosphate (ADP)-induced platelet aggregation was assessed on a Multiplate analyzer. The primary endpoint was the incidence of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major bleeding and the secondary endpoint was in-hospital TIMI minor bleeding. Receiver-operator curve (ROC) analysis was used to derive the optimal platelet aggregation value defining enhanced clopidogrel responders for the association of measurements with major bleeding.
Thirty-four (1.3%) major bleeding events and 137 (5.4%) minor bleeding events were observed. The risk of a major bleeding was significantly higher in patients (n=975) with an enhanced response to clopidogrel as compared with the remaining patients (n=1558) (2.2 vs. 0.8%, unadjusted odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3-5.2, P=0.005; adjusted OR 3.5, 95% CI 1.6-7.3, P=0.001). No significant differences between both groups were observed for the occurrence of minor bleeding events (P=0.68).
Enhanced clopidogrel responsiveness is associated with a higher risk of major bleeding. Whether guidance of antiplatelet treatment based on platelet function testing proves useful for avoiding bleeding events warrants further investigation.
The efficacy of durable polymer drug-eluting stents (DES) is delivered at the expense of delayed healing of the stented vessel. Biodegradable polymer DES aim to avoid this shortcoming and may ...potentially improve long-term clinical outcomes, with benefit expected to accrue over time. We sought to compare long-term outcomes in patients treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES).
We pooled individual patient data from three large-scale multicentre randomized clinical trials (ISAR-TEST 3, ISAR-TEST 4, and LEADERS) comparing biodegradable polymer DES with durable polymer SES and assessed clinical outcomes during follow-up through 4 years. The efficacy endpoint of interest was target lesion revascularization and the safety endpoint of interest was definite stent thrombosis. Out of 4062 patients included in the present analysis, 2358 were randomly assigned to treatment with biodegradable polymer DES (sirolimus-eluting, n= 1501; biolimus-eluting, n= 857) and 1704 patients to durable polymer SES. No heterogeneity across the trials was observed in analyses of the primary and secondary endpoints. At 4 years, the risk of target lesion revascularization was significantly lower among patients treated with biodegradable polymer DES vs. durable polymer SES (hazard ratio 0.82, 95% CI 0.68-0.98, P= 0.029). In addition, the risk of stent thrombosis was significantly reduced with biodegradable polymer DES vs. durable polymer SES (hazard ratio 0.56, 95% CI 0.35-0.90, P= 0.015), driven by a lower risk of very late stent thrombosis (hazard ratio 0.22, 95% CI 0.08-0.61, P= 0.004). In keeping with this, in landmark analysis between 1 and 4 years, the incidence of myocardial infarction was lower for patients treated with biodegradable polymer DES vs. durable polymer SES (hazard ratio 0.59, 95% CI 0.73-0.95, P= 0.031).
Biodegradable polymer DES improve safety and efficacy compared with durable polymer SES during long-term follow-up to 4 years.
Aims Several studies have demonstrated that the mutant *2 allele of the CYP2C19 681G>A loss-of-function polymorphism is associated with diminished metabolization of clopidogrel into its active thiol ...metabolite and an attenuated platelet response to clopidogrel treatment. It is not known whether patients carrying the mutant CYP2C19*2 allele have a higher risk of stent thrombosis (ST) compared with homozygous CYP2C19*1 wild-type allele carriers following percutaneous coronary intervention (PCI). The aim of this study was to assess the impact of the CYP2C19 681G>A loss-of-function polymorphism on ST following PCI performed after pre-treatment with clopidogrel. Methods and results The study population included 2485 consecutive patients undergoing coronary stent placement after pre-treatment with 600 mg of clopidogrel. Genotypes were determined with a TaqMan assay. The primary endpoint of the study was the incidence of definite ST within 30 days following PCI. Of the patients studied, 1805 (73%) were CYP2C19 wild-type homozygotes (*1/*1) and 680 (27%) carried at least one *2 allele (*1/*2 or *2/*2). The cumulative 30-day incidence of ST was significantly higher in CYP2C19*2 allele carriers (*1/*2 or *2/*2) vs. CYP2C19 wild-type homozygotes (*1/*1) 10 patients (1.5%) in CYP2C19*2 allele carriers vs. 7 (0.4%) in CYP2C19 wild-type homozygotes (*1/*1), HR 3.81, 95% CI 1.45–10.02, P = 0.007; P = 0.006 after adjustment for confounding variables. The risk of ST was highest (2.1%) in patients with the CYP2C19 *2/*2 genotype (P = 0.002). Conclusion CYP2C19*2 carrier status is significantly associated with an increased risk of ST following coronary stent placement.
Aims To assess the incidence, timing, and relation of drug-eluting stent (DES) thrombosis to discontinuation of clopidogrel therapy. Methods and results This prospective observational cohort study ...included 6816 consecutive patients that underwent successful DES implantation. Primary endpoint was definite stent thrombosis (ST). During 4 years of follow-up, definite ST was observed in 73 patients, corresponding to a cumulative incidence of 1.2%. Cumulative incidence of ST at 30 days was 0.5 and 0.8% at 1 year, respectively. Discontinuation of clopidogrel therapy was significantly associated with ST only in the first 6 months after the procedure (P < 0.001). During that period, the median time interval from clopidogrel discontinuation to ST was 9 days interquartile range (IQR) 5.5–22.5 while thereafter it was 104.3 days (IQR 7.4–294.8). Conclusion The 4 year incidence of ST after DES implantation is low. A relevant number of ST occur early after discontinuation of clopidogrel therapy. The dependence of ST on discontinuation of clopidogrel therapy seems to be mostly confined to the first 6 months after DES implantation. However, specifically designed randomized studies are required to establish the optimal length of clopidogrel therapy after DES implantation.
Aims Percutaneous treatment of coronary bifurcation disease remains challenging. In patient subsets in which a two-stent strategy is necessary, the culotte technique is a widely used method. We ...sought to examine the clinical and angiographic outcomes of patients treated in this manner at our institution. As quantitative coronary angiographic analysis using standard measurement programmes is problematic, we used a dedicated bifurcation analysis system. Methods and results We prospectively enrolled patients undergoing culotte stenting with drug-eluting stents (Cypher, Endeavor, polymer-free rapamycin-eluting, Taxus) in two German centres. Lesions were classified according to the Medina classification. Angiographic follow-up was scheduled between 6 and 12 months post-index procedure. Clinical follow-up was available up to 12 months. Culotte technique was used in 134 lesions in 132 patients. Of these, 124 (92.5%) represented ‘true bifurcation’ lesion morphology. Kissing balloon inflation was used in 62% of patients. Procedural angiographic success was achieved in all lesions. Follow-up coronary angiography was performed in 108 (81.8%) patients. Median (IQR) late lumen loss was 0.10 (−0.04 – 0.38) mm in the proximal main vessel, 0.34 (0.03 – 0.66) mm in the distal main branch, and 0.30 (−0.01 – 0.72) mm in the side branch. The incidence of binary angiographic restenosis was 22% for the whole bifurcation lesion, 0% in the proximal main vessel, 9.1% in the distal main branch, and 16% in the side branch. At 12 months, 28 of 132 (21%) patients had undergone target lesion revascularization. The incidence of stent thrombosis (at 1 year) was 1.5%. Predictors of angiographic restenosis were older age, increasing bifurcation angle, more severe distal main branch stenosis, and smaller side branch reference diameter; kissing balloon post-dilatation tended to have a protective effect. Conclusion The culotte stenting technique is associated with high procedural success and a relatively low risk of angiographic restenosis. Safety results in our cohort were favourable in terms of a low risk of stent thrombosis.
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.
Whether gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) is a better prognostic marker in patients with coronary heart disease (CHD) remains unknown. The aim of this study was to ...compare the prognostic value of GGT and ALP in patients with CHD.
This study included 3768 patients with CHD. The main study outcome was 3-year all-cause mortality. The median values of GGT and ALP were 36.2 U/L and 69.3 U/L. Patients were divided into subgroups according to GGT or ALP activity > or ≤median. Overall, there were 304 deaths: 195 deaths occurred in patients with GGT >median (n = 1882) and 109 deaths occurred in patients with GGT ≤median (n = 1886); Kaplan–Meier KM estimates of all-cause mortality were 11.9% and 6.4% (unadjusted hazard ratio HR = 1.85, 95% confidence interval CI, 1.46 to 2.34; P < 0.001). According to ALP activity, 186 deaths occurred in patients with ALP >median (n = 1883) and 118 deaths occurred in patients with ALP ≤median (n = 1885); KM estimates of all-cause mortality were 11.4% and 7.1% (unadjusted HR = 1.64 1.30–2.06; P < 0.001). After adjustment, GGT (adjusted HR = 1.32 1.11–1.58; P = 0.002) but not ALP (adjusted HR = 1.20 1.00–1.43; P = 0.051, with both HR calculated per 1 unit increment in logarithmic GGT or ALP scale) remained significantly associated with the risk for mortality. The C statistic of the mortality model with GGT was greater than the C statistic of the model with ALP (0.831 0.802–0.859 vs. 0.826 0.793–0.855; P < 0.001).
In patients with CHD, GGT was a stronger correlate of all-cause mortality than ALP.
•Gamma-glutamyl transferase (GGT) was a stronger correlate of all-cause mortality than alkaline phosphatase (ALP).•GGT was a better discriminator of the risk for all-cause mortality than ALP.•Neither GGT nor ALP improved the risk prediction for cardiac mortality.•GGT and ALP may reflect different aspects of increased cardiovascular risk.
Background No studies have measured plasma myeloperoxidase (MPO) across the entire spectrum of patients with coronary artery disease (CAD). The aim of the study was to compare MPO level across the ...entire spectrum of CAD, to assess the accuracy of MPO in predicting acute coronary syndromes and to define independent correlates of MPO level.
Design This case–control study included 874 patients with angiographically proven CAD. Cases included 680 patients with CAD (382 patients with stable CAD, 107 patients with non‐ST‐segment elevation acute coronary syndromes and 191 patients with ST‐segment elevation acute myocardial infarction). Controls included 194 subjects with normal coronary angiograms. MPO was measured using an enzyme immunoassay before angiography and heparin administration.
Results MPO level median (25th–75th percentiles) was 74·5 (52·5–135·3) µg L−1 in cases vs. 61·2 (44·6–80·9), µg L−1 in controls (P < 0·001). MPO level was 61·2 (47·5–85·8), µg L−1 in patients with stable CAD, 99·2 (62·2–154·9), µg L−1 in patients with non‐ST‐segment elevation acute coronary syndromes and 129·5 (72·2–216·0) µg L−1 in patients with acute myocardial infarction (P < 0·001). Elevated MPO level was associated with acute coronary syndromes with an area under receiver operating characteristic (ROC) curve of 0·731 (95% confidence interval 0·692–0·770; P < 0·001). Independent correlates of MPO level were acute coronary syndrome (P < 0·001), high‐sensitivity C‐reactive protein (P = 0·007), creatinine (P = 0·026), left ventricular ejection fraction (P = 0·027, negative association) and smoking (P = 0·028).
Conclusions MPO level is elevated in patients with CAD and higher levels of MPO were found with progression of CAD from stable CAD to non‐ST‐segment elevation acute coronary syndromes and to acute myocardial infarction.
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Objectives. Optimal antithrombotic/anticoagulation therapy in patients on chronic oral anticoagulation (OAC) undergoing drug‐eluting stent (DES) implantation is unknown. We investigated the ...efficacy and safety of two regimens of antithrombotic/anticoagulation therapy in patients who present for DES implantation whilst on OAC.
Methods. We included a series of 515 patients on OAC who underwent DES implantation between 2002 and 2007. Based on predefined clinical and echocardiographic criteria, 306 patients continued OAC (triple therapy) and 209 patients discontinued OAC (dual therapy) for the time they received antiplatelet therapy with clopidogrel and aspirin stent‐related antithrombotic treatment (SRAT). The primary end point was a composite of death, myocardial infarction, stent thrombosis or stroke.
Results. During SRAT the primary endpoint was observed in 13 patients in the group with triple therapy versus 15 patients in the group with dual therapy Kaplan–Meier estimates 4.2% and 7.2%, odds ratio (OR) = 0.61, 95% confidence interval (CI) 0.29–1.28; P = 0.19. At 2 years of follow‐up, the primary endpoint was observed in 35 patients in the group with triple therapy versus 36 patients in the group with dual therapy (Kaplan–Meier estimates 14.1% and 18.0%, OR = 0.76, 95% CI: 0.48–1.21; P = 0.25). Two‐year incidence of major bleeding was 1.4% (n = 4, triple therapy) versus 3.1% (n = 6, dual therapy) (P = 0.34).
Conclusions. In patients on chronic OAC undergoing DES implantation, clinical and echocardiographic criteria help to define postprocedural antithrombotic/anticoagulation therapy. Based on these criteria, both a double antiplatelet therapy (clopidogrel plus aspirin) and a triple therapy (OAC plus clopidogrel plus aspirin) are associated with favourable safety and efficacy.
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