Machine Learning Identifies New Predictors on Restenosis Risk after Coronary Artery Stenting in 10,004 Patients with Surveillance Angiography.

OBJECTIVE: Machine learning (ML) approaches have the potential to uncover regular patterns in multi-layered data. Here we applied self-organizing maps (SOMs) to detect such patterns with the aim to better predict in-stent restenosis (ISR) at surveillance angiography 6 to 8 months after percutaneous coronary intervention with stenting. METHODS: In prospectively collected data from 10,004 patients receiving percutaneous coronary intervention (PCI) for 15,004 lesions, we applied SOMs to predict ISR angiographically 6-8 months after index procedure. SOM findings were compared with results of conventional uni- and multivariate analyses. The predictive value of both approaches was assessed after random splitting of patients into training and test sets (50:50). RESULTS: Conventional multivariate analyses revealed 10, mostly known, predictors for restenosis after coronary stenting: balloon-to-vessel ratio, complex lesion morphology, diabetes mellitus, left main stenting, stent type (bare metal vs. first vs. second generation drug eluting stent), stent length, stenosis severity, vessel size reduction, and prior bypass surgery. The SOM approach identified all these and nine further predictors, including chronic vessel occlusion, lesion length, and prior PCI. Moreover, the SOM-based model performed well in predicting ISR (AUC under ROC: 0.728); however, there was no meaningful advantage in predicting ISR at surveillance angiography in comparison with the conventional multivariable model (0.726, p = 0.3). CONCLUSIONS: The agnostic SOM-based approach identified-without clinical knowledge-even more contributors to restenosis risk. In fact, SOMs applied to a large prospectively sampled cohort identified several novel predictors of restenosis after PCI. However, as compared with established covariates, ML technologies did not improve identification of patients at high risk for restenosis after PCI in a clinically relevant fashion.

Polymer-free sirolimus-eluting versus polymer-based paclitaxel-eluting stents: an individual patient data analysis of randomized trials.

INTRODUCTION AND OBJECTIVES: The angiographic and clinical efficacy of polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents remain a matter of debate. We sought to investigate angiographic and clinical measures of efficacy of polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents. METHODS: Patient data from the randomized intracoronary stenting and angiographic restenosis-test equivalence between the 2 drug-eluting stents (ISAR-TEST) clinical trial and the LIPSIA Yukon clinical trial (randomized comparison of a polymer-free sirolimus-eluting stent vs a polymer-based paclitaxel-eluting stent in patients with diabetes mellitus) were pooled. The angiographic (primary) endpoint was in-stent late lumen loss at 6 months to 9 months. The clinical (secondary) endpoints were death or myocardial infarction, cardiac death or myocardial infarction, target lesion revascularization, and myocardial infarction. RESULTS: A total of 686 patients (polymer-free sirolimus-eluting stents, n=345 vs polymer-based paclitaxel-eluting stents, n=341) and 751 lesions (polymer-free sirolimus-eluting stents, n=383 vs polymer-based paclitaxel-eluting stents, n=368) were included in the study. Control angiography (606 lesions, 80.6%) showed comparable in-stent late lumen loss for polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents (0.53 [0.59] mm vs 0.46 [0.57] mm; P=.15). Median follow-up was 34.8 months. Polymer-free sirolimus-eluting stents and polymer-based paclitaxel-eluting stents were associated with comparable risk of death or myocardial infarction (relative risk=1.17; 95% confidence interval, 0.49-2.80; P=.71), cardiac death or myocardial infarction (relative risk=1.17; 95% confidence interval, 0.72-1.89; P=.50), target lesion revascularization (relative risk=0.98; 95% confidence interval, 0.65-1.47; P=.93), and myocardial infarction (relative risk=1.79; 95% confidence interval, 0.85-3.76; P=.12). CONCLUSIONS: In this pooled analysis, polymer-free sirolimus-eluting stents were comparable to polymer-based paclitaxel-eluting stents with respect to both angiographic and clinical efficacy.

Image quality and radiation exposure with prospectively ECG-triggered axial scanning for coronary CT angiography: the multicenter, multivendor, randomized PROTECTION-III study.

OBJECTIVES: The purpose of this study was to evaluate image quality and radiation dose using a prospectively electrocardiogram (ECG)-triggered axial scan protocol compared with standard retrospective ECG-gated helical scanning for coronary computed tomography angiography. BACKGROUND: Concerns have been raised regarding radiation exposure during coronary computed tomography angiography. Although the use of prospectively ECG-triggered axial scan protocols may effectively lower radiation dose compared with helical scanning, it is unknown whether image quality is maintained in a clinical setting. METHODS: In a prospective, multicenter, multivendor trial, 400 patients with low and stable heart rates were randomized to either an axial or a helical coronary computed tomography angiography scan protocol. The primary endpoint was to demonstrate noninferiority in image quality with the axial scan protocol, which was assessed on a 4-point scale (1 = nondiagnostic, 4 = excellent image quality). Secondary endpoints included radiation dose and the rate of downstream testing during 30-day follow-up. RESULTS: Image quality in patients scanned with the axial scan protocol (score 3.36 ± 0.59) was not inferior compared with helical scan protocols (3.37 ± 0.59) (p for noninferiority <0.004). Axial scanning was associated with a 69% reduction in radiation exposure (dose-length product [estimated effective dose] 252 ± 147 mGy · cm [3.5 ± 2.1 mSv] vs. 802 ± 419 mGy · cm [11.2 ± 5.9 mSv] for axial vs. helical scan protocols, p < 0.001). The rate of downstream testing did not differ (13.8% vs. 15.9% for axial vs. helical scan protocols, p = 0.555). CONCLUSIONS: In patients with stable and low heart rates, the prospectively ECG-triggered axial scan protocol maintained image quality but reduced radiation exposure by 69% compared with helical scanning. Axial computed tomography data acquisition should be strongly recommended in suitable patients to avoid unnecessarily high radiation exposure.

Validation of the Bleeding Academic Research Consortium definition of bleeding in patients with coronary artery disease undergoing percutaneous coronary intervention.

BACKGROUND: The Bleeding Academic Research Consortium (BARC) has recently proposed a unified definition of bleeding in patients receiving antithrombotic therapy. We investigated the relationship between bleeding events as defined by BARC and 1-year mortality in patients undergoing percutaneous coronary intervention (PCI) and assessed whether the BARC bleeding definition is superior to existing bleeding definitions in regard to mortality prediction in patients after PCI procedures. METHODS AND RESULTS: This study represents a patient-level pooled analysis of 12 459 patients recruited in 6 randomized trials of patients undergoing PCI. Bleeding events were assessed with the use of BARC, Thrombolysis in Myocardial Infarction (TIMI), and Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial criteria. The primary outcome was 1-year mortality. Bleeding occurred in 1233 patients (9.9%) according to BARC (679 patients or 5.4% with BARC class ≥2 bleeding), in 374 patients (3.0%) according to TIMI, and in 491 patients (3.9%) according to REPLACE-2 criteria. There were 340 deaths (2.7%) over the first year after PCI. BARC class ≥2 bleeding was associated with a significant increase in 1-year mortality (adjusted hazard ratio 2.72; 95% confidence interval, 2.03-3.63). The predictivity of a multivariable model for 1-year mortality was significantly improved after inclusion of bleeding defined according to BARC to an extent comparable to that provided by TIMI and REPLACE-2 criteria. CONCLUSIONS: The present study demonstrated a close association between bleeding events defined according to BARC and 1-year mortality after PCI.

Cardiovascular risk assessment based on the quantification of coronary calcium in contrast-enhanced coronary computed tomography angiography.

AIMS: The extent of coronary artery calcification (CAC) has been shown to be a strong and independent predictor for cardiovascular events. Usually, CAC scoring is performed in non-contrast-enhanced computed tomography (CT) examinations. The ability and accuracy of cardiovascular risk classification according to the degree of CAC determined in contrast-enhanced coronary CT angiography (CCTA) has not been investigated so far. The aim of this analysis was to develop and validate a method for CAC risk classification in CCTA. METHODS AND RESULTS: In a test series of 100 patients who underwent both non-enhanced CAC scoring and CCTA, we developed a method to assess the extent of coronary calcification and the associated cardiovascular risk category in CCTA. The accuracy of the developed approach of CAC assessment in CCTA was determined in 500 consecutive patients in comparison to CAC scoring in the non-enhanced scan. CAC scoring results in the non-enhanced scan and CCTA scan showed a high correlation (r = 0.954; P < 0.001). CAC quantification in CCTA correctly identified 98% of patients without CAC as shown in the non-enhanced scan (184 of 188 patients). When compared with non-enhanced CAC scoring, CAC scoring in CCTA grouped more than 95% of high-risk patients correctly into the same risk category according to the 75th age- and gender-specific percentiles or the absolute calcium scores. CONCLUSION: Assessing cardiovascular risk associated with CAC is feasible and accurate in contrast-enhanced CCTA. This new technique may allow for reducing the radiation exposure of coronary CT studies while maintaining an accurate cardiovascular risk assessment, because the addition of non-enhanced scans to CCTA becomes unnecessary for comprehensive coronary CT studies.

Interleukin 18 gene variation and risk of acute myocardial infarction.

Interleukin 18 is an important mediator of inflammation and has been associated with the development and aggravation of cardiovascular diseases. We report that common variation in the interleukin 18 gene is related to acute myocardial infarction, a frequent clinical manifestation of atherosclerosis and thrombosis in coronary arteries. In a population of European, mainly (90%) German, ancestry (2136 cases with acute myocardial infarction and 1211 controls), the association was based on specific alleles and haplotypes derived from a set of six tagging single nucleotide polymorphisms. The rs1946519-G (located in the 5' upstream region), rs360717-C (exon 1), rs5744241-G (intron 1), rs1834481-C (intron 3), and rs3882891-A (intron 5) alleles (P≤0.039) and a haplotype (GCGCAG haplotype; P=0.0028) containing the GCGCA motif derived from these alleles were associated with an increased risk of AMI. Corresponding with this result, the complementary alleles (rs1946519-T, rs360717-T, rs5744241-A, rs1834481-G, and rs3882891-C) and a haplotype (TTAGCG haplotype; P=0.018) with the TTAGC motif showed protective effects. Haplotypes not including the GCGCA or TTAGC motif were not related to AMI (P≥0.22). These observations suggest that the interleukin 18 gene is a susceptibility locus for acute myocardial infarction, a finding of potential interest in the clinical practice.

Impact of smoking on antiplatelet effect of clopidogrel and prasugrel after loading dose and on maintenance therapy.

BACKGROUND: Pharmacodynamic studies reported an amplified on-clopidogrel platelet inhibition in smokers potentially caused by an increased metabolic drug activation via induction of cytochrome P450 1A2. The aims of this analysis were to evaluate the impact of smoking on the antiplatelet effect of clopidogrel and prasugrel and to test the potential interaction of smoking with the treatment effect of these drugs. METHODS: A variety of platelet function results was analyzed from 2 large cohorts of patients undergoing coronary intervention after loading with clopidogrel 600 mg (n = 2,533 and n = 1,996), a cohort of patients undergoing dose adaptation from 75 to 150 mg according to response to clopidogrel (n = 117) and a crossover trial comparing clopidogrel 150 mg with prasugrel 10 mg (n = 87). Linear regression analyses were used to test the impact of smoking on platelet function and to identify independent predictors of on-treatment platelet reactivity. The potential interaction of smoking with the clinical effect of clopidogrel versus prasugrel was analyzed in the TRITON-TIMI 38 cohort (n = 13,608). RESULTS: No significant association of smoking with platelet reactivity on clopidogrel was seen in unadjusted and adjusted analyses. The variables most consistently associated with on-clopidogrel platelet function were age, sex, diabetes, and body mass index. There was no significant interaction of smoking status at presentation with the clinical efficacy of prasugrel versus clopidogrel (P for interaction = .39). CONCLUSIONS: Smoking does not impact on platelet reactivity in patients after loading or on different maintenance doses of clopidogrel. The clinical treatment effect of clopidogrel versus prasugrel is not affected by smoking status at presentation.

Drug-eluting versus bare-metal stents in saphenous vein graft lesions (ISAR-CABG): a randomised controlled superiority trial.

BACKGROUND: Comparative assessment of clinical outcomes after use of drug-eluting stents versus bare-metal stents for treatment of aortocoronary saphenous vein graft lesions has not been undertaken in large randomised trials. We aimed to undertake a comparison in a randomised trial powered for clinical endpoints. METHODS: In this randomised superiority trial, patients with de-novo saphenous vein graft lesions were assigned by computer-generated sequence (1:1:1:3) to receive either drug-eluting stents (one of three types: permanent-polymer paclitaxel-eluting stents, permanent-polymer sirolimus-eluting stents, or biodegradable-polymer sirolimus-eluting stents) or bare-metal stents. Randomisation took place immediately after crossing of the lesion with a guidewire, and was stratified for each participating centre. Investigators assessing data were masked to treatment allocation; patients were not masked to allocation. The primary endpoint was the combined incidence of death, myocardial infarction, and target lesion revascularisation at 1 year. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00611910. FINDINGS: 610 patients were allocated to treatment groups (303 drug-eluting stent, 307 bare-metal stent). Drug-eluting stents reduced the incidence of the primary endpoint compared with bare-metal stents (44 [15%] vs 66 [22%] patients; hazard ratio [HR] 0.64, 95% CI 0.44-0.94; p=0.02). Target lesion revascularisation rate was reduced by drug-eluting stents (19 [7%] vs 37 [13%] patients; HR 0.49, 95% CI 0.28-0.86; p=0.01). No significant differences were seen between drug-eluting stents and bare-metal stents regarding all-cause mortality (15 [5%] vs 14 [5%] patients; HR 1.08, 95% CI 0.52-2.24; p=0.83), myocardial infarction (12 [4%] vs 18 [6%]; HR 0.66, 95% CI 0.32-1.37; p=0.27), or definite or probable stent thrombosis (2 [1%] in both groups; HR 1.00, 95% CI 0.14-7.10; p=0.99). INTERPRETATION: In patients undergoing percutaneous coronary intervention for de-novo saphenous vein graft lesions, drug-eluting stents are the preferred treatment option because they reduce the risk of adverse events compared with bare-metal stents. FUNDING: Deutsches Herzzentrum.

Influence of abciximab on evolution of left ventricular function in patients with non-ST-segment elevation acute coronary syndromes undergoing PCI after clopidogrel pretreatment: lessons from the ISAR-REACT 2 trial.

BACKGROUND: Abciximab reduced the combined endpoint of death, myocardial infarction (MI) and target vessel revascularization in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation after a 600-mg loading dose of clopidogrel. The aim of the present study was to investigate the impact of abciximab on the evolution of left ventricular ejection fraction (LVEF) in these patients. METHODS: The current study included 1,158 patients enrolled in the randomized, double-blind ISAR-REACT 2 (the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial who had paired angiograms obtained at baseline and 6-8 months after randomization. Of them, 586 patients received abciximab and 572 patients received placebo. The primary outcome analysis was LVEF at 6-8-month follow-up. RESULTS: Baseline LVEF was comparable in patients assigned to abciximab or placebo (53.2 ± 12.6 vs. 53.7 ± 12.1%; P = 0.393). At 6-8-month follow-up angiography, there was no difference in LVEF between the abciximab and placebo groups (55.4 ± 11.5 vs. 55.8 ± 11.2%; P = 0.743). Subgroup analysis of patients with elevated baseline troponin (>0.03 µg/L) also revealed comparable LVEF at follow-up in both treatment groups (P = 0.527). The multivariate analysis identified age, arterial hypertension, prior MI, prior coronary artery bypass graft surgery, baseline LVEF, MI at 30 days and repeat PCI as independent correlates of follow-up LVEF. CONCLUSION: Although abciximab reduced the 30-day and 1-year incidence of major adverse cardiac events in patients with NSTE-ACS undergoing primary PCI after pre-treatment with a 600-mg loading dose of clopidogrel, the agent did not improve or impact on the evolution of LVEF over 6-8 months of follow-up.

Lack of impact of calcium-channel blockers on the pharmacodynamic effect and the clinical efficacy of clopidogrel after drug-eluting stenting.

BACKGROUND: Clopidogrel is a prodrug that is metabolized to its active metabolite by the hepatic cytochrome P450 system. Calcium-channel blockers (CCBs) are metabolized by the same pathway and may therefore attenuate the antiplatelet effect of clopidogrel. The aim of this study was to assess the impact of CCB therapy on the pharmacodynamic effect and the clinical efficacy of clopidogrel after drug-eluting stent placement. METHODS: A total of 1,608 consecutive patients were previously enrolled in a study that aimed to assess the relation between platelet reactivity and outcomes after coronary stenting. Here, this cohort was analyzed according to concomitant CCB therapy at admission. The primary pharmacodynamic end point was adenosine diphosphate-induced platelet aggregation (in AU · min) with multiple electrode platelet aggregometry after loading with 600 mg clopidogrel. The primary clinical end point was combination of death or definite stent thrombosis (ST) at 30 days. Secondary end points included definite ST alone, myocardial infarction, stroke, and death. RESULTS: Two hundred thirty-two patients (14.4%) were on CCBs on admission. Compared with patients with CCB medication, patients without CCB medication showed no significant difference in median [interquartile range] platelet aggregation values (232 [142-365] vs 223 [141-368] AU · min, P = .53). There was also no significant difference regarding the clinical end point of death or ST (2 [0.9%] vs 16 [1.2%], odds ratio 0.74, 95% CI 0.17-3.2, P = .69) between both groups. CONCLUSION: In our population, concomitant CCB therapy did not alter clopidogrel-mediated platelet aggregation and did not have a measurable impact on ST and mortality after coronary stenting.

Extended evidence for association between the melanoma inhibitory activity 3 gene and myocardial infarction.

In a genome-wide scan, isolated single nucleotide polymorphisms (SNPs), including rs17465637, in the melanoma inhibitory activity 3 gene (MIA3) on chromosome 1 were identified to be associated with coronary artery disease and myocardial infarction (MI). Because the role of common variation at the MIA3 locus has not yet been investigated, the aim of this case-control study was to determine the impact of haplotype-tagging SNPs and haplotypes in the MIA3 region on the risk of MI. In a set of nine haplotype-tagging SNPs, rs17465637, but none of the other SNPs, was associated with MI. After adjustments were made for age, gender, history of arterial hypertension, history of hypercholesterolaemia, current cigarette smoking and diabetes mellitus, multiple logistic regression analyses showed an increased risk in the carriers of one or two C alleles [adjusted odds ratio (OR) 1.17, 95% confidence interval (CI) 1.04-1.32, and 1.37, 95% CI 1.08-1.74, respectively]. Nine common haplotypes (frequency >1%) were established across the MIA3 region. Two of the haplotypes were associated with an increased risk of MI: the frequent (48%) TGACCAAAG haplotype and the rare (2%) CGACCAAAG haplotype (adjusted OR 1.102, 95% CI 1.002-1.212, and 1.574, 95% CI 1.077-2.298, respectively). Showing association between rs17465637 and MI, this work was consistent with results from the original detection study and most prior replication studies addressing this issue. In addition to correspond with such isolated evidence of association with MI, the present study identified specific haplotypes capturing the risk-related variation in the entire MIA3 region.

Effects of G-CSF on systemic inflammation, coagulation and platelet activation in patients with acute myocardial infarction.

INTRODUCTION: In the prospective, randomised, double-blind, placebo-controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL)-2 trial patients with acute myocardial infarction (AMI) and successful mechanical reperfusion received granulocyte-colony stimulating factor (G-CSF, 10 µg/kg KG s.c.) or placebo for 5 days. Aim of this substudy was to assess the impact of G-CSF on systemic inflammatory and procoagulant responses and platelet activation. METHODS AND RESULTS: Before and five days after G-CSF (n=56) or placebo (n=58) circulating cytokine concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12 and Tumor-Necrosis Factor-α (TNF-α were measured. Prothrombin fragment F1+2 and Tissue Factor activity served as a measure for activated coagulation. Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor (PAC-1), P-selectin and CD40L by flow cytometry. Administration of G-CSF was associated with elevated TNF-α and CRP concentrations compared to the placebo group after 5 days. Other cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12) were comparable after treatment with G-SCF or placebo. Similarly, circulating prothrombin fragments F1+2, TF activity and platelet activation did not differ in both groups. CONCLUSION: Treatment with G-CSF in patients with AMI was associated with enhanced proinflammatory TNF-α and CRP levels but no activation of coagulation.

Prognostic value of coronary computed tomographic angiography in comparison with calcium scoring and clinical risk scores.

BACKGROUND: Several studies have demonstrated a high accuracy of coronary computed tomography angiography (CCTA) for detection of obstructive coronary artery disease (CAD), whereas some studies have also shown a good prediction of cardiac events. However, it remains to be proven whether CCTA is better predictive of events than conventional risk scores or calcium scoring. Therefore, we compared CCTA with calcium scoring and clinical risk scores for the ability to predict cardiac events. METHODS AND RESULTS: Patients (n=2223) with suspected CAD undergoing CCTA were followed up for a median of 28 months. The end point was the occurrence of cardiac events (cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, and coronary revascularization later than 90 days after CCTA). Patients with obstructive CAD had a significantly higher event rate (2.9% per year; 95% confidence interval, 2.1 to 4.0) than those without obstructive CAD, having an event rate 0.3% per year (95% confidence interval, 0.1 to 0.5; hazard ratio, 13.5; 95% confidence interval, 6.7 to 27.2; P<0.001). CCTA had significant incremental predictive value when compared with calcium scoring, both with scores assessing the degree of stenosis (P<0.001) and with scores assessing the number of diseased coronary segments (P=0.027). CONCLUSIONS: In patients with suspected CAD, CCTA not only detects coronary stenosis but also improves prediction of cardiac events over and above conventional risk scores and calcium scoring. This may result in a reclassification of cardiovascular risk in a substantial proportion of patients.

Image quality and radiation exposure with a low tube voltage protocol for coronary CT angiography results of the PROTECTION II Trial.

OBJECTIVES: The purpose of this study was to evaluate image quality and radiation dose using a 100 kVp tube voltage scan protocol compared with standard 120 kVp for coronary computed tomography angiography (CTA). BACKGROUND: Concerns have been raised about radiation exposure during coronary CTA. The use of a 100 kVp tube voltage scan protocol effectively lowers coronary CTA radiation dose compared with standard 120 kVp, but it is unknown whether image quality is maintained. METHODS: We enrolled 400 nonobese patients who underwent coronary CTA: 202 patients were randomly assigned to a 100 kVp protocol and 198 patients to a 120 kVp protocol. The primary end point was to demonstrate noninferiority in image quality with the 100 kVp protocol, which was assessed by a 4-point grading score (1 = nondiagnostic, 4 = excellent image quality). For the noninferiority analysis, a margin of -0.2 image quality score points for the difference between both scan protocols was pre-defined. Secondary end points included radiation dose and need for additional diagnostic tests during follow-up. RESULTS: The mean image quality scores in patients scanned with 100 kVp and 120 kVp were 3.30 ± 0.67 and 3.28 ± 0.68, respectively (p = 0.742); image quality of the 100 kVp protocol was not inferior, as demonstrated by the 97.5% confidence interval of the difference, which did not cross the pre-defined noninferiority margin of -0.2. The 100 kVp protocol was associated with a 31% relative reduction in radiation exposure (dose-length product: 868 ± 317 mGy × cm with 120 kVp vs. 599 ± 255 mGy × cm with 100 kVp; p < 0.0001). At 30-day follow-up, the need for additional diagnostic studies did not differ (13.4% vs. 19.2% for 100 kVp vs. 120 kVp, respectively; p = 0.114). CONCLUSIONS: A coronary CTA protocol using 100 kVp tube voltage maintained image quality, but reduced radiation exposure by 31% as compared with the standard 120 kVp protocol. Thus, 100 kVp scan protocols should be considered for nonobese patients to keep radiation exposure as low as reasonably achievable. (Prospective Randomized Trial on Radiation Dose Estimates of Cardiac CT Angiography in Patients Scanned With a 100 kVp Protocol [PROTECTION II]; NCT00611780).

Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment.

Inflammatory processes in the vessel wall are associated with progression of atherosclerosis and myocardial infarction. Both high levels of C-reactive protein (CRP)and high on-clopidogrel treatment platelet reactivity (HPR) have been linked to an increased risk of ischaemic events after percutaneous coronary intervention (PCI). The aim of this study was to explore the association between biomarker levels of inflammation and platelet reactivity. Stable patients (n=1,223) eligible for this study were under chronic antiplatelet treatment with aspirin and clopidogrel due to prior coronary stent placement. ADP-induced platelet aggregation (in AU*min) was measured on a Multiplate analyser. The primary outcome measure of this retrospective study was the ADP-induced platelet aggregation in patients with versus those without elevated CRP levels. Of the patients 15.5% (n=189) showed elevated CRP levels (≥5 mg/l). Platelet aggregation (median [interquartile range]) was significantly higher in patients with elevated CRP levels compared to patients with normal (<5 mg/l) CRP levels (305 [202-504] AU*min vs. 218 [144-384] AU*min; p<0.001).A multivariable linear regression model that adjusted for known predictors of HPR confirmed a significant independent association between elevated CRP levels and high ADP-induced platelet aggregation values (p=0.0002).Elevated WBC count and fibrinogen levels were also associated with higher platelet aggregation values (p<0.001 for both). In conclusion, elevated levels of CRP, WBC count and fibrinogen were significantly associated with high platelet reactivity in patients under chronic clopidogrel treatment. Whether a direct relation between platelets and inflammation exists, as well as the clinical impact of our results, warrants further investigations.

Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events.

BACKGROUND: The prodrug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding enzymes for clopidogrel activation are polymorphic, leading to reduced or increased function, depending on the respective genotype. Reduced-function alleles have been associated with an increase in cardiovascular events. METHODS: We tested the association of the presence of the ABCB1 (C/T) T-allele, CYP2C19*2 (G/A) A-allele, or CYP2C19*17 (C/T) T-allele with the primary end point of the need of clinically-driven target lesion revascularization (TLR) and the secondary end points of major adverse cardiovascular events (MACE; including death, myocardial infarction [MI], and TLR) at 1 year in a high-risk population of 928 patients with acute MI. RESULTS: Carriers of the CYP2C19*17 T-allele, with increased clopidogrel activation, had a 37% relative reduction in the TLR incidence, the primary end point (14.0% vs 22.3%, P = .002), and a 22% relative reduction of the secondary end point MACE (22.0% vs 28.1%, P = .04) compared with noncarriers, respectively. The association of the T-allele with TLR remained significant in the multivariate analysis (P = .001). The ABCB1 (C/T) and the CYP2C19*2 (G/A) polymorphisms were not associated with the incidence of TLR or MACE. CONCLUSIONS: Based on the genetic analysis in a high-risk population of acute MI patients with interventional treatment and continuous clopidogrel therapy, our study found a protective effect for carriers of an increased-function CYP2C19*17 T-allele with significantly lower rates of TLR and MACE. T-allele carriers with acute MI and increased clopidogrel activation had significantly reduced clinical event rates.

Platelet response to clopidogrel and restenosis in patients treated predominantly with drug-eluting stents.

BACKGROUND: Preclinical studies suggest a relationship between early thrombotic response after vascular injury and later development of restenosis. The aim of this study was to assess the impact of platelet response to clopidogrel on the risk of restenosis after drug-eluting stenting (DES). METHODS: A total of 1,608 consecutive patients were previously enrolled in a study on the relation between platelet reactivity and outcomes after DES. All patients received a loading dose of 600 mg clopidogrel. Blood samples for the assessment of adenosine diphosphate-induced platelet aggregation with multiple electrode platelet aggregometry were drawn directly before percutaneous coronary intervention. Clopidogrel low response was defined as upper quintile of multiple electrode platelet aggregometry measurements. Accordingly, 323 patients (20%) were considered as low and 1,285 (80%) as normal responders. Primary end point of the present study was target lesion revascularization at 1 year. Secondary end points included binary angiographic restenosis and late lumen loss at 6- to 8-month angiography. RESULTS: Target lesion revascularization rates were comparable in both groups (10.9% vs 9.5%, hazard rate [HR] 1.2, 95% CI 0.8-1.7, P = .441). Follow-up angiography revealed no difference in binary angiographic restenosis (13.9% vs 15.9%, P = .445) and late lumen loss (0.32 +/- 0.64 vs 0.35 +/- 0.63 mm, P = .477). Low responders had significantly more stent thromboses (2.5% vs 0.5%, HR 5.4, 95% CI 1.9-15.6, P = .002), Q wave myocardial infarctions (2.5% vs 0.6%, HR 4.0, 95% CI 1.5-10.7, P = .005), and ischemic strokes (1.3% vs 0.2%, HR 5.4, 95% CI 1.2-24.0, P = .028) at 1 year. CONCLUSION: Low platelet responsiveness to clopidogrel, a known predictor of thrombotic complications, does not have a significant impact on restenosis after DES.

Comparison of sequential and helical scanning for radiation dose and image quality: results of the Prospective Multicenter Study on Radiation Dose Estimates of Cardiac CT Angiography (PROTECTION) I Study.

OBJECTIVE: Concerns have been raised about the radiation exposure of coronary CT angiography (CTA). Recently, a prospective ECG-triggered sequential coronary CTA technique was developed to reduce exposure to ionizing radiation. The purpose of this analysis was to determine the impact of a sequential scanning technique on image quality and radiation dose in a prespecified subgroup analysis of the Prospective Multicenter Study on Radiation Dose Estimates of Cardiac CT Angiography I (PROTECTION I) Study when compared with a standard helical scanning technique. MATERIALS AND METHODS: This analysis comprises 685 64-MDCT coronary angiography studies of 47 international study sites in which the image quality was assessed by an experienced coronary CTA investigator using a 4-point score (1 = nondiagnostic, 4 = excellent image quality). Image quality was analyzed in all patients studied with the sequential scanning mode (n = 99) and in randomly selected patients of the population studied with the helical acquisition mode (n = 586). Radiation dose estimates were derived from the dose-length product (DLP) and a conversion coefficient for the chest (0.014 mSv x mGy(-1) x cm(-1)). RESULTS: Although the sequential scanning mode significantly reduced radiation dose estimates by 68% from 11.2 mSv for the helical mode to 3.6 mSv for the sequential mode (p < 0.001), the median diagnostic image quality scores were comparable in both groups. The median diagnostic score for both scanning modes was 3.5 (interquartile range: sequential vs helical mode, 3.25-3.75 vs 3.0-3.75, respectively; p = 0.62). CONCLUSION: The results of the PROTECTION I Study suggest that the prospective ECG-triggered sequential coronary CTA technique significantly reduces radiation dose without impairing image quality when compared with the standard retrospective helical data acquisition in patients with a low and stable heart rate.

Randomized trial of paclitaxel- versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents: the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study.

OBJECTIVES: For patients with sirolimus-eluting stent (SES) restenosis requiring reintervention, we compared a strategy of repeat SES (Cypher, Cordis, Miami Lakes, Florida) implantation with paclitaxel-eluting stent (PES) (Taxus, Boston Scientific, Natick, Massachusetts) implantation. BACKGROUND: Despite their high anti-restenotic efficacy, the widespread utilization of SES therapy has led to a significant absolute number of patients presenting with SES treatment failure. The optimal treatment strategy for such patients remains unclear. METHODS: The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study was a randomized, open-label, active-controlled trial conducted among 450 patients with clinically significant in-SES restenosis at 2 centers in Munich, Germany. After pre-treatment with 600 mg clopidogrel, all patients were randomly assigned to either SES or PES implantation. The primary end point was late lumen loss, based on in-stent analysis, at 6- to 8-month follow-up angiography. Secondary end points were binary angiographic restenosis (diameter stenosis >50%) at 6- to 8-month follow-up, target lesion revascularization, the composite of death or myocardial infarction, and definite stent thrombosis at 12 months. RESULTS: Regarding anti-restenotic efficacy, there were no differences between SES and PES in late loss (0.40 +/- 0.65 mm vs. 0.38 +/- 0.59 mm; p = 0.85), binary restenosis (19.6% vs. 20.6%; p = 0.69), or target lesion revascularization (16.6% vs. 14.6%; p = 0.52). In terms of safety outcomes, the rates of death/myocardial infarction (6.1% vs. 5.8%; p = 0.86) and stent thrombosis (0.4% vs. 0.4%; p > 0.99) were also similar. CONCLUSIONS: In cases of SES restenosis, treatment with either repeat SES or switch to PES was associated with a comparable degree of efficacy and safety. Drug resistance at an individual patient level may play a contributory role to the somewhat higher than expected late loss observed with the SES in the current study. (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis 2 [ISAR-DESIRE 2]; NCT00598715).