High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: A landmark analysis of the ARCTIC study.

BACKGROUND: Individualizing antiplatelet therapy after platelet function testing did not improve outcome after coronary stenting in the Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC) study. Whether results are different during the phase of secondary prevention starting after hospital discharge, when periprocedural events have been excluded, is unknown. METHODS AND RESULTS: In ARCTIC, 2440 patients were randomized before coronary stenting to a strategy of platelet function monitoring (VerifyNow P2Y12/aspirin point-of-care assay) with drug adjustment in suboptimal responders to antiplatelet therapy or to a conventional strategy without monitoring and without drug or dose changes. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary end point of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization through 1 year. After discharge, the primary end point occurred in 8.6% of patients in the monitoring arm and 7.9% in the conventional arm (hazard ratio, 1.105; 95% confidence interval, 0.835-1.461; P=0.48). Stent thrombosis or urgent revascularization occurred in 4.4% and 4.5% in the monitoring and conventional arms, respectively (P=0.99). There was no difference for any of the other ischemic end points. Major bleeding event rates were 1.8% in the monitoring arm and 2.8% in the conventional arm (P=0.11), whereas major or minor bleeding event rates were 2.3% and 3.4%, respectively (P=0.10). CONCLUSIONS: Detection of platelet hyper-reactivity by platelet function testing in patients undergoing coronary stenting with further therapeutic adjustment does not reduce ischemic recurrences after intervention. On-treatment platelet hyperreactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00827411.

Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.

BACKGROUND: Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. METHODS: This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6-18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. FINDINGS: Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15-18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68-2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02-1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07-0·91]; p=0·04). INTERPRETATION: Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. FUNDING: Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

Bedside monitoring to adjust antiplatelet therapy for coronary stenting.

BACKGROUND: Patients' responses to oral antiplatelet therapy are subject to variation. Bedside monitoring offers the opportunity to improve outcomes after coronary stenting by individualizing therapy. METHODS: We randomly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary end point was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later. RESULTS: In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (hazard ratio, 1.13; 95% confidence interval [CI], 0.98 to 1.29; P=0.10). The main secondary end point, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of those in the conventional-treatment group (hazard ratio, 1.06; 95% CI, 0.74 to 1.52; P=0.77). The rate of major bleeding events did not differ significantly between groups. CONCLUSIONS: This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring. (Funded by Allies in Cardiovascular Trials Initiatives and Organized Networks and others; ARCTIC ClinicalTrials.gov number, NCT00827411.).

Impact of pre- and post-procedural anemia on the incidence of acute kidney injury and 1-year mortality in patients undergoing transcatheter aortic valve implantation (from the French Aortic National CoreValve and Edwards 2 [FRANCE 2] Registry).

OBJECTIVES: The relationship between anemia, renal insufficiency, and the outcomes of TAVI patients has not been thoroughly studied. We aimed to evaluate the influence of pre- and post-procedural anemia on the incidence of renal insufficiency, especially AKI, and on the outcomes of TAVI. METHODS: Data from the French national TAVI registry were collected in 3,472 patients who underwent TAVI between January 2010 and December 2012. Of these 2,137 were in the no/mild anemia group, 748 were in the moderate anemia group, and 587 were in the severe anemia group before TAVI. Furthermore, we divided the 3,472 patients into three groups according to post-procedural anemia, measured as post-procedural hemoglobin (Hb) drop: <2 g/dl (n=1,633, group 1), 2 to <4 g/dl (n=1,458, group 2), and >4 g/dl (n = 381, group 3). Procedure and outcome variables were compared. RESULTS: Increased severity of anemia before TAVI was associated with significantly different rates of 1-year mortality (15%, 19%, and 24%, P<0.01), with similar differences in the incidence of AKI (5%, 8%, and 10%, P<0.01). Increased severity of Hb drop was associated with significantly different rates of 1-year mortality (16%, 18%, and 23%, P<0.01), and with similar differences in the incidence of AKI (6%, 7%, and 10%, P=0.04). Both pre- and post-procedural anemia were predictors of the incidence of AKI (OR 1.82, P<0.01; OR 1.82, P<0.01, respectively) and 1-year mortality (HR 1.44, P<0.01; HR 1.50, P<0.01, respectively). CONCLUSIONS: Both pre- and post-procedural anemia were significantly associated AKI and 1-year mortality.

Usefulness of a Simple Clinical Risk Prediction Method, Modified ACEF Score, for Transcatheter Aortic Valve Implantation.

BACKGROUND: We assessed the predictive accuracy of a simple risk score, modified age, creatinine clearance, ejection fraction (ACEFmodif) score, for outcome of transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: We prospectively included 703 consecutive patients undergoing TAVI. Patients were divided into low, middle and high ACEFmodif tertiles. Increased ACEFmodif score was associated with a significantly higher 1-year mortality rate (22%, 28% and 36%, P<0.01) and higher risk of acute kidney injury (AKI; 10%, 10% and 22%, P<0.01). On multivariate logistic regression analysis, ACEFmodif score was the only independent predictor of AKI. On multivariate Cox regression, ACEFmodif score was an independent predictor of 1-year cumulative mortality. Although the area under curve (AUC) showed that all risk scores poorly predicted the incidence of AKI and 1-year cumulative mortality, ACEFmodif score was more efficient in predicting the incidence of AKI compared with STS, LES and ES II (AUC, 0.61, 0.55, 0.54, 0.57, respectively). Furthermore, ACEFmodif score had similar accuracy in predicting 1-year mortality compared with other risk scores (AUC, 0.61, 0.61, 0.61, 0.61, respectively). CONCLUSIONS: ACEFmodif score may provide useful information for predicting AKI, 30-day and 1-year mortality in patients undergoing TAVI, but these results need further confirmation.

Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study.

BACKGROUND: The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy or to a conventional strategy without monitoring and drug adjustment. No significant improvement in clinical outcomes with platelet function monitoring was observed. OBJECTIVE: The purpose of this study is to assess the relationships between CYP2C19 genotypes, clopidogrel pharmacodynamic response, and clinical outcome. METHODS AND RESULTS: In the ARCTIC-GENE study, 1394 patients were genotyped for loss- and gain-of-function CYP2C19 alleles. Randomization of treatment strategy was well balanced. Slow metabolizers identified as carriers of at least one loss-of-function allele CYP2C19*2 (n = 459) were more likely poor responders at randomization (41.6 vs. 31.6%, p = 0.0112) and 14 days later (23.8 vs. 10.4%, p < 0.0001) and more frequently on prasugrel (11.5 vs. 8.1%, p = 0.039) as compared with rapid metabolizers (n = 935). Intensification of antiplatelet treatment did not differ between slow and rapid metabolizers according to the study algorithm based on platelet function only. The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation did not differ between slow and rapid metabolizers (HR 0.988, 95% CI [0.812;1.202], p = 0.90). Likewise, the primary safety outcome did not differ between rapid and slow metabolizer phenotype. CONCLUSIONS: The genetic clopidogrel profile was a good marker of platelet function response on clopidogrel but was not related to clinical outcome suggesting that the genetic added little to the pharmacodynamic information used in the study to adjust antiplatelet therapy. ClinicalTrials.gov: NCT00827411.

Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study.

AIMS: The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. METHOD AND RESULTS: In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6±48.4% versus +0.8±53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %±24.8% vs. -72.9%±32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. CONCLUSION: The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.

High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study.

AIMS: The aim of this study was to compare on-thienopyridine platelet reactivity of elderly patients (≥75 years) vs. younger patients (<75 years). Elderly patients represent a growing and challenging segment of the coronary population for whom the effect of dual antiplatelet therapy on platelet inhibition has not been specifically addressed. METHODS AND RESULTS: The SENIOR-PLATELET study included 1331 coronary patients chronically (>14 days) treated with aspirin and a thienopyridine (clopidogrel 75 mg, n= 1027; clopidogrel 150 mg, n= 139; or prasugrel 10 mg, n= 165). Platelet response to clopidogrel and prasugrel was assessed by the VerifyNow assay and light transmission aggregrometry (LTA). Response to treatment, rate of high platelet reactivity (HPR), and inhibition (HPI) were compared in the two age categories. On-treatment platelet reactivity with clopidogrel 75 mg, 150 mg or prasugrel 10 mg was higher in elderly patients (n= 205) than in younger patients (n= 1126) whichever the test used. The difference in P2Y(12) reaction units (PRU) between the two populations was +45 in patients treated with clopidogrel 75 mg (P< 0.0001), +30 in patients treated with clopidogrel 150 mg (P= 0.17), and +20 with prasugrel 10 mg (P= 0.10). Differences in residual platelet aggregation were consistent when measured by LTA. Elderly patients treated with clopidogrel 75 mg were more likely to have HPR than younger patients (38.2 vs. 18.2%, OR: 2.58, 95% CI: 1.76-3.79; P< 0.0001) even after adjustment for potential confounders (adj OR: 1.83, 95% CI: 1.16-2.87; P= 0.009). CONCLUSION: Elderly patients present an impaired response to clopidogrel with a high rate of HPR. Clopidogrel 150 mg or prasugrel 10 mg blunt, but do not eliminate the difference in response observed between old and young patients.

Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

CONTEXT: Clopidogrel pretreatment is recommended for patients with acute coronary syndromes (ACS) and stable coronary artery disease who are scheduled for percutaneous coronary intervention (PCI), but whether using clopidogrel as a pretreatment for PCI is associated with positive clinical outcomes has not been established. OBJECTIVE: To evaluate the association of clopidogrel pretreatment vs no treatment with mortality and major bleeding after PCI. DATA SOURCES: MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and reference lists of qualifying articles. STUDY SELECTION Studies reporting clinical data on mortality and major bleeding were included. Of the 392 titles identified, 15 articles published between August 2001 and September 2012 met the inclusion criteria: 6 randomized controlled trials (RCTs), 2 observational analyses of RCTs, and 7 observational studies. DATA EXTRACTION: Quality of studies was assessed with the Ottawa Scale and the Jadad Score as appropriate. Results were independently extracted by 2 reviewers. A random-effect model was applied. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization. The main analysis was performed on RCTs and confirmed by observational analyses and observational studies. Prespecified subgroups--clinical presentation and clopidogrel loading dose--were analyzed. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary end points included major cardiac events. RESULTS: Of the 37 814 patients included in the meta-analysis, 8608 patients had participated in RCTs; 10,945, in observational analyses of RCTs; and 18,261, in observational studies. Analysis of RCTs showed that clopidogrel pretreatment was not associated with a reduction of death (absolute risk, 1.54% vs 1.97%; OR, 0.80; 95% CI, 0.57-1.11; P = .17) but was associated with a lower risk of major cardiac events (9.83% vs 12.35%; OR, 0 .77; 95% CI, 0.66-0.89; P < .001). There was no significant association between pretreatment and major bleeding overall (3 .57% vs 3.08%; OR, 1.18; 95% CI, 0.93-1.50; P = .18). Analyses from observational analyses of RCTs and observational studies were consistent for all results. CONCLUSIONS: Among patients scheduled for PCI, clopidogrel pretreatment was not associated with a lower risk of mortality but was associated with a lower risk of major coronary events.

Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis.

CONTEXT: Despite dual antiplatelet therapy, stent thrombosis remains a devastating and unpredictable complication of percutaneous coronary intervention (PCI). OBJECTIVE: To perform a sequential analysis of clinical and genetic factors associated with definite early stent thrombosis. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 10 centers in France between January 2007 and May 2010 among 123 patients undergoing PCI who had definite early stent thrombosis and DNA samples available, matched on age and sex with 246 stent thrombosis-free controls. MAIN OUTCOME MEASURE: Accuracy of early stent thrombosis prediction by 23 genetic variants. RESULTS: Among the 23 genetic variants investigated in 15 different genes, the significant determinants of early stent thrombosis were CYP2C19 metabolic status (adjusted odds ratio [OR], 1.99; 95% CI, 1.47-2.69), ABCB1 3435 TT genotype (adjusted OR, 2.16; 95% CI, 1.21-3.88), and ITGB3 PLA2 carriage (adjusted OR, 0.52; 95% CI, 0.28-0.95). Nongenetic independent correlates were acuteness of PCI (adjusted OR, 3.05; 95% CI, 1.54-6.07), complex lesions (American College of Cardiology/American Heart Association type C) (adjusted OR, 2.33; 95% CI, 1.40-3.89), left ventricular function less than 40% (adjusted OR, 2.25; 95% CI, 1.09-4.70), diabetes mellitus (adjusted OR, 1.82; 95% CI, 1.02-3.24), use of proton pump inhibitors (adjusted OR, 2.19; 95% CI, 1.29-3.75), and higher clopidogrel loading doses (adjusted OR, 0.73; 95% CI, 0.57-0.93). The discriminative accuracy of the clinical-only model was similar to that of a genetic-only model (area under the curve, 0.73 [95% CI, 0.67-0.78] vs 0.68 [95% CI, 0.62-0.74], respectively; P = .34). A combined clinical and genetic model led to a statistically significant increase in the discriminatory power of the model compared with the clinical-only model (area under the curve, 0.78 [95% CI, 0.73-0.83] vs 0.73 [95% CI, 0.67-0.78]; P = .004). CONCLUSIONS: This case-control study identified 3 genes (CYP2C19, ABCB1, and ITGB3) and 2 clopidogrel-related factors (loading dose and proton pump inhibitors) that were independently associated with early stent thrombosis. Future studies are needed to validate the prognostic accuracy of these risk factors in prospective cohorts.

Biomarkers of Thrombosis in ST-Segment Elevation Myocardial Infarction: A Substudy of the ATOLL Trial Comparing Enoxaparin Versus Unfractionated Heparin.

BACKGROUND: The aim was to compare the peri-procedural biomarkers of coagulation and platelet activation in patients randomly allocated to intravenous enoxaparin or unfractionated heparin (UFH) in the ATOLL randomized trial (NCT00718471). METHODS AND RESULTS: A total of 129 patients (n = 58 enoxaparin and n = 71 UFH) admitted for ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) were included in this substudy of the ATOLL trial. Activated partial thromboplastin time ratio, anti-Xa activity, von Willebrand factor antigen, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor and soluble CD40 ligand were measured at sheath insertion (T1) and at the end of the PCI (T2) and correlated with 1-month clinical outcomes. Target anticoagulation levels at T2 were more readily achieved in patients receiving enoxaparin compared to those receiving UFH (80.3 vs 18.2%, p < 0.0001). Increased levels of F1 + 2 and TAT measured at T2 were associated with the incidence of the composite ischemic endpoint (p = 0.04 and p = 0.03) and all-cause mortality (p < 0.0001 and p = 0.002). Release of F1 + 2 between T1 and T2 also predicted the composite ischemic endpoint (312 ± 513 vs 37 ± 292, p = 0.04) and net clinical outcome (185 ± 405 vs 3.2 ± 278, p = 0.03). CONCLUSIONS: During primary PCI, enoxaparin achieved therapeutic levels more frequently than UFH. Higher level of thrombin generation measured at the end of the PCI procedure was associated with more frequent ischemic events.

Evaluation of the learning curve for transcatheter aortic valve implantation via the transfemoral approach.

BACKGROUND: The aim of this study was to evaluate the learning curve in performing transfemoral TAVI (TF-TAVI). METHODS: Between October 2006 and October 2013, 312 consecutive TF-TAVI cases performed by 6 interventional cardiologists, using the Edwards Sapien valve and 104 using the CoreValve, were included in the present analysis. Cumulative sum (CUSUM) failure analysis of combined 30-day safety endpoint was used to evaluate learning curves. RESULTS: The CUSUM analysis revealed a learning curve regarding the occurrence of 30-day adverse events with an improvement after the initial 86 cases using the Edwards valve and 40 cases using the CoreValve. We divided the Edwards valve cases into two groups (early experience: Cases 1 to 86; late experience: Cases 87 to 312). The rate of 30-day mortality and 1-year mortality significantly decreased in the late experience group (17% to 7%, p=0.019; 34% to 21%, p=0.035, respectively). We divided the CoreValve cases into two groups (early experience: Cases 1 to 40; late experience: Cases 41 to 104). The rate of 30-day mortality and 1-year mortality significantly decreased in the late experience group (20% to 6%, p=0.033; 38% to 15%, p=0.040, respectively). The groups including both valves were also analyzed after propensity-matching (early [n=52] vs late [n=52]). This model also showed that 30-day and 1-year mortality rates were significantly lower in the late experience group (13% to 1%, p=0.028; 34% to 20%, p=0.042, respectively). CONCLUSIONS: An appropriate level of experience is needed to reduce the complication rate and mortality in TF-TAVI.

Point-of-care genetic profiling and/or platelet function testing in acute coronary syndrome.

Our aim was to demonstrate that the sequential use of the Verigene® rapid CYP2C19 test for genetic profiling and the VerifyNowTM bedside test for platelet function measurement in ACS patients may optimise P2Y12 inhibition. "Rapid" (CYP2C19*1/*1 or CYP2C19*17 carriers, n=211) and "slow" metabolisers (CYP2C19*2 carriers, n=58) were first put on clopidogrel and prasugrel for ≥ 2 weeks, respectively. Patients with low platelet reactivity (PRU<30) on prasugrel or high platelet reactivity (>208 PRU) on clopidogrel were then switched to clopidogrel and prasugrel, respectively. Our objectives were (i) to demonstrate that the proportion of "rapid" metabolisers on 75 mg of clopidogrel within 30-208 (PRU) of P2Y12 inhibition is non-inferior to "slow" metabolisers on prasugrel 10 mg and (ii) to evaluate the same end-point after switching drugs. The proportion of "rapid" and "slow" metabolisers within 30-208 PRU of P2Y12 inhibition was 71% and 56.9%, respectively, an absolute difference of +14.1% (95% CI, -0.05% to 28.28%) with a non-inferiority margin greater than the predefined margin of -10%. Among patients out of target, all but one "slow" metabolisers displayed low-on prasugrel platelet reactivity while the majority of "rapid" metabolisers (68%) displayed high-on clopidogrel platelet reactivity. After switching, the proportion of patients within 30-208 PRU of P2Y12 inhibition was 83.6% and 79.3% in "rapid" and "slow" metabolisers, respectively (+4.3%, 95% CI -7.3% to 15.9%). In conclusion, this study demonstrates a loose relationship between genotype and platelet function phenotype approaches but that they are complementary to select prasugrel or clopidogrel MD in stented ACS patients.

Clinical Outcome of First- vs Second-Generation DES According to DAPT Duration: Results of ARCTIC-Generation.

There is an apparent benefit with extension of dual antiplatelet therapy (DAPT) beyond 1 year after implantation of drug-eluting stents (DES). Assessment by a Double Randomization of a Conventional Antiplatelet Strategy vs a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation, and of Treatment Interruption vs Continuation One Year After Stenting (ARCTIC)-Generation assessed whether there is a difference of outcome between first- vs second-generation DES and if there is an interaction with DAPT duration in the ARCTIC-Interruption study. ARCTIC-Interruption randomly allocated 1259 patients 1 year after stent implantation to a strategy of interruption of DAPT (n = 624), in which aspirin antiplatelet treatment only was maintained, or DAPT continuation (n = 635) for 6 to 18 additional months. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization. A total of 520 and 722 patients received a first- and a second-generation DES, respectively. After a median follow-up of 17 months (interquartile range, 15-18 months) after randomization, the primary endpoint occurred in 32 (6.2%) and 19 (2.6%) patients with first- and second-generation DES, respectively (hazard ratio: 2.31, 95% confidence interval: 1.31-4.07, P = 0.004). This was observed irrespective of the strategy of interruption or continuation of DAPT and timing of study recruitment. Major bleeding events occurred in 4 (0.8%) and 3 patients (0.4%) with first- and second-generation DES, respectively (hazard ratio: 1.79, 95% confidence interval: 0.40-8.02, P = 0.44). Results did not change after multiple adjustments for potential confounding variables. ARCTIC-Generation showed worse clinical outcome with first- vs second-generation DES, a difference that appeared to persist even with prolonged DAPT.

Hypothalamic-pituitary dysfunction after irradiation of nonpituitary brain tumors in adults.

CONTEXT: Hypothalamic-pituitary (HP) dysfunction is common in children treated with cranial radiotherapy (RT) for brain tumors, but there is little known about the risk of HP dysfunction in adults treated with RT for primary nonpituitary brain tumors. OBJECTIVE: The objective was to study the frequency of HP dysfunction in adults after RT for nonpituitary brain tumors. METHOD: We studied 56 adult patients who received external beam RT for primary nonpituitary brain tumors at time intervals of 12-150 months after RT. The control group consisted of 20 RT-naive patients with primary brain tumors. GH and adrenal axes were assessed using the insulin tolerance test or the glucagon stimulation test. Gonadotroph, thyrotroph, and lactotroph function were assessed using baseline blood measurements. The biological effective dose (BED) to the HP axis was calculated in the RT patients. RESULTS: Hypopituitarism was present in 41% of patients. The frequency of GH, ACTH, gonadotropin, and TSH deficiencies, and hyperprolactinemia was 32, 21, 27, 9, and 32%, respectively. Any degree of hypopituitarism and GH deficiency was significantly associated with longer time interval from RT and greater BED. However, gonadotropin deficiency and hyperprolactinemia were only related to BED, whereas ACTH deficiency was only significantly associated with the time interval from RT. One RT-naive patient was GH deficient. CONCLUSION: Adult patients treated with cranial irradiation for primary nonpituitary brain tumors are at high risk of hypopituitarism, which is time and dose dependent. Long-term surveillance and periodic evaluation are needed. We recommend that adult late effect clinics, similar to those for children, should be established.

Meta-Analysis of the Impact on Mortality of Noninfarct-Related Artery Coronary Chronic Total Occlusion in Patients Presenting With ST-Segment Elevation Myocardial Infarction.

Several observational studies have compared clinical outcome in patients with a co-existing noninfarct-related artery chronic total occlusion (n-IRA CTO) versus those without, suggesting increased all-cause mortality. The goal of this study was to provide a systematic review and meta-analysis evaluating the impact of the presence of an n-IRA CTO on short- and long-term mortality after primary percutaneous coronary intervention. Studies published from January 1980 to January 2014 that compared the incidence of all-cause mortality in patients with ST-segment elevation myocardial infarction with co-existing n-IRA CTO versus those without were identified using an electronic search and reviewed using meta-analytical techniques. Seven studies (5 observational studies and 2 observational analyses of randomized controlled trials) comprising 14,117 patients and 1,554 patients (11.7%) with n-IRA CTO were included. The presence of n-IRA CTO was associated with increased incidence of all-cause mortality at a median follow-up of 25.2 months (interquartile range 24 to 60) compared with no CTO (absolute risk 23.5% vs 9.0%; odds ratio [OR] 2.90, 95% confidence interval [CI] 2.09 to 4.01; p <0.0001). This finding was consistent in the analysis of studies reporting 30-day follow-up (absolute risk 17.2% vs 4.7%; OR 3.79, 95% CI 3.13 to 4.59; p <0.0001). Co-existing n-IRA CTO was also associated with increased mortality in a subanalysis of patients with multivessel disease only (absolute risk 24.2% vs 11.3%; OR 2.23, 95% CI 1.90 to 2.63; p <0.0001). In conclusion, coronary CTO in the nonculprit artery in patients presenting with ST-segment elevation myocardial infarction is associated with increased short- and long-term all-cause mortality.

Efficacy of ex vivo autologous and in vivo platelet transfusion in the reversal of P2Y12 inhibition by clopidogrel, prasugrel, and ticagrelor: the APTITUDE study.

BACKGROUND: Allogenic platelet transfusions (PT) are administered to treat excessive bleeding in patients on P2Y12 receptor inhibitors (RI). We assessed the effect of ex vivo and in vivo PT on platelet activation and aggregation in patients on dual antiplatelet therapy. METHODS AND RESULTS: In the Antagonize P2Y12 Treatment Inhibitors by Transfusion of Platelets in an Urgent or Delayed Timing After Acute Coronary Syndrome or Percutaneous Coronary Intervention Presentation-Acute Coronary Syndrome (APTITUDE-ACS) study, patients presenting with acute coronary syndrome or for elective percutaneous coronary intervention, receiving loading doses of clopidogrel (600 mg, n=13 or 900 mg, n=12), prasugrel 60 mg (n=10), or ticagrelor 180 mg (n=10) were included. PT was performed ex vivo by mixing platelet-rich plasma from blood sampling performed at baseline in increasing proportions with platelet-rich plasma sampled 4 hours after loading dose. The percentage restoration of residual platelet aggregation achieved with 80% proportion PT (residual platelet aggregation 80% PT mix/residual platelet aggregation baseline×100) significantly decreased with increasing potency of P2Y12 RI (83.9±11%, 73±14%, 66.3±15%, 40.9±19% for clopidogrel 600 mg, clopidogrel 900 mg, prasugrel, and ticagrelor, respectively; P for trend <0.0001). In the APTITUDE-Coronary Artery Bypass Graft (APTITUDE-CABG) study, vasodilator-stimulated phosphoprotein-platelet reactivity index, a specific marker of the P2Y12 RI drug-effect, was assessed before and after in vivo PT administered for excessive bleeding in patients undergoing cardiac surgery while on a maintenance dose of aspirin and clopidogrel (n=45), prasugrel (n=6), or ticagrelor (n=3). When compared with baseline, there was a significant relative increase of 23.1% in platelet activation after PT transfusion (42.2±23.6% versus 56.6±18.2%; P=0.0008). CONCLUSIONS: PT restores platelet reactivity in patients with acute coronary syndrome/percutaneous coronary intervention and in patients undergoing cardiac surgery on P2Y12 RI while bleeding with a less effect with increasing potency of P2Y12 inhibition. CLINICAL TRIAL REGISTRATION: URL: http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm and http://www.cnil.fr/. Unique identifiers: No. 301111 and No. 1547216v0.

Revisiting Sex Equality With Transcatheter Aortic Valve Replacement Outcomes: A Collaborative, Patient-Level Meta-Analysis of 11,310 Patients.

BACKGROUND: There has been conflicting clinical evidence as to the influence of female sex on outcomes after transcatheter aortic valve replacement. OBJECTIVES: The aim of this study was to evaluate the impact of sex on early and late mortality and safety end points after transcatheter aortic valve replacement using a collaborative meta-analysis of patient-level data. METHODS: From the MEDLINE, Embase, and the Cochrane Library databases, data were obtained from 5 studies, and a database containing individual patient-level time-to-event data was generated from the registry of each selected study. The primary outcome of interest was all-cause mortality. The safety end point was the combined 30-day safety end points of major vascular complications, bleeding events, and stroke, as defined by the Valve Academic Research Consortium when available. RESULTS: Five studies and their ongoing registry data, comprising 11,310 patients, were included. Women constituted 48.6% of the cohort and had fewer comorbidities than men. Women had a higher rate of major vascular complications (6.3% vs. 3.4%; p < 0.001), major bleeding events (10.5% vs. 8.5%; p = 0.003), and stroke (4.4% vs. 3.6%; p = 0.029) but a lower rate of significant aortic incompetence (grade ≥2; 19.4% vs. 24.5%; p < 0.001). There were no differences in procedural and 30-day mortality between women and men (2.6 % vs. 2.2% [p = 0.24] and 6.5% vs. 6.5% [p = 0.93], respectively), but female sex was independently associated with improved survival at median follow-up of 387 days (interquartile range: 192 to 730 days) from the index procedure (adjusted hazard ratio: 0.79; 95% confidence interval: 0.73 to 0.86; p = 0.001). CONCLUSIONS: Although women experience more bleeding events, as well as vascular and stroke complications, female sex is an independent predictor of late survival after transcatheter aortic valve replacement. This should be taken into account during patient selection for this procedure.

Effect of gender after transcatheter aortic valve implantation: a meta-analysis.

BACKGROUND: The effect of gender on patients with aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) remains to be defined. METHODS: MEDLINE, Cochrane Library, and Scopus databases were searched for articles describing sex differences in baseline characteristics, procedures, and outcomes. All-cause death at follow-up of at least 1 year was the primary end point, and the independent effect of female gender was evaluated with pooled analysis using a random-effect model and with meta-regression. RESULTS: Six studies with 6,645 patients were included, half of them being women presenting with lower European System for Cardiac Operative Risk Evaluation (EuroSCORE) compared with men. At 30 days, more frequent major vascular complications and major and life-threatening bleeding occurred in women, with lower rates of moderate to severe aortic regurgitation, whereas 30-day mortality was similar. After a median follow-up of 365 days (range, 365 to 730 days) all-cause mortality was 24.0% in women and 34.0% in men. A pooled analysis of the multivariable approach found female gender was significantly related to a lower risk of death (odds ratio, 0.82; 95% CI, confidence interval, 0.73 to 0.93; I(2) = 0%). A meta-regression analysis showed age, ejection fraction, previous cardiovascular accident, renal insufficiency, and access site did not influence these data. CONCLUSIONS: Female patients undergoing TAVI present with a lower burden of comorbidities. The counterbalance between higher rates of vascular complications but lower of valve regurgitation may explain the reduced risk for women after TAVI, independently from baseline features and access site.