Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI.

BACKGROUND: In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain. METHODS: We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention). RESULTS: The rates of clinically significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001; hazard ratio for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80; P<0.001). The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups (Kaplan-Meier estimates, 6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; P values for all comparisons were nonsignificant). CONCLUSIONS: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy. (Funded by Janssen Scientific Affairs and Bayer Pharmaceuticals; PIONEER AF-PCI ClinicalTrials.gov number, NCT01830543 .).

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial.

BACKGROUND: Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months. METHODS: In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. FINDINGS: Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840). INTERPRETATION: A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. FUNDING: Janssen Research & Development and Bayer AG.

Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study.

BACKGROUND: The FRISC-II trial was the first randomised trial to show a reduction in death or myocardial infarction with an early invasive versus a non-invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome. Here we provide a remaining lifetime perspective on the effects on all cardiovascular events during 15 years' follow-up. METHODS: The FRISC-II prospective, randomised, multicentre trial was done at 58 Scandinavian centres in Sweden, Denmark, and Norway. Between June 17, 1996, and Aug 28, 1998, we randomly assigned (1:1) 2457 patients with non-ST-elevation acute coronary syndrome to an early invasive treatment strategy, aiming for revascularisation within 7 days, or a non-invasive strategy, with invasive procedures at recurrent symptoms or severe exercise-induced ischaemia. Plasma for biomarker analyses was obtained at randomisation. For long-term outcomes, we linked data with national health-care registers. The primary endpoint was a composite of death or myocardial infarction. Outcomes were compared as the average postponement of the next event, including recurrent events, calculated as the area between mean cumulative count-of-events curves. Analyses were done by intention to treat. FINDINGS: At a minimum of 15 years' follow-up on Dec 31, 2014, data for survival status and death were available for 2421 (99%) of the initially recruited 2457 patients, and for other events after 2 years for 2182 (89%) patients. During follow-up, the invasive strategy postponed death or next myocardial infarction by a mean of 549 days (95% CI 204-888; p=0·0020) compared with the non-invasive strategy. This effect was larger in non-smokers (mean gain 809 days, 95% CI 402-1175; pinteraction=0·0182), patients with elevated troponin T (778 days, 357-1165; pinteraction=0·0241), and patients with high concentrations of growth differentiation factor-15 (1356 days, 507-1650; pinteraction=0·0210). The difference was mainly driven by postponement of new myocardial infarction, whereas the early difference in mortality alone was not sustained over time. The invasive strategy led to a mean of 1128 days (95% CI 830-1366) postponement of death or next readmission to hospital for ischaemic heart disease, which was consistent in all subgroups (p<0·0001). INTERPRETATION: During 15 years of follow-up, an early invasive treatment strategy postponed the occurrence of death or next myocardial infarction by an average of 18 months, and the next readmission to hospital for ischaemic heart disease by 37 months, compared with a non-invasive strategy in patients with non-ST-elevation acute coronary syndrome. This remaining lifetime perspective supports that an early invasive treatment strategy should be the preferred option in most patients with non-ST-elevation acute coronary syndrome. FUNDING: Swedish Heart-Lung Foundation, Swedish Foundation for Strategic Research, and Uppsala Clinical Research Center.

Darapladib for preventing ischemic events in stable coronary heart disease.

BACKGROUND: Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. METHODS: In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). RESULTS: During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). CONCLUSIONS: In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

Balancing the risk of spontaneous ischemic and major bleeding events in acute coronary syndromes.

Evaluation of antithrombotic treatments for acute coronary syndromes (ACS) requires balancing ischemic and bleeding risks to assess net benefit. We sought to compare the relative effects of ischemic and bleeding events on mortality. METHODS: In the PLATelet inhibition and patient Outcomes (PLATO) trial, we compared spontaneous ischemic events (myocardial infarction or stroke) with spontaneous major bleeding events (PLATO major, Thrombolysis In Myocardial Infarction [TIMI] major, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] severe) with respect to risk of mortality using time-dependent Cox proportional hazards models. The comparison was performed using ratio of hazard ratios for mortality increase after ischemic vs bleeding events. RESULTS: A total of 822 patients (4.4%) had ≥1 spontaneous ischemic event; 485 patients (2.6%), ≥1 spontaneous PLATO major bleed, 282 (1.5%), ≥1 spontaneous TIMI major bleed; and 207 (1.1%), ≥1 spontaneous severe GUSTO bleed. In patients who had both events, bleeding occurred first in most patients. Regardless of classification, major bleeding events were associated with increased short- and long-term mortality that were not significantly different from the increase associated with spontaneous ischemic events: ratio of hazard ratios (95% CIs) for short- and long-term mortality after spontaneous ischemic vs bleeding events: 1.46 (0.98-2.19) and 0.92 (0.52-1.62) (PLATO major); 1.26 (0.80-1.96) and 1.19 (0.58-2.24) (TIMI major), 0.72 (0.47-1.10) and 0.83 (0.38-1.79) (GUSTO severe) (all P>0.05) CONCLUSIONS: In patients with ACS on dual antiplatelet therapy, spontaneous major bleeding events seem "prognostically equivalent" to spontaneous ischemic complications. This result allows quantitative comparisons between both actual and predicted bleeding and ischemic risks. Our findings help to better define net clinical benefit of antithrombotic treatments and more accurately estimate mortality after ischemic and bleeding events in patients with ACS.

Clinical events preceding switching and discontinuation of oral anticoagulant treatment in patients with atrial fibrillation.

AIMS: Switching between oral anticoagulants and treatment discontinuation are common events related to therapy with non-vitamin K antagonist oral anticoagulants (NOACs). However, knowledge on the reasons leading to these treatment changes is scarce. The aim of this study was to identify clinical events preceding anticoagulant switching and NOAC discontinuation during oral anticoagulant therapy in patients with atrial fibrillation. METHODS AND RESULTS: We performed a nationwide register-based study including Danish atrial fibrillation patients initiating a NOAC between August 2011 and February 2016 (n = 50 623). We explored potential reasons leading to changes in anticoagulant treatment by identifying clinical events preceding switches from vitamin K antagonists (VKA) to NOAC, switches from NOAC to VKA, and discontinuations of NOACs. Among 23 531 anticoagulant users changing treatment, we identified 13 295 switches from VKA to NOAC, 5206 switches from NOAC to VKA, and 8995 discontinuations of NOACs. Approximately half of all treatment changes were preceded by a hospitalization. A relevant specific clinical event or procedure was identified prior to 18.3% of switches from VKA to NOAC, prior to 23.0% of switches from NOAC to VKA, and prior to 26.6% of discontinuations. Switches from VKA to NOAC were most often preceded by thromboembolic events (7.0%), whereas cardioversion was the most common specific event prior to a switch from NOAC to VKA (11.4%). Discontinuations were most often preceded by bleeding events (7.6%). CONCLUSION: For about one in five patients, treatment changes during anticoagulant therapy were preceded by a major clinical event. However, the majority of patients changed treatment for reasons not recorded in health registries.

Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study.

AIMS: Growth differentiation factor-15 (GDF-15) predicts death and composite cardiovascular (CV) events in patients with acute coronary syndrome (ACS). We investigated the independent associations between GDF-15 levels and major bleeding, the extent of coronary lesions and individual CV events in patients with ACS. METHODS AND RESULTS: Growth differentiation factor-15 was analysed at baseline ( ITALIC! n = 16 876) in patients with ACS randomized to ticagrelor or clopidogrel in the PLATO (PLATelet inhibition and patient Outcomes) trial. Growth differentiation factor-15 levels were related to extent of coronary artery disease (CAD) and to all types of non-coronary artery bypass grafting (CABG)-related major bleeding, spontaneous myocardial infarction (MI), stroke, and death during 12-month follow-up. In Cox proportional hazards models adjusting for established risk factors for CV disease and prognostic biomarkers (N-terminal pro B-type natriuretic peptide, cystatin C, high-sensitive C-reactive protein, and high-sensitive troponin T), 1 SD increase in ln GDF-15 was associated with increased risk of major bleeding with a hazard ratio (HR) 1.37 (95% confidence interval: 1.25-1.51) and with a similar increase in risk across different bleeding locations. For the same increase in ln GDF-15, the HR for the composite of CV death, spontaneous MI, and stroke was 1.29 (1.21-1.37), CV death 1.41 (1.30-1.53), all-cause death 1.41 (1.31-1.53), spontaneous MI 1.15 (1.05-1.26), and stroke 1.19 (1.01-1.42). The ITALIC! C-statistic improved for the prediction of CV death and non-CABG-related major bleeding when adding GDF-15 to established risk factors. CONCLUSIONS: In patients with ACS, higher levels of GDF-15 are associated with raised risks of all types of major non-CABG-related bleeding, spontaneous MI, and stroke as well as CV and total mortality and seem to improve risk stratification for CV-mortality and major bleeding beyond established risk factors. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov; NCT00391872.

Dietary patterns and the risk of major adverse cardiovascular events in a global study of high-risk patients with stable coronary heart disease.

OBJECTIVES: To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease. BACKGROUND: A Mediterranean dietary pattern has been associated with lower cardiovascular (CV) mortality. It is less certain whether foods common in western diets are associated with CV risk. METHODS: At baseline, 15 482 (97.8%) patients (mean age 67 ± 9 years) with stable coronary heart disease from 39 countries who participated in the Stabilisation of atherosclerotic plaque by initiation of darapladib therapy (STABILITY) trial completed a life style questionnaire which included questions on common foods. A Mediterranean diet score (MDS) was calculated for increasing consumption of whole grains, fruits, vegetables, legumes, fish, and alcohol, and for less meat, and a 'Western diet score' (WDS) for increasing consumption of refined grains, sweets and deserts, sugared drinks, and deep fried foods. A multi-variable Cox proportional hazards models assessed associations between MDS or WDS and MACE, defined as CV death, non-fatal myocardial infarction, or non-fatal stroke. RESULTS: After a median follow-up of 3.7 years MACE occurred in 7.3% of 2885 subjects with an MDS ≥15, 10.5% of 4018 subjects with an MDS of 13-14, and 10.8% of 8579 subjects with an MDS ≤12. A one unit increase in MDS >12 was associated with lower MACE after adjusting for all covariates (+1 category HR 0.95, 95% CI 0.91, 0.98, P = 0.002). There was no association between WDS (adjusted model +1 category HR 0.99, 95% CI 0.97, 1.01) and MACE. CONCLUSION: Greater consumption of healthy foods may be more important for secondary prevention of coronary artery disease than avoidance of less healthy foods typical of Western diets.

Use of Antithrombotic Therapy and Long-Term Clinical Outcome Among Patients Surviving Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The effectiveness and safety of antithrombotic therapy (AT) among patients with a history of intracerebral hemorrhage remain uncertain. We therefore determined the prevalence of indication for AT among patients hospitalized with first-time intracerebral hemorrhage and examined the impact of subsequent AT use on the long-term clinical outcome. METHODS: We performed a population-based cohort study using nationwide Danish medical registries. Patients with risk of thromboembolism surviving the first 30 days after hospitalization because of intracerebral hemorrhage were identified and followed up. We estimated the hazard ratio of all-cause death, thromboembolic events, or major bleeding according to use of AT. RESULTS: We identified 6369 patients between 2005 and 2013. Among these patients, 2978 (47%) had indication for AT, and during the follow-up, (median: 2.3 year) 1281 (43%) died, 497 (17%) had a thromboembolic event, and 536 (18%) had major bleeding. Postdischarge use of oral anticoagulation therapy among patients with indication for oral anticoagulation therapy was associated with a significant lower risk of death (adjusted hazard ratio, 0.59; 95% confidence interval, 0.43-0.82) and thromboembolic events (adjusted hazard ratio 0.58; 95% confidence interval, 0.35-0.97) and no increased risk of major bleeding (adjusted hazard ratio 0.65; 95% confidence interval, 0.41-1.02). In contrast, use of platelet inhibitors among patients with indication for platelet inhibitors was not related to statistically significantly improved clinical outcome. CONCLUSIONS: Approximately 1 of 2 patients surviving intracerebral hemorrhage had a high risk of thromboembolism. Postdischarge use of oral anticoagulation therapy was associated with a lower risk of all-cause mortality and thromboembolic events and no increased risk of major bleeding.

Pharmacological and emerging therapies in the treatment of chronic angina.

Chronic angina is a common manifestation of ischaemic heart disease. Medical treatments are the mainstay approach to reduce the occurrence of angina and improve patients' quality of life. This Series paper focuses on commonly used standard treatments (eg, nitrates, ß blockers, and calcium-channel blockers), emerging anti-angina treatments (which are not available in all parts of the world), and experimental treatments. Although many emerging treatments are available, evidence is scarce about their ability to reduce angina and ischaemia.

Impact of glycoprotein IIb/IIIa inhibitors on the efficacy and safety of ticagrelor compared with clopidogrel in patients with acute coronary syndromes: Analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel. METHODS: PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours. RESULTS: A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05). CONCLUSIONS: In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment.

Substantial differences in initiation of oral anticoagulant therapy and clinical outcome among non-valvular atrial fibrillation patients treated in inpatient and outpatient settings.

AIMS: Patients with atrial fibrillation (AF) are encountered and treated in different healthcare settings, which may affect the quality of care. We investigated the use of oral anticoagulant (OAC) therapy and the risk of thrombo-embolism (TE) and bleeding, according to the healthcare setting. METHODS AND RESULTS: Using national Danish registers, we categorized non-valvular AF patients (2002-11) according to the setting of their first-time AF contact: hospitalization (inpatients), ambulatory (outpatients), or emergency department (ED). Event rates and hazard ratios (HRs), calculated using Cox regression analysis, were estimated for outcomes of TE and bleeding. We included 116 051 non-valvular AF patients [mean age 71.9 years (standard deviation 14.1), 51.3% males], of whom 55.2% were inpatients, 41.9% outpatients, and 2.9% ED patients. OAC therapy 180 days after AF diagnosis among patients with a CHADS2 ≥ 2 was 42.1, 63.0, and 32.4%, respectively. Initiation of OAC therapy was only modestly influenced by CHADS2 and HAS-BLED scores, regardless of the healthcare setting. The rate of TE was 4.30 [95% confidence interval (CI) 4.21-4.40] per 100 person-years for inpatients, 2.28 (95% CI 2.22-2.36) for outpatients, and 2.30 (95% CI 2.05-2.59) for ED patients. The adjusted HR of TE, with inpatients as reference, was 0.74 (95% CI 0.71-0.77) for outpatients and 0.89 (95% CI 0.79-1.01) for ED patients. CONCLUSION: In a nationwide cohort of non-valvular AF patients, outpatients were much more likely to receive OAC therapy and had a significantly lower risk of stroke/TE compared with inpatients and ED patients. However, across all settings investigated, OAC therapy was far from optimal.

Case Study: Ticagrelor in PLATO and Prasugrel in TRITON-TIMI 38 and TRILOGY-ACS Trials in Patients With Acute Coronary Syndromes.

Cross-trial comparisons are typically inappropriate as there are often numerous differences in study designs, populations, end points, and loading doses of the study drugs. These differences are clearly reflected in the most recent updates to the European Society of Cardiology (ESC) non-ST elevation acute coronary syndrome (NSTE-ACS) and ST elevation myocardial infarction (STEMI) guidelines, which include recommendations for the use of the antiplatelet agents ticagrelor, prasugrel, and clopidogrel, based in part on results from the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38, TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY-ACS) and PLATelet inhibition and patient Outcomes (PLATO) trials. Here, we describe each of these trials in detail and explain the differences between them that make direct comparisons difficult. In conclusion, this information, along with the current guidelines and recommendations, will assist clinicians in deciding the most appropriate treatment pathway for their patients with NSTE-ACS and STEMI.

Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes.

OBJECTIVE: Ticagrelor is an orally administered antiplatelet agent used to reduce thrombotic events in patients with acute coronary syndromes. Data from two studies in patients with acute coronary syndromes with large amounts of pharmacokinetic (PK) data (phase IIb DISPERSE-2 study (n = 609)); phase III PLATO PK substudy (n = 6,381)), along with non-linear mixed effects modeling software, were used to develop population PK models for ticagrelor and its metabolite, AR-C124910XX, and to evaluate the impact of demographic and clinical factors on the PK of ticagrelor and AR-C124910XX. METHODS: 32 covariates relating to disease history, biomarkers, clinical chemistry, and concomitant medications were assessed. RESULTS: A one-compartment model with population mean PK parameters of firstorder absorption rate constant (0.67/h), apparent systemic clearance (14 L/h), and apparent volume of distribution (221 L) was shown to best describe the PK profile of ticagrelor. Patients co-administered moderate CYP3A inducers or inhibitors increased (by 110%, 95% confidence interval (CI), 52 - 192%) or decreased (by 64%, 95% CI, 39 - 73%) apparent ticagrelor clearance, respectively, while habitual smoking decreased apparent ticagrelor clearance by 22% (95% CI, 19 - 25%). Ticagrelor bioavailability was 21% (95% CI, 19 - 22%) lower at treatment initiation (visit 1) versus subsequent visits. Compared with Caucasian patients, ticagrelor bioavailability was 39% (95% CI, 33 - 46%) higher in Asian patients and 18% (95% CI, 6 - 28%) lower in Black patients. CONCLUSIONS: In the current analyses, the population PK models developed for ticagrelor and AR-C124910XX described the data obtained in the DISPERSE-2 and PLATO studies well, and were consistent with previous phase I PK studies.

Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial.

AIM: To assess clinical outcomes, efficacy, and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation. METHODS AND RESULTS: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a randomized, double-blind, placebo-controlled, multicentre trial that included 11 785 (64.7%) men and 6416 (35.3%) women with atrial fibrillation or flutter randomized to receive either warfarin or apixaban. The primary efficacy endpoint was stroke or systemic embolism; secondary efficacy endpoints were death from any cause and cardiovascular death. The primary safety endpoint was major bleeding; secondary safety endpoints were a composite of major bleeding and non-major clinically relevant bleeding. The risk of stroke or systemic embolism was similar in women vs. men [adjusted hazard ratio (adjHR): 0.91; 95% confidence interval (CI): 0.74-1.12; P = 0.38]. However, among patients with history of stroke or transient ischaemic attack, women had a lower risk of recurrent stroke compared with men (adjHR: 0.70; 95% CI: 0.50-0.97; P = 0.036). Women also had a lower risk of all-cause death (adjHR: 0.63; 95% CI: 0.55-0.73; P < 0.0001) and cardiovascular death (adjHR: 0.62; 95% CI: 0.51-0.75; P < 0.0001), and a trend towards less major bleeding (adjHR: 0.86; 95% CI: 0.74-1.01; P = 0.066) and major or non-major clinically relevant bleeding (adjHR: 0.89; 95% CI: 0.80-1.00; P = 0.049). The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex. CONCLUSION: In the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinically relevant bleeding than men. The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women. TRIAL REGISTRATION: ARISTOTLE ClinicalTrials.gov number, NCT00412984.

Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.

AIMS: Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. METHODS AND RESULTS: A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 × 10(-6)) and ARC (P = 4.6 × 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. CONCLUSION: In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment. CLINICAL TRIAL REGISTRATION: NCT00391872.

High-sensitivity troponin I for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

BACKGROUND: High-sensitivity troponin-I (hs-TnI) measurement improves risk assessment for cardiovascular events in many clinical settings, but the added value in atrial fibrillation patients has not been described. METHODS AND RESULTS: At randomization, hs-TnI was analyzed in 14 821 atrial fibrillation patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban with warfarin. The associations between hs-TnI concentrations and clinical outcomes were evaluated by using adjusted Cox analysis. The hs-TnI assay detected troponin (≥1.3 ng/L) in 98.5% patients, 50% had levels >5.4, 25% had levels >10.1, and 9.2% had levels ≥23 ng/L (the 99th percentile in healthy individuals). During a median of 1.9 years follow-up, annual rates of stroke or systemic embolism ranged from 0.76% in the lowest hs-TnI quartile to 2.26% in the highest quartile (>10.1 ng/L). In multivariable analysis, hs-TnI was significantly associated with stroke or systemic embolism, adjusted hazard ratio 1.98 (1.42-2.78), P=0.0007. hs-TnI was also significantly associated with cardiac death; annual rates ranged from 0.40% to 4.24%, hazard ratio 4.52 (3.05-6.70), P<0.0001, in the corresponding groups, and for major bleeding hazard ratio 1.44 (1.11-1.86), P=0.0250. Adding hs-TnI levels to the CHA2DS2VASc score improved c-statistics from 0.629 to 0.653 for stroke or systemic embolism, and from 0.591 to 0.731 for cardiac death. There were no significant interactions with study treatment. CONCLUSIONS: Troponin-I is detected in 98.5% and elevated in 9.2% of atrial fibrillation patients. The hs-TnI level is independently associated with a raised risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2DS2VASc score. The benefits of apixaban in comparison with warfarin are consistent regardless of hs-TnI levels. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Biomarkers in relation to the effects of ticagrelor in comparison with clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) trial.

BACKGROUND: Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial. METHODS AND RESULTS: Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group CONCLUSIONS: Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Biomarkers for risk stratification of patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: Insights from the Platelet Inhibition and Patient Outcomes trial.

BACKGROUND: The incremental prognostic value of admission measurements of biomarkers beyond clinical characteristics and extent of coronary artery disease (CAD) in patients treated with primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is unclear. METHODS: Centrally analyzed plasma for biomarker measurements was available in 5,385 of the STEMI patients treated with PPCI in the PLATO trial. Extent of CAD was graded by operators in association with PPCI. We evaluated the prognostic value of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15) beyond clinical characteristics and extent of CAD using Cox proportional hazards analyses, C-index, and net reclassification improvement (NRI). Outcomes were cardiovascular death (CVD) and spontaneous myocardial infarction (MI). RESULTS: Angiographic data on extent of CAD improved the prediction of CVD compared to clinical risk factors alone, increasing the C-index from 0.760 to 0.778, total NRI of 0.31. Biomarker information provided additional prognostic value for CVD beyond clinical risk factors and extent of CAD, C-indices ranging from 0.792 to 0.795 for all biomarkers, but with a higher NRI for NT-proBNP. Extent of CAD and high-sensitivity cardiac troponin T were not associated with spontaneous MI. The prediction of spontaneous MI beyond clinical characteristics and extent of CAD (C-index 0.647) was improved by both NT-proBNP (C-index 0.663, NRI 0.22) and GDF-15 (C-index 0.652, NRI 0.05). CONCLUSIONS: Biomarker measurement on admission is feasible and provides incremental risk stratification in patients with STEMI treated with PPCI, with NT-proBNP and GDF-15 being most valuable due to the association with both CVD and spontaneous MI.

An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI).

BACKGROUND: Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. DESIGN: PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with stent placement. Approximately 2,100 subjects will be randomized in a 1:1:1 ratio to receive either rivaroxaban 15 mg once daily plus clopidogrel 75 mg daily for 12 months (a WOEST trial-like strategy), or rivaroxaban 2.5 mg twice daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, an ATLAS trial-like strategy), or dose-adjusted VKA once daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, traditional triple therapy). All patients will be followed up for 12 months for the primary composite end point of Thrombolysis in Myocardial Infarction major bleeding, bleeding requiring medical attention, and minor bleeding (collectively, clinically significant bleeding). CONCLUSION: The PIONEER AF-PCI study is the first randomized comparison of VKA vs novel oral anticoagulant therapy in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications.