CSL112 (Apolipoprotein A-I [Human]) Strongly Enhances Plasma Apoa-I and Cholesterol Efflux Capacity in Post-Acute Myocardial Infarction Patients: A PK/PD Substudy of the AEGIS-I Trial.

INTRODUCTION: Cholesterol efflux capacity (CEC) is impaired following acute myocardial infarction (AMI). CSL112 is an intravenous preparation of human plasma-derived apoA-I formulated with phosphatidylcholine (PC). CSL112 is intended to improve CEC and thereby prevent early recurrent cardiovascular events following AMI. AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b study, designed to evaluate the hepatic and renal safety of CSL112. Here, we report an analysis of a pharmacokinetic (PK) and pharmacodynamic (PD) substudy of AEGIS-I. METHODS: AMI patients were stratified by renal function and randomized 3:3:2 to 4, weekly, 2-hour infusions of low- and high-dose (2 g and 6 g) CSL112, or placebo. PK/PD assessments included plasma concentrations of apoA-I and PC, and measures of total and ABCA1-dependent CEC, as well as lipids/lipoproteins including high density lipoprotein cholesterol (HDL-C), non-HDL-C, low density lipoprotein cholesterol (LDL-C), ApoB, and triglycerides. Inflammatory and cardio-metabolic biomarkers were also evaluated. RESULTS: The substudy included 63 subjects from AEGIS-I. CSL112 infusions resulted in rapid, dose-dependent increases in baseline corrected apoA-I and PC, which peaked at the end of the infusion (Tmax ≈ 2 hours). Similarly, there was a dose-dependent elevation in both total CEC and ABCA1-mediated CEC. Mild renal impairment did not affect the PK or PD of CSL112. CSL112 administration was also associated with an increase in plasma levels of HDL-C but not non-HDL-C, LDL-C, apoB, or triglycerides. No dose-effects on inflammatory or cardio-metabolic biomarkers were observed. CONCLUSION: Among patients with AMI, impaired CEC was rapidly elevated by CSL112 infusions in a dose-dependent fashion, along with an increase in apoA-I plasma concentrations. Findings from the current sub-study of the AEGIS-I support a potential atheroprotective benefit of CSL112 for AMI patients.

Novel Oral Anticoagulant Based Versus Vitamin K Antagonist Based Double Therapy Among Stented Patients With Atrial Fibrillation: Insights From the PIONEER AF-PCI Trial.

BACKGROUND: Among stented patients with atrial fibrillation, double therapy with a novel oral anticoagulant plus single antiplatelet therapy (SAPT) reduces bleeding or cardiovascular rehospitalizations compared with a vitamin K antagonist (VKA) based triple therapy regimen. A recent study demonstrated that apixaban based double therapy reduced bleeding compared with VKA based double therapy. However, it remains unknown whether rivaroxaban based double therapy is superior to a VKA based double therapy. METHODS: Patient with stented atrial fibrillation (n=2124) were randomized to 3 groups: rivaroxaban 15 mg od plus a P2Y12 inhibitor (Group 1, n=709); rivaroxaban 2.5 mg bid plus dual antiplatelet therapy (DAPT; Group 2, n=709); and warfarin plus DAPT (Group 3, n=706). Before randomization, subjects were stratified according to a prespecified duration of DAPT (1, 6, or 12 months). After the prespecified DAPT duration, subjects in Group 2 were switched to rivaroxaban 15 mg plus low dose aspirin, and those in Group 3 were switched to VKA plus low dose aspirin. The Wei, Lin, and Weissfeld time to multiple events method was used to compare the occurrence of all bleeding and cardiovascular rehospitalizations among subjects on a novel oral anticoagulant versus VKA based double therapy. RESULTS: A total of 906 subjects were prespecified to a 1 or 6 months DAPT duration and received at least one dose of study drug. Twenty subjects (3.3%) assigned to novel oral anticoagulant+SAPT, and 15 (5.1%) subjects assigned to VKA+SAPT experienced multiple rehospitalizations. In total, 124 (20.3%) events occurred among subjects on novel oral anticoagulant+SAPT compared with 87 (29.6%) among subjects on VKA+SAPT (hazard ratio=0.65 [95% CI, 0.45-0.93], P=0.008). CONCLUSIONS: Among stented patients with atrial fibrillation, rivaroxaban plus SAPT was superior to warfarin plus SAPT in lowering total bleeding and cardiovascular rehospitalization. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01830543.

Cost Implications of Anticoagulation Strategies After Percutaneous Coronary Intervention Among Patients With Atrial Fibrillation (A PIONEER-AF PCI Analysis).

The PIONEER AF-PCI trial demonstrated that in atrial fibrillation patients who underwent intracoronary stenting, either rivaroxaban 15 mg daily plus P2Y12 inhibitor monotherapy (Group 1) or 2.5 mg rivaroxaban twice daily plus dual antiplatelet therapy (DAPT) (Group 2) was associated with fewer recurrent hospitalizations, primarily for bleeding and cardiovascular events, compared with standard-of-care vitamin K antagonist and DAPT (Group 3). Associated costs are unknown. This study estimates costs associated with rivaroxaban strategies compared with vitamin K antagonist and DAPT. Medication costs were estimated using wholesale acquisition costs, medication discontinuation rates, and costs of monitoring. Using a large US healthcare claims database, the mean adjusted increase in 1-year cost of care for individuals with atrial fibrillation and percutaneous coronary intervention (PCI) rehospitalized for bleeding, cardiovascular, and other events was compared with those not rehospitalized. Using adjudicated rehospitalization rates from PIONEER AF-PCI, cost differences were estimated. Rates of rehospitalization for bleeding were 6.5%, 5.4%, 10.5%, and 20.3%, 20.3%, 28.4% for cardiovascular events in Groups 1, 2, and 3. Medication and monitoring costs were $3,942, $4,115, and $1,703. One-year costs for all recurrent hospitalization costs and/or patient for the groups were $24,535, $20,205, and $29,756. One-year cost increase associated with bleeding rehospitalizations and/or patient was $4,160, $3,212, and $6,876 and was $13,264, $11,545, and $17,220 for cardiovascular rehospitalizations and/or patient. Overall estimated cost per patient was $28,476, $24,320, and $31,458. Compared with warfarin, both rivaroxaban treatment strategies had higher medication costs, but these were more than accounted for by fewer hospitalizations.

D-Dimer Levels and Effect of Rivaroxaban on Those Levels and Outcomes in Patients With Acute Coronary Syndrome (An ATLAS ACS-TIMI 46 Trial Substudy).

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.

Total bleeding with rivaroxaban versus warfarin in patients with atrial fibrillation receiving antiplatelet therapy after percutaneous coronary intervention.

Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12 months: (1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (N = 696); (2) rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) (N = 706); and (3) dose-adjusted warfarin plus DAPT (N = 697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49-0.85], p < 0.001, NNT = 11; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48-0.80], p < 0.001, NNT = 10). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49-0.89], p < 0.001, NNT = 14; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48-0.85], p = 0.002, NNT = 13). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10-11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13-14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01830543 (PIONEER AF-PCI).

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.

Recurrent Hospitalization Among Patients With Atrial Fibrillation Undergoing Intracoronary Stenting Treated With 2 Treatment Strategies of Rivaroxaban or a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy.

BACKGROUND: Patients with atrial fibrillation who undergo intracoronary stenting traditionally are treated with a vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT), yet this treatment leads to high risks of bleeding. We hypothesized that a regimen of rivaroxaban plus a P2Y12 inhibitor monotherapy or rivaroxaban plus DAPT could reduce bleeding and thereby have a favorable impact on all-cause mortality and the need for rehospitalization. METHODS: Stented subjects with nonvalvular atrial fibrillation (n=2124) were randomized 1:1:1 to administration of reduced-dose rivaroxaban 15 mg daily plus a P2Y12 inhibitor for 12 months (group 1); rivaroxaban 2.5 mg twice daily with stratification to a prespecified duration of DAPT of 1, 6, or 12 months (group 2); or the reference arm of dose-adjusted VKA daily with a similar DAPT stratification (group 3). The present post hoc analysis assessed the end point of all-cause mortality or recurrent hospitalization for an adverse event, which was further classified as the result of bleeding, a cardiovascular cause, or another cause blinded to treatment assignment. RESULTS: The risk of all-cause mortality or recurrent hospitalization was 34.9% in group 1 (hazard ratio=0.79; 95% confidence interval, 0.66-0.94; P=0.008 versus group 3; number needed to treat=15), 31.9% in group 2 (hazard ratio=0.75; 95% confidence interval, 0.62-0.90; P=0.002 versus group 3; number needed to treat=10), and 41.9% in group 3 (VKA+DAPT). Both all-cause death plus hospitalization potentially resulting from bleeding (group 1=8.6% [P=0.032 versus group 3], group 2=8.0% [P=0.012 versus group 3], and group 3=12.4%) and all-cause death plus rehospitalization potentially resulting from a cardiovascular cause (group 1=21.4% [P=0.001 versus group 3], group 2=21.7% [P=0.011 versus group 3], and group 3=29.3%) were reduced in the rivaroxaban arms compared with the VKA arm, but other forms of rehospitalization were not. CONCLUSIONS: Among patients with atrial fibrillation undergoing intracoronary stenting, administration of either rivaroxaban 15 mg daily plus P2Y12 inhibitor monotherapy or 2.5 mg rivaroxaban twice daily plus DAPT was associated with a reduced risk of all-cause mortality or recurrent hospitalization for adverse events compared with standard-of-care VKA plus DAPT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830543.

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 .).

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

The treatment of missing data in a large cardiovascular clinical outcomes study.

BACKGROUND: The potential impact of missing data on the results of clinical trials has received heightened attention recently. A National Research Council study provides recommendations for limiting missing data in clinical trial design and conduct, and principles for analysis, including the need for sensitivity analyses to assess robustness of findings to alternative assumptions about the missing data. A Food and Drug Administration advisory committee raised missing data as a serious concern in their review of results from the ATLAS ACS 2 TIMI 51 study, a large clinical trial that assessed rivaroxaban for its ability to reduce the risk of cardiovascular death, myocardial infarction or stroke in patients with acute coronary syndrome. This case study describes a variety of measures that were taken to address concerns about the missing data. METHODS: A range of analyses are described to assess the potential impact of missing data on conclusions. In particular, measures of the amount of missing data are discussed, and the fraction of missing information from multiple imputation is proposed as an alternative measure. The sensitivity analysis in the National Research Council study is modified in the context of survival analysis where some individuals are lost to follow-up. The impact of deviations from ignorable censoring is assessed by differentially increasing the hazard of the primary outcome in the treatment groups and multiply imputing events between dropout and the end of the study. Tipping-point analyses are described, where the deviation from ignorable censoring that results in a reversal of significance of the treatment effect is determined. A study to determine the vital status of participants lost to follow-up was also conducted, and the results of including this additional information are assessed. RESULTS: Sensitivity analyses suggest that findings of the ATLAS ACS 2 TIMI 51 study are robust to missing data; this robustness is reinforced by the follow-up study, since inclusion of data from this study had little impact on the study conclusions. CONCLUSION: Missing data are a serious problem in clinical trials. The methods presented here, namely, the sensitivity analyses, the follow-up study to determine survival of missing cases, and the proposed measurement of missing data via the fraction of missing information, have potential application in other studies involving survival analysis where missing data are a concern.

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.

Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51).

OBJECTIVES: The present analysis reports on the pre-specified subgroup of ST-elevation myocardial infarction (STEMI) patients, in whom anticoagulant therapy has been of particular interest. BACKGROUND: In ATLAS ACS-2-TIMI-51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51), rivaroxaban reduced cardiovascular events across the spectrum of acute coronary syndrome (ACS). METHODS: Seven thousand eight hundred seventeen patients in ATLAS ACS-2-TIMI 51 presented with a STEMI. After being stabilized (1 to 7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for intention-to-treat (ITT) and modified ITT (mITT) analyses. RESULTS: Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (ITT: 8.4% vs. 10.6%, hazards ratio [HR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.97, p = 0.019; mITT: 8.3% vs. 9.7%, HR: 0.85, 95% CI: 0.70 to 1.03, p = 0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, p = 0.042) and was evident in analyses that included events while patients received background dual antiplatelet therapies (ITT: 7.9% vs. 11.9%, p = 0.010; mITT: 7.7% vs. 10.1%, p = 0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, p = 0.006; mITT: 2.2% vs. 3.9%, p = 0.006), which was not seen with 5 mg of rivaroxaban. Rivaroxaban versus placebo increased non-coronary artery bypass grafting Thrombolysis In Myocardial Infarction major bleeding (2.2% vs. 0.6%, p < 0.001) and intracranial hemorrhage (0.6% vs. 0.1%, p = 0.015) without a significant increase in fatal bleeding (0.2% vs. 0.1%, p = 0.51). CONCLUSIONS: In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Admission hyperglycemia and acute myocardial infarction: outcomes and potential therapies for diabetics and nondiabetics.

Hyperglycemia, in both diabetic and nondiabetic patients, has a significant negative impact on the morbidity and mortality of patients presenting with an acute myocardial infarction (AMI). Contemporary evidence indicates that persistent hyperglycemia after initial hospital admission continues to exert negative effects on AMI patients. There have been a number of studies demonstrating the benefit of tight glucose control in patients presenting with AMI, but a lack of convincing clinical data has led to loose guidelines and poor implementation of glucose targets for this group of patients. The CREATE-ECLA study, which hypothesized that a fixed high dose of glucose, insulin, and potassium (GIK) would change myocardial substrate utilization from free fatty acids to glucose and therefore protect ischemic myocardium, failed to demonstrate improved clinical outcomes in AMI patients. Studies that specifically investigated intensive insulin therapy, including DIGAMI-2 and HI-5, also failed to improve clinical outcomes such as mortality. There are a number of reasons that these trials may have fallen short, including the inability to reach glucose targets and inadequate power. There is now a need for a large placebo-controlled randomized trial with an adequate sample size and adherence to glucose targets in order to establish the benefit of treating hyperglycemia in patients presenting with AMI.

Pharmacokinetic evaluation of rivaroxaban for the treatment of acute coronary syndromes.

INTRODUCTION: Arterial and venous thrombotic states, including myocardial infarction (MI), stroke and deep vein thrombosis with subsequent pulmonary embolism, are a significant cause of cardiovascular mortality and morbidity. Factor Xa (FXa) plays a pivotal role in thrombus formation. Its inhibition following acute coronary syndromes (ACS) blocks amplification of thrombin generation and subsequent clot formation, resulting in a risk reduction in recurrent MI, stroke and death. For this reason, a predictable form of oral anticoagulation continues to be an ongoing need. Rivaroxaban , the first oral FXa inhibitor, acts by direct inhibition of FXa and does not require an antithrombin cofactor for its activity. AREAS COVERED: This paper describes the pharmacokinetics (PK) of low-dose rivaroxaban tested in patients with ACS. Age, gender, renal function and body weight have no clinically significant effects on the PK of the drug in treatment of ACS. Caution should be maintained during co-administration of strong CYP3A4 inducers and inhibitors. Among patients with moderate and severe hepatic impairment and in those with associated coagulopathies, rivaroxaban however is contraindicated. EXPERT OPINION: The mortality benefit with low-dose rivaroxaban in ACS patients was first demonstrated in ATLAS ACS2 TIMI-51 trial. With its rapid oral bioavailability, predictable PK, low drug-drug interaction and no need for monitoring, the use of low-dose rivaroxaban in addition to dual antiplatelet therapy offers an appealing new option in improving outcomes following ACS in the modern era of novel oral FXa inhibitors.

Rivaroxaban in patients with a recent acute coronary syndrome.

BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. RESULTS: Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). CONCLUSIONS: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome.

BACKGROUND: Although therapy with aspirin or aspirin plus a thienopyridine reduces the incidence of long-term adverse cardiovascular events among patients with acute coronary syndrome (ACS), there remains a significant residual risk of cardiovascular death, recurrent myocardial infarction (MI), and stroke. In a phase 2 trial (ClinicalTrials.gov NCT00402597) in which the addition of the factor Xa inhibitor rivaroxaban was compared with placebo, among ACS patients receiving either aspirin alone or dual-antiplatelet therapy with aspirin and a thienopyridine, the end point of death, MI, or stroke compared with placebo was reduced (87/2331 [3.9%] vs 62/1160 [5.5%]; hazard ratio 0.69, [95% CI 0.50-0.96], P = .027). Two candidate doses of rivaroxaban were selected for further evaluation in a pivotal phase 3. DESIGN: The second ATLAS-ACS 2 TIMI 51 Trial is an international, randomized, double-blind, event-driven (n = 983) phase 3 trial involving more than 15,570 patients hospitalized with ACS (ClinicalTrials.gov NCT00809965). All patients are treated with a background of standard therapy including low-dose aspirin, and patients are stratified by the administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Within each stratum, patients are randomly assigned in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily, or rivaroxaban 5 mg twice daily, or placebo twice daily. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke. The primary safety end point is thrombolysis in MI major bleeding not associated with coronary artery bypass graft surgery. SUMMARY: The ATLAS-ACS 2 TIMI 51 is testing the hypothesis that anticoagulation with the oral factor Xa inhibitor rivaroxaban reduces cardiovascular death, MI, and stroke among patients with ACS treated with guideline-based therapies for ACS.

Initial clinical results using intracardiac electrogram monitoring to detect and alert patients during coronary plaque rupture and ischemia.

OBJECTIVES: We report the first clinical studies of intracardiac ST-segment monitoring in ambulatory humans to alert them to significant ST-segment shifts associated with thrombotic occlusion. BACKGROUND: Despite improvements in door-to-balloon times, delays in symptom-to-door times of 2 to 3 h remain. Early alerting of the presence of acute myocardial infarction could prompt patients to seek immediate medical evaluation. METHODS: Intracardiac monitoring was performed in 37 patients at high risk for acute coronary syndromes. The implanted monitor continuously evaluated the patients' ST segments sensed from a conventional pacemaker right ventricle apical lead, and alerted patients to detected ischemic events. RESULTS: During follow-up (median 1.52 years, range 126 to 974 days), 4 patients had ST-segment changes of ≥3 SDs of their normal daily range, in the absence of an elevated heart rate. This in combination with immediate hospital monitoring led to angiogram and/or intravascular ultrasonography, which confirmed thrombotic coronary occlusion/ruptured plaque. The median alarm-to-door time was 19.5 min (6, 18, 21, and 60 min, respectively). Alerting for demand-related ischemia at elevated heart rates, reflective of flow-limiting coronary obstructions, occurred in 4 patients. There were 2 false-positive ischemia alarms related to arrhythmias, and 1 alarm due to a programming error that did not prompt cardiac catheterization. CONCLUSIONS: Shifts exceeding 3 SD from a patient's daily intracardiac ST-segment range may be a sensitive/specific marker for thrombotic coronary occlusion. Patient alerting was associated with a median alert-to-door time of 19.5 min for patients at high risk of recurrent coronary syndromes who typically present with 2- to 3-h delays.

Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Substudy.

OBJECTIVES: The goal of this analysis was to determine whether intensive statin therapy, compared with moderate-dose statin therapy, leads to a reduction in major adverse cardiovascular events (MACE) among patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). BACKGROUND: When compared with moderate-dose statins, intensive statin therapy reduces MACE among patients with ACS. The role of intensive statin therapy specifically among patients who undergo PCI for ACS is unknown. METHODS: Outcomes were compared in 2,868 patients who underwent PCI for ACS just prior to enrollment in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial, which randomized patients to either atorvastatin 80 mg or pravastatin 40 mg daily. The incidence of the primary composite end point of all-cause mortality, myocardial infarction, unstable angina leading to hospitalization, and revascularization after 30 days and stroke was evaluated, as was the incidence of target vessel revascularization (TVR) and non-TVR during follow-up. RESULTS: Treatment with 80 mg atorvastatin reduced the incidence of the composite end point (21.5% vs. 26.5%, hazard ratio: 0.78, 95% confidence interval: 0.67 to 0.91, p=0.002) and lowered the incidence of both TVR (11.4% vs. 15.4%, p=0.001) and non-TVR (8.0% vs. 10.5%, p=0.017) compared with 40 mg pravastatin. After adjusting for on-treatment serum low-density lipoprotein cholesterol and C-reactive protein concentrations, the odds of TVR with high-dose statin therapy remained significant (odds ratio: 0.74, p=0.015) while the odds of non-TVR did not (odds ratio: 0.92, p=0.55). CONCLUSIONS: Among patients with ACS who undergo PCI, intensive statin therapy reduces MACE compared with moderate-dose statin therapy. The reduction in the incidence of TVR was independent of low-density lipoprotein cholesterol and C-reactive protein lowering and may therefore be due, at least in part, to a pleiotropic effect of high-dose statin therapy. (PROVE IT-TIMI 22; NCT00382460).