Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice.

MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes.

Non-vitamin K antagonist oral anticoagulants (NOACs) post-percutaneous coronary intervention: a network meta-analysis.

BACKGROUND: Clinicians must balance the risks of bleeding and thrombosis after percutaneous coronary intervention (PCI) in people with an indication for anticoagulation. The potential of non-vitamin K antagonists (NOACs) to prevent bleeding complications is promising, but evidence remains limited. OBJECTIVES: To review the evidence from randomised controlled trials assessing the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) compared to vitamin K antagonists post-percutaneous coronary intervention (PCI) in people with an indication for anticoagulation. SEARCH METHODS: We identified studies by searching CENTRAL, MEDLINE, Embase, the Conference Proceedings Citation Index - Science and two clinical trials registers in February 2019. We checked bibliographies of identified studies and applied no language restrictions. SELECTION CRITERIA: We searched for randomised controlled trials (RCT) that compared NOACs and vitamin K antagonists for people with an indication for anticoagulation who underwent PCI. DATA COLLECTION AND ANALYSIS: Two review authors independently checked the results of searches to identify relevant studies, assessed each included study, and extracted study data. We conducted random-effects, pairwise analyses using Review Manager 5 and network meta-analyses (NMA) using the R package 'netmeta'. We ranked competing treatments by P scores, which are derived from the P values of all pairwise comparisons, and allow ranking of treatments on a continuous 0 to 1 scale. MAIN RESULTS: We identified nine RCTs that met the inclusion criteria, but four were ongoing trials, and were not included in this analysis. We included five RCTs, with 8373 participants, in the NMA (two RCTs compared apixaban to a vitamin K antagonist, two RCTs compared rivaroxaban to a vitamin K antagonist, and one RCT compared dabigatran to a vitamin K antagonist). Very low- to moderate-certainty evidence suggests little or no difference between NOACs and vitamin K antagonists in death from cardiovascular causes (not reported in the dabigatran trial), myocardial infarction, stroke, death from any cause, and stent thrombosis. Apixaban (RR 0.85, 95% CI 0.77 to 0.95), high dose rivaroxaban (RR 0.86, 95% CI 0.74 to 1.00), and low dose rivaroxaban (RR 0.80, 95% CI 0.68 to 0.92) probably reduce the risk of recurrent hospitalisation compared with vitamin K antagonists. No studies looked at health-related quality of life. Very low- to moderate-certainty evidence suggests that NOACs may be safer than vitamin K antagonists in terms of bleeding. Both high dose dabigatran (RR 0.53, 95% CI 0.29 to 0.97), and low dose dabigatran (RR 0.38, 95% CI 0.21 to 0.70) may reduce major bleeding more than vitamin K antagonists. High dose dabigatran (RR 0.83, 95% CI 0.72 to 0.96), low dose dabigatran (RR 0.66, 95% CI 0.58 to 0.75), apixaban (RR 0,67 , 95% Cl 0.51 to 0.88), high dose rivaroxaban (RR 0.66, 95% CI 0.52 to 0.83), and low dose rivaroxaban (RR 0.71, 95% CI 0.57 to 0.88) probably reduce non-major bleeding more than vitamin K antagonists. The results from the NMA were inconclusive between the different NOACs for all primary and secondary outcomes. AUTHORS' CONCLUSIONS: Very low- to moderate-certainty evidence suggests no meaningful difference in efficacy outcomes between non-vitamin K antagonist oral anticoagulants (NOAC) and vitamin K antagonists following percutaneous coronary interventions (PCI) in people with non-valvular atrial fibrillation. NOACs probably reduce the risk of recurrent hospitalisation for adverse events compared with vitamin K antagonists. Low- to moderate-certainty evidence suggests that dabigatran may reduce the rates of major and non-major bleeding, and apixaban and rivaroxaban probably reduce the rates of non-major bleeding compared with vitamin K antagonists. Our network meta-analysis did not show superiority of one NOAC over another for any of the outcomes. Head to head trials, directly comparing NOACs against each other, are required to provide more certain evidence.

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.

Anticoagulation in Atherosclerotic Disease.

The prevention of atherothrombotic events is an essential therapeutic goal in the treatment of patients with arteriosclerotic diseases. After plaque rupture, a rapidly growing thrombus can lead to acute vascular occlusion and thus heart attack, stroke or limb ischaemia. The acute therapy combines anticoagulation and platelet inhibition. However, the only available therapy so far in the primary and secondary prevention of stable patients is the platelet inhibitors aspirin and clopidogrel. Despite the use of antiplatelet therapies, including aspirin and P2Y12-receptor antagonists, some patients with artery disease continue to experience recurrent cardiovascular ischaemic events due to excessive thrombin generation beyond the acute period. As a result, studies have tested non-vitamin K antagonist oral anticoagulants (NOACs), specifically the factor Xa inhibitors, either alone or in combination with antiplatelet therapy, in the management of arterial disease. For the first time, the COMPASS study investigated low-dose anticoagulation in stable coronary heart disease or peripheral arterial disease. The addition of 2 × 2.5 mg rivaroxaban to long-term aspirin therapy not only prevented cardiovascular death, myocardial infarction and stroke, but even reduced all-cause mortality by a relative 18% after a mean follow-up of 23 months. This benefit came at the expense of more gastrointestinal bleeding, which might be reduced by the addition of a proton pump inhibitor (investigations are ongoing). Interestingly, however, there was no increase in fatal or intracranial haemorrhages. Therefore, a new standard therapy for high-risk patients with atherosclerotic disease may become available in the near future.

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).

Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity.

Aim: Anthracyclines such as doxorubicin are widely used in cancer therapy but their use is limited by cardiotoxicity. Up to date there is no established strategy for the prevention of anthracyclin-induced heart failure. In this study, we evaluated the role of the cardiac myocyte mineralocorticoid receptor (MR) during doxorubicin-induced cardiotoxicity. Methods and results: A single high-dose or repetitive low-dose doxorubicin administration lead to markedly reduced left ventricular function in mice. Treatment with the MR antagonist eplerenone prevented doxorubicin-induced left ventricular dysfunction. In order to identify the cell types and molecular mechanisms involved in this beneficial effect we used a mouse model with cell type-specific MR deletion in cardiac myocytes. Cardiac myocyte MR deletion largely reproduced the effect of pharmacological MR inhibition on doxorubicin-induced cardiotoxicity. RNAseq from isolated cardiac myocytes revealed a repressive effect of doxorubicin on gene expression which was prevented by MR deletion. Conclusions: We show here that (i) eplerenone prevents doxorubicin-induced left ventricular dysfunction in mice, and (ii) this beneficial effect is related to inhibition of MR in cardiac myocytes. Together with present clinical trial data our findings suggest that MR antagonism may be appropriate for the prevention of doxorubicin-induced cardiotoxicity.

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 .).

Dabigatran and rivaroxaban do not affect AA- and ADP-induced platelet aggregation in patients receiving concomitant platelet inhibitors.

Dabigatran and rivaroxaban are novel, vitamin K-independent oral anticoagulants (NOACs) and act via antagonism of the coagulation factor (F) IIa (dabigatran) or FXa (rivaroxaban), respectively. Compared to vitamin-K-antagonists, NOACs have shown non-inferiority of risk and benefit in patients with non valvular atrial fibrillation (AF). In clinical practice there is increasing use of NOACs combined with platelet inhibitors in patients with AF and coronary artery disease. However, whether NOACs affect the function of platelet inhibitors remains incompletely known. This observational study aimed to assess the platelet function in patients receiving dabigatran or rivaroxaban and concomitant platelet inhibitors. A single centre observational study was performed analysing the platelet aggregation of patients treated with dabigatran or rivaroxaban with or without concomitant platelet inhibitors. Measurements before the initiation of NOAC therapy served as the respective control group. Platelet aggregation was measured by multiple electrode aggregometry and was induced with adenosine diphosphate (ADP, 6.5 µM) and arachidonic acid (AA, 0.5 mM), respectively. In order to evaluate whether NOACs interact with platelet inhibition by ASA or the P2Y12-antagonist clopidogrel, 87 patients were grouped according to their concomitant antiplatelet medication. Comparing the ADP- and AA-induced platelet aggregation in patients without concomitant platelet inhibitors (n = 45) no significant differences under therapy with dabigatran (d) or rivaroxaban (r) compared to the control group (c) were observed. In patients taking clopidogrel as a concomitant platelet inhibitor (n = 21), neither dabigatran nor rivaroxaban affected the ADP-induced platelet aggregation (c 20 ± 11, d 21 ± 14, r 18 ± 8 AU*min, p = 0.200). Patients receiving dabigatran or rivaroxaban in combination with ASA (n = 42; 21 ASA only, 21 ASA + clopidogrel) showed no significant differences of the AA-induced aggregation compared to the control group (c 10 ± 8, d 9 ± 7, r 10 ± 8 AU*min, p = 0.810). The antiplatelet effects of ASA and clopidogrel monitored by AA- or ADP-induced platelet aggregation were not affected by NOAC therapy.

Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.

TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran.

BACKGROUND/OBJECTIVES: Novel (or non-vitamin K antagonist) oral anti-coagulants (NOACs) are antagonists of coagulation factors (F) Xa (rivaroxaban) or IIa (dabigatran), and their non-inferiority compared with vitamin K antagonists has been demonstrated in patients with non-valvular atrial fibrillation. However, it is still not fully understood if and how dabigatran and rivaroxaban impact platelet function. This observational study aimed to assess platelet function in patients receiving dabigatran or rivaroxaban. METHODS/RESULTS: This was a single centre, observational study quantifying platelet aggregation in 90 patients treated with NOACs by multiple electrode aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly higher in 35 patients receiving dabigatran (d) compared with control (c) patients (d 108±31 vs. c 85±30arbitrary units [AU]∗min, p<0.001). Patients receiving rivaroxaban (r) showed no differences compared with the control group (r 88±32 vs. c 85±30AU∗min, p=0.335). In intraindividual time courses of 16 patients, a significantly higher aggregation was found after the administration of dabigatran (before vs. after; 83±29 vs. 100±31AU∗min, p=0.009). CONCLUSION: In this observational study, the TRAP-induced platelet aggregation was enhanced in cardiovascular patients receiving dabigatran. This might be explained by a change in the expression profile of thrombin receptors on the surface of platelets. Rivaroxaban had no influence on platelet aggregation.

[Prophylaxis of thromboembolism in atrial fibrillation: new oral anticoagulants and left atrial appendage closure]. / Embolieprophylaxe bei Vorhofflimmern: Neue orale Antikoagulanzien und Vorhofohrverschluss.

Thrombo-embolic prophylaxis is a key element within the therapy of atrial fibrillation/atrial flutter. Besides new oral anticoagulants the concept of left atrial appendage occlusion has approved to be a good alternative option, especially in patients with increased risk of bleeding.

Selenium prevents microparticle-induced endothelial inflammation in patients after cardiopulmonary resuscitation.

INTRODUCTION: Microparticles are elevated in patients after successful cardiopulmonary resuscitation (CPR) and may play a role in the development of endothelial dysfunction seen in post-cardiac arrest syndrome (PCAS), a life threatening disease with high mortality. To identify mechanisms of endothelial activation and to develop novel approaches in the therapy of PCAS, the impact of selenium, a trace element with antioxidative properties, was characterized in endothelial dysfunction induced by microparticles of resuscitated patients. Additionally, course of plasma selenium levels was characterized in the first 72 hours post-CPR. METHODS: Endothelial cells were exposed to microparticles isolated of the peripheral blood of resuscitated patients, and leukocyte-endothelial interaction was measured by dynamic adhesion assay. Expression of adhesion molecules was assessed by immunoblotting and flow chamber. Blood samples were drawn 24, 48 and 72 hours after CPR for determination of plasma selenium levels in 77 resuscitated patients; these were compared to 50 healthy subjects and 50 patients with stable cardiac disease and correlated with severity of illness and outcome. RESULTS: Microparticles of resuscitated patients enhance monocyte-endothelial interaction by up-regulation of ICAM-1 and VCAM-1. Selenium administration diminished ICAM-1 and VCAM-1-mediated monocyte adhesion induced by microparticles of resuscitated patients, suggesting that selenium has anti-inflammatory effects after CPR. Lowered selenium plasma levels were observed in resuscitated patients compared to controls and selenium levels immediately and 24 hours after CPR, inversely correlated with clinical course and outcome after resuscitation. CONCLUSIONS: Endothelial dysfunction is a pivotal feature of PCAS and is partly driven by microparticles of resuscitated patients. Administration of selenium exerted anti-inflammatory effects and prevented microparticle-mediated endothelial dysfunction. Decline of selenium was observed in plasma of patients after CPR and is a novel predictive marker of ICU mortality, suggesting selenium consumption promotes inflammation in PCAS.

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.

Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk.

Rivaroxaban is a direct factor Xa inhibitor that is widely available to reduce the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation and one or more risk factors for stroke. Rivaroxaban provides practical advantages compared with warfarin and other vitamin K antagonists, including a rapid onset of action, few drug interactions, no dietary interactions, a predictable anticoagulant effect, and no requirement for routine coagulation monitoring. However, questions have emerged relating to the responsible use of rivaroxaban in day-to-day clinical practice, including patient selection, dosing, treatment of patients with renal impairment, conversion from use of vitamin K antagonists to rivaroxaban and vice versa, coagulation tests, and management of patients requiring invasive procedures or experiencing bleeding or an ischemic event. This article provides practical recommendations relating to the use of rivaroxaban in patients with nonvalvular atrial fibrillation, based on clinical trial evidence, relevant guidelines, prescribing information, and the authors' clinical experience.

Rivaroxaban for stroke prevention in atrial fibrillation and secondary prevention in patients with a recent acute coronary syndrome.

The occurrence of disabling stroke, the major fatal consequence of atrial fibrillation, can be reduced by almost two-thirds with warfarin oral anticoagulation. Recent estimates on the prevalence of atrial fibrillation in the USA suggest that approximately 3 million people suffer from this common cardiac arrhythmia, therefore, the socioeconomic impact of adequate oral anticoagulation is enormous. Rivaroxaban, a direct orally available factor Xa inhibitor, is the first of a new class of drugs that target a central factor of the coagulation cascade upstream of thrombin. In the ROCKET AF clinical trial, rivaroxaban demonstrated noninferiority compared with warfarin for stroke prevention in patients with atrial fibrillation, while intracranial and fatal bleeding occurred less frequently with rivaroxaban treatment. Rivaroxban has recently been approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation by the US FDA and EMA. Very recently, rivaroxaban in addition to dual antiplatelet therapy, was shown to reduce mortality in patients with a recent acute coronary syndrome in the ATLAS ACS 2-TIMI 51 clinical trial. The clinical evaluation of rivaroxaban in cardiovascular disease and the results of the ROCKET AF study, the landmark clinical trial of rivaroxaban for stroke prevention, are discussed along with the unique pharmacological profile of rivaroxaban.

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.).