Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Platelet Reactivity in Patients on Aspirin and Clopidogrel Therapy Measured by a New Bedside Whole-Blood Assay.

Various tests are available for measuring on-treatment platelet reactivity. The pharmacologically most specific assays are time-consuming and elaborate. A highly specific and convenient assay would be desirable for clinical routine. In this pilot study, we aimed to examine the ability of a novel bedside whole-blood assay-ROTEM platelet-to evaluate platelet inhibition compared with established assays. Platelet reactivity was investigated in 93 patients. Forty-Seven patients were on permanent aspirin therapy and 46 on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. We used ROTEM platelet impedance aggregometry (ROTEM-PTL), light transmission aggregometry (LTA), Multiplate electrode aggregometry (MEA) and vasodilator-stimulated phosphoprotein flow cytometry. Receiver operating characteristic (ROC) analyses showed ROTEM-PTL differentiates well between patients on medication and healthy individuals: aspirin: ROCAUC 0.99 (95% confidence interval, 0.97-1.01); P < 0.0001; DAPT treatment: ROCAUC 0.80 (95% confidence interval, 0.69-0.91); P < 0.001. Pearson regression analyses showed moderate correlations between assays. Aspirin: MEA versus ROTEM-PTL r = 0.435, P ≤ 0.001; LTA versus ROTEM-PTL r = 0.048, P = 0.180. DAPT: MEA versus ROTEM-PTL r = 0.398, P = 0.001; LTA versus ROTEM-PTL r = 0.409, P = 0.001; vasodilator-stimulated phosphoprotein versus ROTEM-PTL r = 0.164, P = 0.055. ROTEM platelet distinguished well between treated and healthy individuals but correlated moderately with other assays. Clinical trials are needed to investigate the ability of this new assay to identify patients at risk of adverse events.

Dose reduction, oral application, and order of intake to preserve aspirin antiplatelet effects in dipyrone co-medicated chronic artery disease patients.

BACKGROUND: Dipyrone comedication in aspirin-treated patients is associated with impaired pharmacodynamic response to aspirin (high on-treatment platelet reactivity [HTPR]). Additionally, in small observational studies, an association with impaired outcome has been described. In this uncontrolled, hypothesis-generating study, we aimed to investigate strategies to prevent this drug-drug interaction in patients with coronary artery disease (CAD). METHODS: We analyzed pharmacodynamic response to aspirin in 80 dipyrone co-medicated CAD patients. Aspirin antiplatelet effects were measured using arachidonic acid (AA)-induced light-transmission aggregometry (LTA). Platelet reactivity was associated with daily dose, administration form, and frequency. Additionally, we conducted a time-series analysis in patients with HTPR to aspirin with re-evaluation of pharmacodynamic response to aspirin after 5 days. RESULTS: Patients' mean age was 75.5 ± 9.8 years. Forty-three (54%) were male, 22 (27.5%) obese, and 38 (47.5%) diabetics. Baseline characteristics, cardiovascular risk factors, comorbidities, comedication, or laboratory parameters did not differ between patients with or without HTPR. HTPR to aspirin occurred in 34 out of 80 patients (42.5%). The incidence of HTPR was associated with dipyrone daily dose (< 1 g/day: HTPR 20% vs. > 3 g/day: HTPR 50%, p > 0.0001) and form of administration (i.v. 87.5% vs. oral 37.5%; p < 0.0001). A strict order of intake (aspirin 30 min prior to dipyrone) restored aspirin antiplatelet effects in all patients (HTPR before 100% vs. HTPR after 0%, p = 0.0002). CONCLUSION: This study shows that dipyrone should be used with caution in aspirin-treated patients. If dipyrone seems indispensable, the lowest effective dose and a strict order of intake seem favorable.

Non-vitamin K oral anticoagulants (NOAC) and the risk of myocardial infarction: Differences between factor IIa and factor Xa inhibition?

Guidelines already recommend non-vitamin K oral anticoagulants (NOAC) over vitamin-K antagonists (VKA) for stroke prevention in patients with atrial fibrillation. However, recommendations are lacking with respect to which NOAC to use. At the moment, NOACs may employ two different molecular mechanisms: Factor IIa inhibition (dabigatran) and factor Xa inhibition (apixaban, edoxaban, rivaroxaban). The focus of this review is to compare and contrast potential differences between factor IIa- and factor Xa inhibition with respect to risk of myocardial infarction and to detail underlying mechanisms.

Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE.

BACKGROUND: The non-opioid analgesic dipyrone can trigger life-threatening blood formation disorders. However, it is frequently used, as many patients with coronary artery disease (CAD) rely on non-opioid analgesics to relieve pain. In this study, we investigated the incidence of death, myocardial infarction (MI) or stroke in CAD patients with aspirin and dipyrone comedication as compared to aspirin-alone. METHODS: We conducted an observational pilot study in 72 CAD patients with aspirin ± dipyrone comedication in the department of cardiology of the University Hospital Düsseldorf. The primary end point was a composite of death, myocardial infarction (MI) or stroke. The secondary end points were the components of the primary end point. The median follow-up period was 3.2years. RESULTS: The primary end point occurred 67% of patients in the aspirin+dipyrone group as compared to 31% in the aspirin-alone group (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.7 to 12.3; P=0.0028;). All-cause mortality was significantly higher in the aspirin+dipyrone group (44%) than the aspirin-alone group (22%; OR 2.8, 95% CI 1.01 to 7.8; P=0.049). Ischemic events (MI and stroke) were more frequent in the aspirin+dipyrone group as compared to the aspirin alone group as well (OR 4, 95% CI 1.1 to 14; P=0.03). CONCLUSION: In this hypothesis generating pilot analysis, dipyrone medication in aspirin treated coronary artery disease patients is associated with an increased cumulative incidence of death, MI or stroke as well as all-cause mortality and ischemic events. These data have to be confirmed in larger registries and trials. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01402804; Identifier: NCT01402804; Date of registration: July 25, 2011.

SeQuent Please vs. Pantera Lux drug coated balloon angioplasty in real life: Results from the Düsseldorf DCB registry.

BACKGROUND: In-stent restenosis (ISR) is still a major concern in interventional cardiology. Drug coated balloon (DCB) angioplasty has been shown to be a promising option in treatment of ISR. However heterogeneity of different DCBs in suppression of neointimal growth has been described in a porcine model of coronary ISR. Therefore, in this registry analysis, we compared two frequently used paclitaxel eluting DCBs, the SeQuent Please and the Pantera Lux DCB. METHODS: 571 patients were treated with DCB angioplasty at the Heinrich-Heine University Düsseldorf between 2009 and 2012. Follow-up was conducted during ambulatory care at our department. Major adverse cardiac events (death, myocardial infarction [MI] and target lesion revascularization) were registered during hospitalization and follow-up. RESULTS: Patient characteristics, prior diseases, clinical presentation, ejection fraction, procedural success and lost-for-follow-up did not differ between patients treated with the SeQuent Please and. The Pantera Lux DCB. MACE during hospital course were similar as well (Pantera Lux: 6 patients [1.6%] vs. SeQuent®Please: 3 patients [1.5%], relative risk 1.06, 95% confidence interval 0.3-4.2, P=0.93). Event free survival was significantly longer in patients treated with the Pantera Lux DCB as compared to SeQuent Please DCB (Hazard ratio: 0.65, 95% confidence interval 0.43-0.98; P value of log-rank test: 0.0405). CONCLUSION: MACE free survival was longer in Pantera Lux DCB treated patients as compared to SeQuent Please treated patients. This finding has to be confirmed in future clinical trials.