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.

Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study.

BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ±â€Š89 vs. 7 ±â€Š1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

Excess Mortality in Aspirin and Dipyrone (Metamizole) Co-Medicated in Patients With Cardiovascular Disease: A Nationwide Study.

Background Pain is a major issue in our aging society. Dipyrone (metamizole) is one of the most frequently used analgesics. Additionally, it has been shown to impair pharmacodynamic response to aspirin as measured by platelet function tests. However, it is not known how this laboratory effect translates to clinical outcome. Methods and Results We conducted a nationwide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting analysis was conducted to investigate the rate of mortality, myocardial infarction, and stroke/transient ischemic attack between patients on aspirin-dipyrone co-medication compared with aspirin-alone medication. Permanent aspirin-alone medication was given to 26,200 patients, and 5946 patients received aspirin-dipyrone co-medication. In the inverse probability of treatment weighted sample, excess mortality in aspirin-dipyrone co-medicated patients was observed (15.6% in aspirin-only group versus 24.4% in the co-medicated group, hazard ratio [HR], 1.66 [95% CI, 1.56-1.76], P<0.0001). Myocardial infarction and stroke/transient ischemic attack were increased as well (myocardial infarction: 1370 [5.2%] versus 355 [5.9%] in aspirin-only and co-medicated groups, respectively; HR, 1.18 [95% CI, 1.05-1.32]; P=0.0066, relative risk [RR], 1.14; number needed to harm, 140. Stroke/transient ischemic attack, 1901 [7.3%] versus 506 [8.5%] in aspirin-only and co-medicated groups, respectively; HR, 1.22 [95% CI, 1.11-1.35]; P<0.0001, RR, 1.17, number needed to harm, 82). Conclusions In this observational, nationwide analysis, aspirin and dipyrone co-medication was associated with excess mortality. This was in part driven by ischemic events (myocardial infarction and stroke), which occurred more frequently in co-medicated patients as well. Hence, dipyrone should be used with caution in aspirin-treated patients for secondary prevention.

Lipid lowering therapy in cardiovascular disease: From myth to molecular reality.

Lipid-lowering therapy is one major cornerstone of medical treatment of cardiovascular disease in order to modulate atherosclerosis. Statins, ezetimibe and novel PCSK9-inhibitors are already recommended in current guidelines and were shown to improve lipid profiles and have positive effects on the rate of ischemic events and cardiovascular mortality. Recent studies suggest that the concept of "The lower the better" might be valid at least regarding low density lipoproteins. In addition, lowering lipoprotein (a) still displays a major challenge in lipid therapy. Furthermore, also lowering triglycerides seems to improve cardiovascular outcome. Regarding triglycerides, icosapent ethyl, a polyunsaturated fatty acid recently attracted attention showing cardiovascular risk reduction due to triglyceride lowering. Therefore, new therapeutic strategies and drug classes are eagerly awaited. Targeting LDL, bempedoic acid and the siRNA inclisiran provide promising results. Moreover, regarding TG a monoclonal antibody called evinacumab and an antisense-oligonucleotide against ANGPTL3 showed effective TG-lowering. At least, using antisense-oligonucleotides against ApoC-III and Lp(a) resulted in promising outcomes. In this review, current and future options for lipid management are presented depending on different drug classes.