Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects. J Thromb Haemost 2016; 14: 316-23. Essentials• It is unknown whether single rivaroxaban doses should best be administered in the morning or evening.• Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban.• Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations.• Evening intake of rivaroxaban better matches the morning hypofibrinolysis.Summary. Background: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. Materials and methods: Sixteen healthy male or female volunteers with a mean age of 26 AE 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an antiactivated factor X assay and liquid chromatography-mass spectrometry. Main results: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL À1 [95% con- 106 AE 34 nmol L À1 , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. Conclusions: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.
We conclude, that the reduction in afterload did not cause the typical changes in wave contour of the peripheral pulse curve which occur with organic nitrates. Most likely changes in the a/b ratio reflect changes in LV preload.
A biological rhythm in platelet function is well known. Multiple electrode aggregometry (MEA) is a widely used assay to measure platelet aggregability. Rivaroxaban is a new oral anticoagulant frequently used in an increasing number of indications. In this randomized, crossover trial we investigated whether a biological rhythm exists in MEA measurements and potential effects of rivaroxaban on platelet aggregation. Sixteen healthy volunteers were included in the study and blood samples were obtained at 08:00, 12:00, 16:00 and 20:00 h. Each subject was tested without rivaroxaban intake first and randomly assigned to 3 days of rivaroxaban intake at 08:00 or 3 days of rivaroxaban intake at 20:00 h and vice versa. In MEA measurements, a significant increase in platelet aggregation after addition of ristocetin at 12:00 h compared to other investigated time-points (122 ± 8 AU at 12:00 h vs. 109 ± 9 AU at 08:00 h, 114 ± 10 AU at 16:00 h and 103 ± 8 AU at 20:00 h, p = 0.027) could be detected. There was no biological rhythm detectable using other agonists (ADP, arachidonic acid, thrombin-receptor activating peptide-6). After rivaroxaban intake at 08:00 h an increased ristocetin-induced platelet aggregation was measured in the next morning (126 ± 4 AU (rivaroxaban at 08:00 h) vs. 109 ± 9 AU (no rivaroxaban), 111 ± 6 AU (rivaroxaban at 20:00 h; p = 0.002). No other effects of rivaroxaban on platelet function were found. We detected a biological rhythm in ristocetin-induced platelet aggregation with a peak at 12:00 h (noon). No influence of selective Xa inhibition on platelet aggregation was detected.
BackgroundVaccination efficiency has been demonstrated to be reduced in patients with systemic autoimmune rheumatic disease (SARD) compared with the general population.ObjectivesTo assess the humoral response to mRNA vaccine in patients with (SARD) and the effect of immunosuppressive medication in a matched cohort study.MethodsPatients with SARD were enrolled and matched 1:1 for gender and age with healthy control subjects (HC). Differences in the humoral response to two doses of mRNA vaccine BNT162b2 in terms of seroconversion rate and SARS-COV-2 antibody titer between the two groups and impact of treatment within SARD patients was assessed using Fisher’s exact test, Student’s t-test, Mann-Whitney test and Kruskal-Wallis test, adjusting for multiple testing.ResultsWe enrolled 82 patients with SARD and 82 matched HC (Table 1). Among patients the seroconversion rate was significantly lower after the 1st dose (65% compared to 100% in HC, p<0.0001) but levelled up after the 2nd dose (94% vs. 100%). While the difference in seroconversion rate was independent of treatment regime (no disease modifying anti-rheumatic drug (DMARD), DMARD monotherapy, DMARD combination therapy), the seroconversion rate of SARD patients on mono- or combination DMARD therapy was also significantly lower as compared to those receiving no DMARD therapy (56% for monotherapy and 57% for combination therapy compared to 77% for no DMARD therapy, p=0.002 and p=0.004 respectively; Figure 1A). Seroconversion rate after the 2nd dose was significantly lower for patients on combination DMARD therapy compared to all other groups (81% compared to 95% for monotherapy, and 100% for both no DMARD therapy and HC respectively, all p<0.0001); also antibody titers after the 2nd dose were lower when comparing patients on combination DMARD therapy to all other groups (49 binding antibody units (BAU)/ml versus 1673 BAU/ml in HC, p<0.0001; 2500 BAU/ml in those on no DMARD therapy, p<0.0001; and 687 BAU/ml in those on DMARD monotherapy, p=0.0072; Figure 1B). Considering effects of individual compounds, mycophenolate mofetil in mono- or combination therapy led to lower antibody titers after the 2nd dose as compared to HC or patients receiving no DMARDs (2 BAU/ml versus 1673 BAU/ml and 2500 BAU/ml respectively, both p<0.0001).Figure 1.Seroconversion rate (A) and anti-SARS-Cov 2 S antibody levels (B) after the 1stand 2ndvaccination between the healthy control (HC) group and patients according to therapyTable 1.Study subject characteristicsSARD (n=82)HC (n=82)Age, mean (±SD)52.05 (±14.06)52.15 (±13.42)Female, n (%)65 (79%)65 (79%)Different disease entity, n (%):33 (40%) Systemic lupus erythematosus Systemic sclerosis13 (16%) Other connective tissue diseases*15 (18%) Vasculitides#17 (21%) Miscellaneous$4 (5%)Treatment groups, n (%):43 (52%) csDMARD or b/tsDMARD monotherapy csDMARD and/or b/tsDMARD combination therapy16 (20%) No therapy23 (28%)Treatment agents, n (%):13 (16%) Methotrexate Mycophenolate14 (17%) Hydroxychloroquine28 (34%) Azathioprine13 (10%) Belimumab3 (4%) Tocilizumab3 (4%) Tacrolimus2 (2%) Olumiant1 (1%)*dermato-/polymyositis (n=4), mixed connective tissue disease (n=2), primary Sjögren’s syndrome (n=6), undifferentiated connective tissue disease (n=3)#antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (n=3), Behcet’s disease (n=1), large-vessel vasculitis (n=3), polymyalgia rheumatica (n=10)$ adult-onset Still’s disease (n=1), immune deficiency (n=2), sarcoidosis (n=1)b/tsDMARD: biological/targeted synthetic disease modifying antirheumatic drug; csDMARD: conventional synthetic disease modifying antirheumatic drug; HC: healthy control; n: number; SARD: systemic autoimmune rheumatic disease; SD: standard deviation;ConclusionPatients with SARD showed a good response after the 2nd vaccination with the mRNA vaccine. However, the choice of immunosuppressive regimen has a marked effect on both seroconversion rate and overall antibody titer.AcknowledgementsWe thank Sylvia Taxer and Zoltan Vass for their support.Disclosure of InterestsPeter Mandl Speakers bureau: AbbVie, Janssen, Novartis, Consultant of: AbbVie, Janssen, Novartis, Grant/research support from: AbbVie, BMS, Lilly, Novartis, MSD, UCB, Selma Tobudic: None declared, Helmut Haslacher: None declared, Daniel Mrak: None declared, Thomas Nothnagl: None declared, Thomas Perkmann: None declared, Helga Radner Speakers bureau: Gilead, Merck Sharp, Pfizer, Abbvie, Consultant of: Gilead, Merck Sharp, Pfizer, Abbvie, Judith Sautner Speakers bureau: Otsuka, Novartis, Consultant of: Lilly, Astro Pharma, UCB, Abbvie, Elisabeth Simader Grant/research support from: Pfizer, Bristol-Myers Squibb, Florian Winkler: None declared, Heinz Burgmann: None declared, Daniel Aletaha Speakers bureau: Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Consultant of: Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Grant/research support from: Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi, Stefan Winkler: None declared, Stephan Blüml Speakers bureau: Novartis, Abbvie, Consultant of: Gilead, Merck, Novartis, Abbvie
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