Dabigatran Research Articles

The Effect of Pharmacological Thromboprophylaxis, Tourniquet and Drainage on Hemorrhagic Complications in the Early Stage after Knee Arthroplasty: Preliminary Results

Background — venous thromboembolic complications (VTC) are potential life-threatening complications following knee arthroplasty (KA). An optimal thromboprophylaxis strategy should reduce the risk of developing VTC without increasing the risk of hemorrhagic complications. The purpose of the study is to evaluate the effect of the drugs (acetylsalicylic acid, dabigatran etexilate and rivaroxaban) for the pharmacological thromboprophylaxis and the features of the surgical procedure (use of the tourniquet and drainage) on hemorrhagic complications in early periods after knee arthroplasty. Materials and Methods. 335 patients (65 men and 270 women), without additional risk factors for the development of thromboembolic complications, were included into the study. Those patients were admitted for planned primary / revision knee arthroplasty and corresponded to inclusion / non-inclusion criteria. Patients were randomized into three clinical groups, depending on the drug used thromboprophylaxis. During the inpatient treatment period, all patients recorded the development of symptomatic VTCs and the development of hemorrhagic complications. According to the clinical indications, the number of knee joint punctures was taken into account: patella balloting, restricted flexion and a smooth joint contour. Results. Symptomatic VTCs were not observed during the study period. The volume of intraoperative blood loss did not depend on the drugs used for thromboprophylaxis, and was determined only by the surgical technique (ρs= -0.615, p = 0.0001). The use of the tourniquet during the procedure significantly reduced intraoperative blood loss (p = 0.023). No relation between surgical technique and anemia on the 5th day (ρs = 0.11, p = 0.05), as well as between surgical technique and total blood loss (ρs = 0.12, p = 0.01) was established; weak reliable correlation between the use of the tourniquet and hidden blood loss (ρs = -0.22, p = 0.01) was reported. A negative average significant correlation was observed (ρs = -0.42, p = 0.01) for the volume of total blood loss and hemoglobin level on the 5th day after the surgery. The number of postoperative punctures was comparable in the study groups. Conclusion. Sample of present size is not sufficient to make conclusions about the equal efficacy of using acetylsalicylic acid, dabigatran and rivaroxaban for thromboprophylaxis after knee arthroplasty in patients without additional risk factors for thrombosis. Data on the significant correlation of the surgical technique with the volume of intraoperative and latent blood loss, as well as total blood loss and hemoglobin level on the 5th day after the operation allow to suggest a possible effect of the drug for thromboprophylaxis on blood loss stargin from 2nd day after the procedure.

P1901Use of direct thrombin inhibitor on the day of atrial fibrillation ablation decreases incidence of silent cerebral ischemia detected by magnetic resonance imaging

Abstract Background There is increasing evidence to use direct oral anticoagulants (DOACs) in atrial fibrillation (AF) ablation. Uninterrupted use of DOACs is recommended for peri-procedural anticoagulation; the ways of choosing and/or using DOACs depend on physicians' decisions and preferences. Uninterrupted dabigatran (DAB), a direct thrombin inhibitor, reportedly decreased the risk of major bleeding (MB) in AF ablation, compared to uninterrupted warfarin (NEJM 2017; 376:1627). Among DOACs, only regular-dose of DAB (150 mg b.i.d.), showed superiority to warfarin for preventing ischemic thromboembolism (TE) in patients with non-valvular AF, implicating the powerful anti-thrombotic agent. DAB may decrease the potential risk of procedure-related TE. Purpose To evaluate whether use of DAB on the day of AF ablation decreases the prevalence of silent cerebral ischemia (SCI) detected by magnetic resonance imaging (MRI). Methods 414 AF patients on DOACs were enrolled and admitted on the day before AF ablation. Among 354 patients on factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), the original DOACs were switched to DAB (150 mg b.i.d.) on the day of the procedure in 172 patients (Group D); the treatment remained unchanged in 182 patients (Group non-D). In both groups, DOACs were continuously used throughout the procedure. After propensity-score matching, procedure-related parameters/events and the incidence of MRI-detected SCI were compared between Group D (n=134) and Group non-D (n=134). These parameters in patients originally taking DAB, used without interruption during the procedure (uninterrupted DAB, n=55), were also compared to Group D (n=55) after propensity-score matching. Results Baseline activated clotting time (ACT) before initial heparin injection was increased in Group D vs. Group-non-D (179±25* vs. 146±23 sec, *p<0.05 vs. Group non-D). The time to achieve optimal ACT (>300 sec) was shorter in Group D (34±29* vs. 43±32 min). The amounts of heparin needed to achieve optimal ACT and the total amount of heparin used during the procedure were unchanged between Group D and Group non-D. The incidence of SCI decreased in Group D (13.1%* vs. 21.9%), suggesting the potential anti-thrombotic efficacy of DAB. No MB or symptomatic TE events were observed in either group. Baseline ACT, the time to achieve ACT >300 sec, and the incidence of SCI in Group D were comparable to those in uninterrupted DAB (183±38 vs. 181±32 sec, 39±31 vs. 42±28 min, and 14.5% vs. 16.4%, respectively). No MB or symptomatic TE events were observed either in Group D or uninterrupted DAB. Conclusions Temporarily switching to DAB from the other DOACs and using it on the day of procedure enable us to achieve optimal ACT quickly and decrease the incidence of SCI, showing similar potential anti-thrombotic efficacy to uninterrupted DAB. Use of DAB on the day of AF ablation also benefits from the availability of its antidote in the case of MB during the procedure.

Differences In Gastrointestinal Safety Profiles Among Novel Oral Anticoagulants: Evidence From A Network Meta-Analysis.

BackgroundThere is no consensus at present regarding the differences in the risk of GI bleeding across various NOAC regimens. Therefore, we performed a network meta-analysis to compare the risk of gastrointestinal bleeding after different NOAC regimens.MethodsPubMed, Cochrane, Web of Science, Clinicaltrial.gov and Clinicaltrialresults.org were searched for randomized controlled trials (RCTs) assessing gastrointestinal bleeding of all NOAC regimens from inception to January 2018. The primary endpoint was major gastrointestinal (MGI) bleeding. The meta-regression was performed to access the association between the MGI bleeding events and mortality. The network meta-analysis was carried out with the Bayesian random-effect model.ResultsA total of 25 RCTs, including 139,392 patients, were identified. Meta-regression analysis showed that MGI bleeding was correlated with fatal bleeding events (odds ratios [OR], 1.76; 95% confidence interval [CI], 1.13–2.77], P=0.015). The network meta-analysis results showed that compared to the conventional regimens, rivaroxaban was associated with increased risk of MGI bleeding (OR, 1.37; 95% credible interval [CrI], 1.00–1.85), but not the apixaban (OR, 0.77; 95% CrI, 0.53–1.07]), edoxaban (OR, 0.86; 95%CrI, 0.52–1.18) and dabigatran etexilate (OR, 1.22; 95% CrI, 0.82–1.69). Compared to rivaroxaban, apixaban (OR, 0.56; 95% CrI, 0.35–0.88) and edoxaban (OR, 0.62; 95% CrI, 0.35–0.96) showed a significantly lower risk of MGI bleeding. Apixaban had the highest probability of being the safest option with regard to the risk of MGI bleeding (89.1%), followed by edoxaban (77.4%), conventional therapy (51.4%), dabigatran etexilate (23.8%) and rivaroxaban (8.3%).ConclusionThe risk of GI bleeding significantly varies among different NOAC regimens, and evidence shows that apixaban and edoxaban had the most favorable MGI bleeding safety profile, while rivaroxaban and dabigatran etexilate were the least safe.

480P - Drug-drug interaction profile of tepotinib with CYP3A and P-gp substrates

BackgroundTepotinib is an oral, highly selective MET inhibitor being investigated in MET-driven solid tumors. Cancer patients often receive co-medications, many of which are subject to cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp)-dependent pharmacokinetics.The potential of tepotinib to alter the exposure to such drugs was investigated in two clinical drug-drug interaction (DDI) trials. MethodsThe effect of multiple doses of the RP2D of tepotinib (500mg QD) on the exposure of single doses of the sensitive CYP3A4 substrate midazolam and the sensitive P-gp substrate dabigatran etexilate were tested in healthy subjects, using randomized single-sequence two-period cross-over designs. The primary endpoints were Cmax and AUC for the respective probe drugs; their corresponding ratios of the geometric least-squares means (GLSM) (90% CI) in the presence/absence of tepotinib were reported. Additional PK measures, safety and tolerability were also evaluated. ResultsMost participants were male (12/12 midazolam; 19/20 dabigatran etexilate); mean age 34 years (range 19–44). There was no increase in midazolam exposure with co-administration of tepotinib (Table), suggesting that no effect on the metabolism of CYP3A is to be expected. Co-administration of tepotinib led to a 39–45% increase in dabigatran etexilate exposure. No clinically relevant effects on laboratory values, vital signs or ECG parameters were observed or reported as an AE.Table480PTableCYP3A substrate (Midazolam) Ratio of GLSM% (90% CI)P-gp substrate (Dabigratan) Ratio of GLSM% (90% CI)Tepotinib + Midazolam / MidazolamTepotinib + Dabigatran etexilate / Dabigatran etexilateAUC0-t1.01 (0.89; 1.15)1.51 (1.27; 1.80)AUC0-∞1.01 (0.89; 1.15)1.45 (1.23; 1.70)Cmax1.04 (0.87;1.24)1.38 (1.22; 1.58)AUC0-t, area under the plasma concentration-time curve from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification;AUC0-∞, area under the plasma concentration-time curve from time zero (= dosing time) extrapolated to infinity; Cmax, maximum plasma concentration observed; GLSM, geometric least-squares mean. ConclusionsAfter multiple doses of tepotinib at the RP2D (500mg QD), there was no relevant exposure increase of the sensitive CYP3A substrate midazolam, and a<2-fold mean exposure increase of the sensitive P-gp substrate dabigatran etexilate, indicating that tepotinib is a weak P-gp inhibitor. Tepotinib was considered safe and well tolerated in these studies of healthy volunteers. In summary, the potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the intended posology is considered low. Clinical trial identificationNCT03492437 and NCT03628339. Editorial acknowledgementMedical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK). Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA. DisclosureÖ. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. R. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.

P1860Unfractionated heparin dose and complication rate in catheter ablation of atrial fibrillation, a comparison between uninterrupted therapy with phenprocoumon and direct oral anticoagulants

Abstract Background Catheter ablation of atrial fibrillation is known for the combining risks of thromboembolism (TE) and major bleedings. This urges a better understanding and optimization of the intraprocedural anticoagulation management. Differences in unfractionated heparin (UFH) requirements and anticoagulation time (ACT) levels between patients on different uninterrupted oral anticoagulation (OAC) agents have been studied. However, the clinical relevance, in terms of periprocedural TE and bleeding events, of UFH administration according to ACT monitoring among patients on different OAC agents, needs to be addressed. Objective To evaluate how the ACT monitoring and differences in intraprocedural UFH requirements among different anticoagulant agents, may translate to clinical outcome, in terms of periprocedural incidence of thromboembolic and bleeding events. Methods We retrospectively studied 1571 cases who underwent catheter ablation for atrial fibrillation between January 2011 and May 2017. Cases were on an uninterrupted oral OAC therapy of Vitamin K Antagonists (VKA)(713), Rivaroxaban (RG)(385), Dabigatran (DG)(260), Apixaban (AG)(192) and Edoxaban (EG)(21). First ACT measurements after the initial bolus of UFH (1ehz748.0610U), mean ACT measurements, total UFH doses/kg (Body Weight)/min (duration of procedure) and incidence of major periprocedural events were compared among the above OAC groups. Results The mean ACT (sec) was significantly lower in the AG and greater in the VKA (313,7±47 vs 340,5±49, p&lt;0,001). Significantly lower UFH doses (U/kg/min) were required to reach the target ACT in VKA compared to RG, DG, AG and EG (0,69±0,4 vs 1,41±0,76; 1,42±0,7; 1,63±0,8; 1,37±0,4 respectively, p&lt;0,001) The proportion of patients who achieved a target ACT value within 30 minutes after the fixed first UFH Bolus of 10 000 U was significantly lower in DG and AG compared to VKA, EG and RG group (51,5% and 49% vs 53%, 71,4%, and 61,8% respectively p=0,005). The incidence of periprocedural TE events and bleedings showed no significant difference among OAC groups. However, the 22 patients with a periprocedural TE event had significantly lower UFH doses (U)/ Duration of catheter ablation (min) compared to the ones without periprocedural TE (62,71±44,5 vs 94,4±66,4, p=0,026), despite equivalent mean ACT values between these two groups. Patients with a periprocedural TE had also a significantly older Age (69,6±10 vs 64±10 p=0,01, higher CHADSVASC Score (3,64±1,76 vs 2,63±1,7 p=0,006), longer duration of procedure (188,9±79,1 vs 144,9±57 p=0,0001) and higher pre-Ablation INR values (2,2±0,6 vs 1,7±0,6 p=0,002). Conclusions The average UFH doses required to reach the target ACT were lower in VKA than in NOAC- groups. The incidence of periprocedural TE events and bleedings was equivalent among OAC groups. Patients with TE showed a lower UFH requirement compared to no-TE group, with both groups having mean ACT ≥300 sec.

890P - Assessing the clinical relevance of drug-drug interactions (DDI) with darolutamide (DARO)

BackgroundDARO is an androgen receptor antagonist with a distinct molecular structure, which has demonstrated prolonged metastasis-free survival vs placebo (PBO) in the phase 3 ARAMIS study in non-metastatic castration-resistant prostate cancer patients. These typically older patients often receive multiple comedications. We assessed DDIs with DARO both in vitro and in clinical trial development. MethodsThe effects of induction and inhibition of transporters and CYP enzymes on DARO, and the effect of DARO on other comedications were studied in vitro and in several phase 1 trials using rifampicin (CYP3A4, P-gp inducer), itraconazole (ICZ; CYP3A4, P-gp inhibitor), rosuvastatin (BCRP, OATP1B1, OATP1B3 and OAT3 substrate), midazolam (CYP3A4 substrate) and dabigatran etexilate (P-gp substrate). The impact of comedication on DARO was investigated in a population pharmacokinetic (popPK) and covariate analysis of a subset of ARAMIS patients. The adverse event (AE) profile for comedication use between PBO and DARO was also analysed. ResultsConcomitant rifampicin led to a 3.5-fold decrease in DARO area under the curve (AUC) vs DARO alone. ICZ resulted in 1.8-fold increase in DARO AUC vs DARO alone. No significant effect of comedications that are CYP or P-gp inhibitors was identified in the popPK analysis; proton pump inhibitors did not significantly affect the PK of DARO. Effects of DARO on CYP inhibition in vitro were negligible and coadministration of midazolam or dabigatran showed no clinically relevant effects. Rosuvastatin AUC increased by 5.2-fold with DARO vs rosuvastatin alone, attributed mainly to BCRP inhibition. The incidence of AEs in ARAMIS was low; comedication use (98.7% in DARO, 98.0% in PBO arms) and AE profile were similar between study arms. ConclusionsDDIs with DARO and P-gp or CYP enzyme substrates, e.g. antithrombotics, calcium channel blockers or proton pump inhibitors, are not expected. Strong CYP3A4 inducers, e.g. rifampicin and carbamazepine, showed some interaction with DARO. Effects of CYP3A4 or P-gp inhibitors on DARO were not considered clinically relevant. DARO may increase the exposure of concomitant BCRP substrates, e.g. statins, although a safety and AE analysis from ARAMIS did not indicate any relevant impact of DARO. Clinical trial identificationNCT03237416, NCT03048110, NCT02671097, NCT02200614. Editorial acknowledgementMedical writing support: Lucy Smithers, PhD, and editorial support: Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines. Legal entity responsible for the studyBayer. FundingBayer and Orion Corporation. DisclosureC.R. Zurth: Full / Part-time employment: Bayer. K. Fizazi: Honoraria (self), Advisory / Consultancy: Merck, Sharp & Dohme; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Advisory / Consultancy: Orion; Advisory / Consultancy: CureVac; Advisory / Consultancy: Clovis. R. Fricke: Full / Part-time employment: Bayer. H. Gieschen: Full / Part-time employment: Bayer. K. Graudenz: Full / Part-time employment: Bayer. M. Koskinen: Full / Part-time employment: Orion Corporation. B.A. Ploeger: Full / Part-time employment: Bayer. O. Prien: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M.R. Smith: Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Clovis; Advisory / Consultancy: Gilead; Honoraria (self): Hinova; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. T. Tammela: Honoraria (self), Research grant / Funding (institution): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lidds AB; Advisory / Consultancy, Research grant / Funding (institution): Astellas. N.D. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas.

Long-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model

BackgroundAlzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment. ObjectivesThis study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD. MethodsTgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood–brain barrier (BBB) integrity. ResultsAnticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB. ConclusionsLong-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.

Total costs of treating venous thromboembolism: implication of different cost perspectives in a Danish setting

Aim: Optimal use of scarce resources is a focus in the healthcare sector, as resources devoted to health care are limited. Costs and health economic analyses can help guide decision-making concerning treatments. One important factor is the choice of cost perspective that can range from a focus on narrow drug budget costs to broader economic perspectives. In the case of treatment with oral anticoagulants in patients with venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, the aim of this cost analysis was to illustrate the differences in costs when applying different cost perspectives.Methods: In a cost analysis, pairwise comparisons of average costs of 6 months standard treatment with either a low molecular weight heparin parenteral anticoagulant (LMWH) and a Vitamin K Antagonist (VKA) versus one of the non-vitamin K oral anticoagulants [NOACs; dabigatran etexilate, rivaroxaban, apixaban, and edoxaban) used in daily clinical practice in Denmark for VTE patients were carried out. Each analysis included the results from five different cost analyses with increasingly broader cost perspectives going from the narrowest “drug cost only” perspective to the broadest “societal” perspective.Results: Focusing on “drug costs only”, LMWH/VKA was associated with the lowest costs compared to all NOACs. However, including the economic impact of preventing recurrent VTE and limit bleedings, apixaban and rivaroxaban resulted in slightly lower health care costs than LMWH/VKA. When applying the “societal perspective”, the total costs saved with apixaban and rivaroxaban compared to LMWH/VKA further increased, with apixaban having the lowest total costs.Conclusions: The present study’s case of oral anticoagulants in VTE treatment illustrated the importance of the cost perspective in the choice of therapy. If decision-making were based on drug costs only, instead of applying a health care sector or societal cost perspective, suboptimal decisions may be likely.

Effects of Dabigatran in Mouse Models of Aging and Cerebral Amyloid Angiopathy.

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) (Tg N = 7; WT N = 10) or vehicle (Tg N = 9; WT N = 7) by gavage for 4 weeks. Anticoagulation effects of DE were confirmed using thrombin time assay. No mice experienced intracerebral hemorrhage. Cerebral microhemorrhage analysis, performed using Prussian-blue and H&E staining, showed no significant change in either number or size of cerebral microhemorrhage in DE-treated animals. Analysis of biochemical parameters for endothelial activation (ICAM-1), blood-brain barrier disruption (IgG, claudin-5, fibrinogen), microglial activation (Iba-1), or astrocyte activation (GFAP) showed neither exacerbation nor protective effects of DE in either Tg2576 or WT mice. Our study provides histological and biochemical evidence that aged mice, with or without predisposing factors for brain hemorrhage, tolerate anticoagulation with dabigatran. The absence of dabigatran-induced intracerebral hemorrhage or increased frequency of acute microhemorrhage may provide some reassurance for its use in high-risk patient populations.

Idarucizumab in major trauma patients: a single centre real life experience.

Trauma care providers are facing an increasing number of elderly patients on direct oral anticoagulants prior to injury. For dabigatran etexilate (DAB), the specific antagonist idarucizumab (IDA) has been approved since 2015 as a reversal agent. However, only limited data regarding the use of IDA in trauma patients are available. We performed a retrospective analysis of trauma patients under DAB for whom IDA administration was deemed necessary to reverse DAB's antithrombotic effect. A total of 15 (9 male) patients were treated with IDA during the study period. The mean age was 81 ± 10years.Intracranial haemorrhage (n = 7) and long bone fractures (n = 5) were the most common types of injury. Three patients were diagnosed as polytrauma. In all but one patient, atrial fibrillation was the indication for DAB intake. The median dose of IDA was 2.5g (IQR 2.5-5). IDA administration decreased DAB plasma levels from 112.4 (IQR 73.4-123.4) to 5 (IQR 4-12) ng/mL (p = 0.031), thrombin time from 114.8 ± 48.3 to 16.2 ± 0.5s (p < 0.0001) and activated partial thromboplastin time form 45.4 ± 11.3 to 34.2 ± 7.0s (p = 0.0025). No thromboembolic events or side effects attributed toIDA were observed. All patients survived until hospital discharge. In trauma patients under DAB prior to injury, IDA decreased DAB plasma levels and normalized coagulation parameters. IDA appears to be safe, and no serious side effects were observed in this small cohort of patients.

Reversal of the anticoagulant effect of direct thrombin inhibitor dabigatran etexilate in acute ischemic stroke and intracranial hemorrhage using idarucizumab – A case study

Reversal of the anticoagulant effect of direct thrombin inhibitor dabigatran etexilate in acute ischemic stroke and intracranial hemorrhage using idarucizumab – A case study - IJN- Print ISSN No: - 2581-8236 Online ISSN No:- 2581-916X Article DOI No:- 10.18231/j.ijn.2019.028, IP Indian Journal of Neurosciences-IP Ind

Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis

Patients with cerebral venous thrombosis (CVT) are at risk of recurrent venous thrombotic events (VTEs). Non-vitamin K oral anticoagulants have not been evaluated in randomized controlled trials in CVT. To compare the efficacy and safety of dabigatran etexilate with those of dose-adjusted warfarin in preventing recurrent VTEs in patients who have experienced a CVT. RE-SPECT CVT is an exploratory, prospective, randomized (1:1), parallel-group, open-label, multicenter clinical trial with blinded end-point adjudication (PROBE design). It was performed from December 21, 2016, to June 22, 2018, with a follow-up of 25 weeks, at 51 tertiary sites in 9 countries (France, Germany, India, Italy, the Netherlands, Poland, Portugal, Russia, and Spain). Adult consecutive patients with acute CVT, who were stable after 5 to 15 days of treatment with parenteral heparin, were screened for eligibility. Patients with CVT associated with central nervous system infection or major trauma were excluded, but those with intracranial hemorrhage from index CVT were allowed to participate. After exclusions, 120 patients were randomized. Data were analyzed following the intention-to-treat approach. Dabigatran, 150 mg twice daily, or dose-adjusted warfarin for a treatment period of 24 weeks. Primary outcome was a composite of patients with a new VTE (recurrent CVT, deep vein thrombosis of any limb, pulmonary embolism, and splanchnic vein thrombosis) or major bleeding during the study period. Secondary outcomes were cerebral venous recanalization and clinically relevant non-major bleeding events. In total, 120 patients with CVT were randomized to the 2 treatment groups (60 to dabigatran and 60 to dose-adjusted warfarin). Of the randomized patients, the mean (SD) age was 45.2 (13.8) years, and 66 (55.0%) were women. The mean (SD) duration of exposure was 22.3 (6.16) weeks for the dabigatran group and 23.0 (5.20) weeks for the warfarin group. No recurrent VTEs were observed. One (1.7%; 95% CI, 0.0-8.9) major bleeding event (intestinal) was recorded in the dabigatran group, and 2 (3.3%; 95% CI, 0.4-11.5) (intracranial) in the warfarin group. One additional patient (1.7; 95% CI, 0.0-8.9) in the warfarin group experienced a clinically relevant non-major bleeding event. Recanalization occurred in 33 patients in the dabigatran group (60.0%; 95% CI, 45.9-73.0) and in 35 patients in the warfarin group (67.3%; 95% CI, 52.9-79.7). This trial found that patients who had CVT anticoagulated with either dabigatran or warfarin had low risk of recurrent VTEs, and the risk of bleeding was similar with both medications, suggesting that both dabigatran and warfarin may be safe and effective for preventing recurrent VTEs in patients with CVT. ClinicalTrials.gov identifier: NCT02913326.

Physiologically-Based Pharmacokinetic Modeling Approach to Predict Rifampin-Mediated Intestinal P-Glycoprotein Induction.

Physiologically‐based pharmacokinetic (PBPK) modeling is a powerful tool to quantitatively describe drug disposition profiles in vivo, thereby providing an alternative to predict drug–drug interactions (DDIs) that have not been tested clinically. This study aimed to predict effects of rifampin‐mediated intestinal P‐glycoprotein (Pgp) induction on pharmacokinetics of Pgp substrates via PBPK modeling. First, we selected four Pgp substrates (digoxin, talinolol, quinidine, and dabigatran etexilate) to derive in vitro to in vivo scaling factors for intestinal Pgp kinetics. Assuming unbound Michaelis‐Menten constant (K m) to be intrinsic, we focused on the scaling factors for maximal efflux rate (Jmax) to adequately recover clinically observed results. Next, we predicted rifampin‐mediated fold increases in intestinal Pgp abundances to reasonably recover clinically observed DDI results. The modeling results suggested that threefold to fourfold increases in intestinal Pgp abundances could sufficiently reproduce the DDI results of these Pgp substrates with rifampin. Hence, the obtained fold increases can potentially be applicable to DDI prediction with other Pgp substrates.

Современные пероральные препараты для профилактики тромбоэмболических осложнений – критический обзор доказательной базы в контексте соотношения риск/польза

Modern oral medications used to prevent venous thromboembolism (VTE) have gained widespread use with major orthopaedic and trauma procedures. There are no accurate multicenter data on the frequency of usage of different prophylactic medications in our country but discussions of the colleagues at specialized web forums make us suspect that factor Xa and dabigatran etexilate inhibitors are in the top three next to low molecular weight heparins. Marketing and promotion strategies of pharmaceutical companies are likely to be of immense importance in that with the contribution of clinical research studies for pharmaceutical drugs. However, preferences of European and American orthopaedic surgeons for the choice of drugs are completely different from those of Russian surgeons. Vitamin K antagonists, acetylsalicylic acid, low molecular weight heparins are commonly used for antithrombotic therapy abroad. Different approaches of Russian and foreign orthopaedic surgeons to the choice of drugs can be explained by a different use of a high-quality evidence base. In our opinion, a collision component can be involved in the endpoints of clinical trials that will be discussed in the present critical review.

Impact of different anticoagulation therapies on heparin dosage applied to atrial fibrillation patients undergoing atrial fibrillation catheter ablation

Objective: Differences in the activated coagulation time (ACT) during ablation and adequate heparin dosing were observed among atrial fibrillation (AF) patients undergoing AF catheter ablation receiving different anticoagulation therapies and the suitable heparin dosing during ablation among patients treated with different anticoagulation therapies was explored. Methods: Patients who received warfarin (n=100), low-molecular-weight heparin (n=100), dabigatran etexilate (n=98, 110 mg, Bid) and rivaroxaban (n=48, 20 mg, Qd) were included. All of them underwent the first AF ablation during January 2016 to December 2017 and patients with hepatic and renal dysfunction were excluded. Initial bolus heparin (100 U/kg, intravenous) was applied to all patients. Additional heparin dosage was added according to the ACT, which was measured in 15-minute interval to maintain the ACT within 250-350 seconds until the end of ablation. Patient characteristics, ACT and complications were compared among various groups. Results: The baseline general characteristics among patients were similar. The baseline ACTs in the dabigatran groups were significantly longer than those in the rivaroxaban group ((133±36) seconds vs. (113±22) seconds, P<0.05). The 15 min ACT in the warfarin group was longer than in the dabigatran group ((259±56) seconds vs. (243±43) seconds, P<0.05). The 15-minute ACTs were significantly longer in the warfarin ((259±56) seconds) and dabigatran ((243±43) seconds) groups compare with low-molecular-weight heparin group ((224±40) seconds) and rivaroxaban group ((226±32) seconds) (all P<0.05). The same trend was also observed in the rate of reaching ACT goal after initial-standard-dosage of heparin (warfarin (53%, 53/100), dabigatran (45%,44/98), low-molecular-weight heparin (28%,28/100), rivaroxaban (23%,11/48), P<0.05). The 1 hour ACT in the warfarin group ((254±49) seconds) was significantly longer than the other three groups (dabigatran (233±33) seconds, low-molecular-weight heparin (226±34) seconds, rivaroxaban (231±30) seconds, all P<0.01). The rate of reaching ACT goal at 1 hour were significantly higher in the warfarin group (66%,35/53) than in the dabigatran group (41%,18/44), and rivaroxaban group (27%,3/11) (all P<0.05). The total heparin required was significantly higher in rivaroxaban group than in the dabigatran and warfarin groups (all P<0.05). During the perioperative period, no patient exhibited any thromboembolic complications, and only a few minor bleeding complications was observed among patients, which was similar between the four groups (P>0.05). Conclusion: Higher dosage of heparin is required during AF ablation to achieve the satisfactory anticoagulant intensity for AF patients under dabigatran etexilate (110 mg, Bid), low-molecular-weight heparin and rivaroxaban (20 mg, Qd) anticoagulation therapy before AF ablation.

Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant

Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. To investigate the safety of a standardized perioperative DOAC management strategy. The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (<50 ng/mL) at the time of the procedure. The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high-bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high-bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.

Perioperative management of trauma surgery patients treated with direct oral anticoagulants

As the population gets older the prevalence of atrial fibrillation and venous thromboembolism also increases. Therefore, more patients require anticoagulation and currently direct oral anticoagulants (DOAC), such as dabigatran etexilate, apixaban, rivaroxaban and edoxaban are preferred to vitaminK antagonists (VKA), mainly because of the more favorable risk-benefit profile with respect to bleeding. Older patients in particular frequently present at the accident and emergency department due to falls and an increased risk of fractures. The perioperative management of these patients who are treated with DOACs is achallenge in the clinical routine and needs special consideration. This article discusses these issues in an interdisciplinary approach and develops strategies for the perioperative management of patients treated with DOACs and undergoing trauma or orthopedic surgery.

Renal Excretion of Dabigatran: The Potential Role of Multidrug and Toxin Extrusion (MATE) Proteins.

Following oral administration, dabigatran etexilate (DABE) is rapidly hydrolyzed to its active form, dabigatran. DABE, but not dabigatran, presents as a P-glycoprotein (P-gp) substrate and has increasingly been used as a probe drug. Therefore, although dosed as DABE, a P-gp drug-drug interaction (DDI) is reported as a dabigatran plasma concentration ratio (perpetrator versus placebo). Because the majority of a DABE dose (80 to 85%) is recovered in urine as unchanged dabigatran (renal active secretion is ∼25% of total clearance), dabigatran was evaluated in vitro as a substrate of various human renal transporters. Active (pyrimethamine-sensitive) dabigatran uptake was observed with human embryonic kidney (HEK) 293 cells expressing multidrug and toxin extrusion protein 1 (MATE1) and 2K (MATE2K), with Michaelis-Menten constant (Km) values of 4.0 and 8.0 μM, respectively. By comparison, no uptake of 2 μM dabigatran (versus mock-transfected HEK293 cells) was evident with HEK293 cells transfected with organic cation transporters (OCT1 and OCT2) and organic anion transporters (OAT1, 2, 3, and 4). The efflux ratios of dabigatran across P-gp- and BCRP (breast cancer resistance protein)-MDCK (Madin-Darby canine kidney) cell monolayers were 1.5 and 2.0 (versus mock-MDCK cell monolayers), suggesting dabigatran is a relatively poor P-gp and BCRP substrate. Three of five drugs (verapamil, ketoconazole, and quinidine) known to interact clinically with dabigatran, as P-gp inhibitors, presented as MATE inhibitors in vitro (IC50 = 1.0 to 25.2 μM). Taken together, although no basolateral transporter was identified for dabigatran, the results suggest that apical MATE1 and MATE2K could play an important role in its renal clearance. MATE-mediated renal secretion of dabigatran needs to be considered when interpreting the results of P-gp DDI studies following DABE administration.

Exposure Response Supports Therapeutic Drug Monitoring for Dabigatran Etexilate in Patients with Atrial Fibrillation.

Background Dabigatran etexilate has become widely used for the prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF). Currently, there is limited information in real-world patients relating to dabigatran etexilate exposure and response. Methods This retrospective cohort study used administrative health data for NVAF patients dispensed dabigatran etexilate between July 1, 2011 and December 31, 2015. Outcomes of cerebrovascular accident (CVA), systemic embolism, and hemorrhage were extracted. Simulated pharmacokinetic parameters were obtained using a published population pharmacokinetic model of dabigatran etexilate. Area under the curve calculated for a 24-hour period at steady state (AUC ss ), the exposure parameter, was derived using these simulations and the dosing data and the exposure–response relationship were investigated. The risk of adverse outcomes at AUC ss quartiles was compared using Poisson regression and expressed using incidence rate ratios (95% confidence interval) adjusted for known potential confounders. Results In total, 2,660 NVAF patients had been dispensed dabigatran etexilate. For these patients there was a decreased risk of hemorrhage (0.51, 0.32–0.79) when dabigatran AUC ss was in the second quartile range of 1.70 to 1.96 mg h/L and thromboembolism/CVA (0.34, 0.16–0.76) when in the third quartile range of 1.97 to 2.26 mg h/L. An increased risk of hemorrhage (1.68, 1.18–2.38) was observed when AUC ss was in the fourth quartile range of 2.27 to 12.76 mg h/L. Conclusion An exposure–response relationship for dabigatran etexilate was described, where the most effective response was observed when AUC ss was in the range of 1.70 to 2.26 mg h/L. Hence, it is feasible to develop guidance for optimal dosing to improve outcomes for patients with NVAF.

TREATMENT WITH THE DIRECT THROMBIN INHIBITOR DABIGATRAN ETEXILATE REDUCES OXIDATIVE STRESS IN VIVO IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

The coagulation factor thrombin is a multifunctional serine protease that contributes to oxidative stress and inflammation. Thrombin has been shown to be neurotoxic and is elevated in the brain and cerebrovasculature in Alzheimer's disease (AD). We have identified thrombin as a key mediator of cerebrovascular activation in AD and have data demonstrating that thrombin inhibition diminishes vascular activation in an animal model of AD. Transgenic Tg4510 AD mice overexpress tau with the P301L familial frontotemporal dementia mutation and exhibit profound tau-related pathology in the hippocampus and cortex. These mice also show blood vessel abnormalities and changes in both oxidative stress and inflammatory markers. Here, we hypothesize that thrombin inhibition will reduce oxidative stress and inflammation related to tau pathology in vivo. 15-month-old Tg4510 mice were treated with 100 mg/kg once a day for 7 days with the direct thrombin inhibitor dabigatran etexilate or vehicle control via oral gavage. 24 hours after the final drug dose, mice were sacrificed and brains were collected. The cerebellum was removed and the brain was homogenized and Western analysis performed. Blots were probed and quantified for oxidative stress-related proteins, inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), NAPDH oxidase 4 (NOX4); antioxidant proteins SOD1 and SOD2 as well as the inflammatory cytokine interleukin 1beta (IL-1β). Treatment of mice with dabigatran for 7 days reduced thrombin expression and activity in the brain, shown by significantly decreased prothrombin and fibrin expression. Tg4510 mice that received dabigatran showed significant reduction in the expression of oxidative stress proteins (iNOS, eNOS, NOX4) as well as a concomitant increase in antioxidant SOD1 and SOD2. In addition, dabigatran treatment also lowered expression of IL-1β. Taken together, these data indicate that short-term treatment with a direct thrombin inhibitor was effective at lowering oxidative stress in the brains of aged Tg4510 mice. This finding supports our hypothesis that targeting thrombin, a key mediator of vascular activation and neurotoxicity, may be effective in reducing AD-related pathology. Further studies are needed to better understand the mechanisms of action and possible neuroprotective benefits of the thrombin inhibitor dabigatran.