The Dabigatran debate

Kaba, Riyaz A.; Ara, Farhana; Ward, David; Emanuel, Subo

doi:10.5339/gcsp.2014.41

Cited by 5 publications

(5 citation statements)

References 11 publications

(14 reference statements)

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“…Naturally, a pharmacokinetic interaction is best monitored by plasma levels of DOACs. Whereas anti-Xa for apixaban and rivaroxaban and the plasma diluted thrombin time for dabigatran would be more suitable for a pharmacodynamic interaction (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…Dabigatran demonstrated a higher adjROR for ischemic stroke than apixaban, edoxaban and rivaroxaban, which could be explained by dabigatran's negative publicity a year after it accessed the market in 2010-2011 (31). The FAERS database shows a peak with the highest rates of reports between 2011-2014 (18).…”

Section: Discussionmentioning

confidence: 99%

“…Further, we re-analyzed our results for the period 2015-2023, this is to account for the fact that during 2010-2014 a trial had been ongoing against Boehringer Ingelheim, dabigatran's manufacturer (18). Thus, to mitigate any additional negative reporting bias, we analyzed our data excluding the years 2012-2014.…”

Section: Sensitivity Analysismentioning

confidence: 99%

“…Thus, the data was re-analyzed for 2012-2020. Second, a lawsuit occurred over Pradaxa, dabigatran's trade name, from 2010 to 2014 (18,31). An additional analysis excluding that period did not significantly alter the results.…”

Section: Conclusion and Clinical Implicationsmentioning

confidence: 99%

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Ischemic Stroke Risk in Patients on Direct Oral Anticoagulants with Levetiracetam: A Pharmacovigilance Study

Abou Kaoud,

Nissan,

Segev

et al. 2023

Preprint

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Background: Levetiracetam is widely used in post stroke epilepsy. However, it is suspected to possess P-glycoprotein induction properties and therefore a potential significant interaction with DOACs . Our aim was to search for ischemic stroke signals with levetiracetam and the DOACs. Methods: In this retrospective, pharmacovigilance study, we used the Food and Drug Administration adverse event reporting system to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the reporting odds ratio adjusted to age and sex (adj.ROR) and the lower bound of the shrinkage 95% confidence interval (Ω025 > 0 is deemed significant for an interaction). Results: We identified 1,841 (1.5%), 3,731 (5.3%), 338 (4.9%), and 1,723 (1.3%), ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban respectively. When heparin/enoxaparin was used as the comparator the adjusted ROR of the interaction effect was 3.57 (95%CI, 2.81-4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam resulting in higher reports of ischemic stroke with the combination compared to each drug alone. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke. Conclusions: We show a strong signal for the levetiracetam interaction with apixaban, dabigatran, edoxaban, and rivaroxaban leading to a 3-5 folds increased reporting risk of ischemic stroke. Our findings suggest the need for pharmacodynamic monitoring, while concomitantly prescribing levetiracetam with the DOACs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sensitivity Analysismentioning

confidence: 99%

Section: Conclusion and Clinical Implicationsmentioning

confidence: 99%

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Ischemic Stroke Risk in Patients on Direct Oral Anticoagulants with Levetiracetam: A Pharmacovigilance Study

Abou Kaoud,

Nissan,

Segev

et al. 2023

Preprint

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“… 6 7 Furthermore, inhibition of FXa in patients with APS±SLE, with rivaroxaban (a highly selective direct FXa inhibitor), led to inhibition of complement and coagulation factors. 8 Infact, both FXa and Thr are both controversial therapeutic targets, with rivaroxaban (FXa targeting) having shown both positive 9 and negative outcomes 10 in patients, while dabigatran (Thr targeting) has also been the subject of some debate, 11 and unlike rivaroxaban, dabigitran has never shown any effects on complement activation. Therefore, increased understanding of the mechanisms of coagulation–complement interactions has the potential to improve measures of disease activity and to develop new therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage

et al. 2022

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ObjectivesThe significance of antibodies directed against activated factor X (FXa) and thrombin (Thr) in patients with SLE and/or antiphospholipid syndrome (APS) is unknown. FXa and Thr are coregulated by antithrombin (AT) and activate complement. Therefore, we studied the ability of anti activated factor X (aFXa) and/or anti-(a)Thr IgG from patients with SLE±APS to modulate complement activation.MethodsPatients with SLE±APS were selected on the basis of known aThr and/or aFXa IgG positivity, and the effects of affinity-purified aFXa/aThr IgG on FXa and Thr-mediated C3 and C5 activation were measured ±AT. Structural analyses of FXa and Thr and AT–FXa and AT–Thr complexes were analysed in conjunction with the in vitro ability of AT to regulate aFXa–FXa and aThr–Thr-mediated C3/C5 activation.ResultsUsing affinity-purified IgG from n=14 patients, we found that aThr IgG increased Thr-mediated activation of C3 and C5, while aFXa IgG did not increase C3 or C5 activation. Structural analysis identified potential epitopes and predicted a higher likelihood of steric hindrance of AT on FXa by aFXa IgG compared with the AT–Thr–aThr IgG complex that was confirmed by in vitro studies. Longitudinal analysis of 58 patients with SLE (±APS) did not find a significant association between positivity for aFXa or aTHr IgG and C3 levels or disease activity, although there was a trend for patients positive for aFXa IgG alone or both aFXa and aThr IgG to have lower levels of C3 compared with aThr IgG alone during clinical visits.ConclusionsWe propose a novel method of complement regulation in patients with SLE±APS whereby aFXa and aThr IgG may have differential effects on complement activation.

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Levetiracetam Interaction with Direct Oral Anticoagulants: A Pharmacovigilance Study

Abou Kaoud,

Nissan,

Segev

et al. 2023

CNS Drugs

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The Dabigatran debate

Cited by 5 publications

References 11 publications

Ischemic Stroke Risk in Patients on Direct Oral Anticoagulants with Levetiracetam: A Pharmacovigilance Study

Ischemic Stroke Risk in Patients on Direct Oral Anticoagulants with Levetiracetam: A Pharmacovigilance Study

Antibodies to FXa and thrombin in patients with SLE differentially regulate C3 and C5 cleavage

Levetiracetam Interaction with Direct Oral Anticoagulants: A Pharmacovigilance Study

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