Oral anticoagulation in end-stage renal disease and atrial fibrillation: is it time to just say no to drugs?

Black‐Maier, Eric; Piccini, Jonathan P.

doi:10.1136/heartjnl-2016-310540

Cited by 17 publications

(19 citation statements)

References 12 publications

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“…This is the case of patients of atrial fibrillation and chronic kidney diseases. [23][24][25][26][27] Thus, the search for safer anticoagulant drugs with little-to-none bleeding risk continues. Towards this goal, several FXI(a)-targeting agents are in development including small molecules (BMS-986177 and EP-7041), [35][36][37][38][39][40][41] monoclonal antibodies (AB023, MAA868, and Osocimab), [42][43][44][45] aptamers (FELIAP), [48,49] and sulfated glycosaminoglycan mimetics (SPGG and SCI).…”

Section: Discussionmentioning

confidence: 99%

Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia

2020

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The inhibition of factor XIa (FXIa) is a trending paradigm for the development of new generations of anticoagulants without a substantial risk of bleeding. In this report, we present the discovery of a benzyl tetra-phosphonate derivative as a potent and selective inhibitor of human FXIa. Biochemical screening of four phosphonate/phosphate derivatives has led to the identification of the molecule that inhibited human FXIa with an IC 50 value of~7.4 μM and a submaximal efficacy of~68 %. The inhibitor was at least 14-fold more selective to FXIa over thrombin, factor IXa, factor Xa, and factor XIIIa. It also inhibited FXIa-mediated activation of factor IX and prolonged the activated partial thromboplastin time of human plasma. In Michaelis-Menten kinetics experiment, inhibitor 1 reduced the V MAX of FXIa hydrolysis of a chromogenic substrate without significantly affecting its K M suggesting an allosteric mechanism of inhibition. The inhibitor also disrupted the formation of FXIa-antithrombin complex and inhibited thrombin-mediated and factor XIIa-mediated formation of FXIa from its zymogen factor XI. Inhibitor 1 has been proposed to bind to or near the heparin/polyphosphate-binding site in the catalytic domain of FXIa. Overall, inhibitor 1 is the first benzyl tetraphosphonate small molecule that allosterically inhibits human FXIa, blocks its physiological function, and prevents its zymogen activation by other clotting factors under in vitro conditions. Thus, we put forward benzyl tetra-phosphonate 1 as a novel lead inhibitor of human FXIa to guide future efforts in the development of allosteric anticoagulants.

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Section: Discussionmentioning

confidence: 99%

Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia

2020

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“…10 Existing data suggest that warfarin increases bleeding risk, including hemorrhagic stroke, and mortality without reducing all-cause stroke risk in patients with atrial fibrillation and ESRD on HD. 20,21 These observations are likely multifactorial but include alterations in hemostasis, leading to increased hemorrhagic and thrombotic complications in the ESRD population as well as labile INR control in patients with ESRD (time in therapeutic range in the 40%-50% range). 21,22 The altered risk to benefit ratio of anticoagulation in these patients coupled with expert group opinions may lead prescribers to withhold anticoagulation altogether in patients with NVAF and ESRD on HD.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 These observations are likely multifactorial but include alterations in hemostasis, leading to increased hemorrhagic and thrombotic complications in the ESRD population as well as labile INR control in patients with ESRD (time in therapeutic range in the 40%-50% range). 21,22 The altered risk to benefit ratio of anticoagulation in these patients coupled with expert group opinions may lead prescribers to withhold anticoagulation altogether in patients with NVAF and ESRD on HD. 2 Our study did not directly evaluate efficacy of apixaban because of the short duration.…”

Section: Discussionmentioning

confidence: 99%

A Multicenter Analysis of Factors Associated With Apixaban-Related Bleeding in Hospitalized Patients With End-Stage Renal Disease on Hemodialysis

et al. 2017

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“…Patient recruitment started in September 2016 and will continue until December 2021. 65 Primary outcome is time to major bleeding. Unfortunately, recruitment was withdrawn in March 2018 due to no patients being enrolled in the first year.…”

Section: Ongoing Trialsmentioning

confidence: 99%

Oral Anticoagulants in Patients With Atrial Fibrillation and End-Stage Renal Disease

Zaman

Bhandari

2019

J Cardiovasc Pharmacol Ther

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The role of oral anticoagulants (OAC) in atrial fibrillation (AF) is well established. However, none of the randomized controlled trials included patients with end-stage renal disease (ESRD) leaving a lack of evidence in this large, challenging and unique patient group. Patients on hemodialysis (HD) with AF have additional risk factors for stroke due to vascular comorbidities, HD treatment, age, and diabetes. Conversely, they are also at increased risk of major bleeding due to uremic platelet impairment. Anticoagulants increase bleeding risk in patients with ESRD and HD up to 10-fold compared with non chronic kidney disease (CKD) patients on warfarin. There are conflicting data and recommendations regarding use of OACs in ESRD which will be reviewed in this article. We conclude by proposing a modified strategy for OAC use in ESRD based on the latest evidence.

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Oral anticoagulation in end-stage renal disease and atrial fibrillation: is it time to just say no to drugs?

Cited by 17 publications

References 12 publications

Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia

Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia

A Multicenter Analysis of Factors Associated With Apixaban-Related Bleeding in Hospitalized Patients With End-Stage Renal Disease on Hemodialysis

Oral Anticoagulants in Patients With Atrial Fibrillation and End-Stage Renal Disease

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