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Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants.

ABSTRACT: Direct oral anticoagulants (DOACs) have rapidly become the drug class of choice for anticoagulation therapy in secondary care. It is known that gastrointestinal hemorrhage are potential side effects of the DOAC drug class. In this study we have investigated the relevance of molecular structure and on/off-target pharmacology as a predictor of adverse drug reactions (ADRs) for the DOAC drug class. Use of the Reaxys MedChem module allowed for data mining of all possible reported off-target effects of the DOAC class members. For the first time, the MHRA Yellow card database in combination with prescribing rates in the United Kingdom (data for n = 30 566 936 DOAC Rx (up to 2017) and ADR data n = 22 275 (up to 2018)) were used for our data comparison of DOACs. From the underlying reported data, we were able to rank the DOACs in terms of the likely adverse events we would expect to observe. We identified potential risks of ADRs based on the DOACs pharmacology including the expected GI hemorrhage, but also the unexpected risk of stroke, pulmonary embolism and kidney injury. Statistically significant (P < .001) differences were found between all DOACs and their total number of ADRs. Although the risks are small, strong statistical correlation between observed pharmacology and national ADR data is observed in three out of the five areas of concern.

SUBMITTER: Ferro CJ

PROVIDER: S-EPMC7272392 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants.

Ferro Charles J CJ Solkhon Fay F Jalal Zahraa Z Al-Hamid Abdullah M AM Jones Alan M AM

Pharmacology research & perspectives 20200601 3

Direct oral anticoagulants (DOACs) have rapidly become the drug class of choice for anticoagulation therapy in secondary care. It is known that gastrointestinal hemorrhage are potential side effects of the DOAC drug class. In this study we have investigated the relevance of molecular structure and on/off-target pharmacology as a predictor of adverse drug reactions (ADRs) for the DOAC drug class. Use of the Reaxys MedChem module allowed for data mining of all possible reported off-target effects ...[more]

PMID: 32500654

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Project description:Background & aimsWhile direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited.MethodsLiver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low-molecular-weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti-Xa peak levels and thrombomodulin-modified thrombin generation assays (TM-TGAs) were measured in a subgroup of 35/28 DOAC patients.ResultsAmong patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child-Pugh-stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure-related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow-up of 10.5 (IQR: 4.0-27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS-B/C (at 12 months: 36.9% vs CPS-A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59-6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82-9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti-Xa peak levels were higher in patients with CPS-B/C (345 [95% CI: 169-395] vs CPS-A: 137 [95% CI: 96-248] ng/mL, P = .048) and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients.ConclusionsAnticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

Project description:BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT.MethodsTo provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK.ResultsAlthough HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin.ConclusionsCurrently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

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Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants.

Publications

Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants.

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