Acenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients. The best regression model to predict stable dosage in the Primary Cohort included clinical factors (age and body mass index, BSA) and genetic variants (VKORC1, CYP2C9* and CYP4F2 polymorphisms) and explained up to 50% of stable dose. In the validation study the clinical algorithm yielded an adjusted R²=0.15 (estimation´s standard error=4.5) and the genetic approach improved the dose forecast up to 30% (estimation´s standard error=4.6). Again, the best model combined clinical and genetic factors (R² = 0.48; estimation´s standard error=4) which provided the best results of doses estimates within 20% of the real dose in patients taking lower (≤ 7 mg/week) or higher (≥ 25 mg/week) acenocoumarol doses. In conclusion, we developed a prediction algorithm using clinical data and three polymorphisms in VKORC1, CYP2C9* and CYP4F2 genes that provided a steady acenocoumarol dose for about 50% of patients in the Validation Cohort. Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses, those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication.

Aim: To analyze the effectiveness and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients attended in clinical practice. Methods: Observational and prospective study of AF patients that started treatment with DOACs. Results: 1443 patients (age 77.2 ± 9.7 years, CHA2DS2-VASc = 4.1 ± 1.5) were included. 46.0% were taking rivaroxaban, 24.4% dabigatran, 22.5% apixaban and 7.1% edoxaban. Patients taking dabigatran were younger, had lower CHA2DS2-VASc and lesser renal insufficiency. Patients taking apixaban had higher CHA2DS2-VASc and more renal insufficiency. Rates of stroke/major bleeding/intracranial bleeding were 0.7/1.3/0.2 events/100 patient-years, respectively. Conclusion: This was the first prospective study that analyzed the use of all DOACs in AF patients in Spain, showing a good profile in terms of safety and effectiveness in accordance with pivotal studies.

BackgroundAlgorithms combining both clinical and genetic data have been developed to improve oral anticoagulant therapy. Three polymorphisms in two genes, VKORC1 and CYP2C9, are the main coumarin dose determinants and no additional polymorphisms of any relevant pharmacogenetic importance have been identified.ObjectivesTo identify new genetic variations in VKORC1 with relevance for oral anticoagulant therapy.Methods and Results3949 consecutive patients taking acenocoumarol were genotyped for the VKORC1 rs9923231 and CY2C9* polymorphisms. Of these, 145 patients with a dose outside the expected range for the genetic profile determined by these polymorphisms were selected. Clinical factors explained the phenotype in 88 patients. In the remaining 57 patients, all with higher doses than expected, we sequenced the VKORC1 gene and genetic changes were identified in 14 patients. Four patients carried VKORC1 variants previously related to high coumarin doses (L128R, N = 1 and D36Y, N =  3).Three polymorphisms were also detected: rs17878544 (N = 5), rs55894764 (N = 4) and rs7200749 (N = 2) which was in linkage disequilibrium with rs17878544. Finally, 2 patients had lost the rs9923231/rs9934438 linkage. The prevalence of these variations was higher in these patients than in the whole sample. Multivariate linear regression analysis revealed that only D36Y and rs55894764 variants significantly affect the dose, although the improvement in the prediction model is small (from 39% to 40%).ConclusionOur strategy identified novel associations of VKORC1 variants with higher acenocoumarol doses albeit with a low effect size. Further studies are necessary to test their influence on the VKORC1 function and the cost/benefit of their inclusion in pharmacogenetic algorithms.

Atrial fibrillation is a frequent complication among patients with severe coronavirus disease-2019 (COVID-19) infection. Both direct and indirect mechanisms through COVID-19 have been described to explain this relationship. COVID-19 infection increases the risk of developing both arterial and venous thrombotic complications through systemic coagulation activation, leading to increased mortality. Chronic oral anticoagulation is essential to reduce the thromboembolic risk among AF patients. Switching to low-molecular-weight heparin has been recommended during hospitalization for COVID-19 infection. Of note, at discharge, the prescription of direct oral anticoagulants may offer some advantages over vitamin K antagonists. However, oral anticoagulants should only be prescribed after the consideration of drug–drug interactions with antiviral therapies as well as of the risk of hepatotoxicity, which is common among individuals with severe COVID-19 pneumonia. Not all anticoagulants have the same risk of hepatotoxicity; dabigatran has shown a good efficacy and safety profile and could have a lower risk of hepatotoxicity. Furthermore, its metabolism by cytochrome P450 is absent and it has a specific reversal agent. Therefore, dabigatran may be considered as a first-line choice for oral anticoagulation at discharge after COVID-19 infection. In this review, the available information on the antithrombotic management of AF patients at discharge after COVID-19 infection is updated. In addition, a practical algorithm, considering renal and liver function, which facilitates the anticoagulation choice at discharge is presented.

In addition to VKORC1 and CYP2C9, CYP4F2 gene has a slight but significant role in reaching INR >2.5 during the first weeks of acenocoumarol therapy.

A few trials so far have evaluated the effectiveness of algorithms designed to calculate doses in oral anticoagulant therapy, with negative or contradictory results. We compared a genotype-guided algorithm vs physician management for the initiation of acenocoumarol. In a two-arm, prospective, randomised study with patients with atrial fibrillation who started therapy, the first dose was administered to all patients according to the physician's criteria. At 72 hours, the corresponding dose was calculated based on INR in the standard care group (SC, N=92), whereas genetic data (VKORC1, CYP2C9 and CYP4F2) were also considered for the genotype-guided dosing (pharmacogenetic) group (PGx, N=87) by using an algorithm previously validated in 2,683 patients. The primary outcomes were: patients with steady dose, the time needed to reach the same and the percentage of therapeutic INRs. After 90 days, 25% of the SC and 39% of the PGx patients reached the steady dose (p=0.038). Kaplan-Meier analysis showed that PGx group needed fewer days to reach therapeutic INR (p=0.033). Additionally, PGx had a higher percentage of therapeutic INRs than SC patients (50% and 45%, respectively) (p=0.046). After six months the proportion of steadily anticoagulated patients remained significantly higher in PGx (p=0.010). In conclusion, genotype-guided dosing was associated with a higher percentage of patients with steady dose than routine practice when starting oral anticoagulation with acenocoumarol.

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