The effect of administering preprocedural VITamin K on the international normalized ratio in patients anticoagulated with ACEnocoumarol (VITKACE-study): a prospective cohort study.

BACKGROUND: The effect of the vitamin K antagonist acenocoumarol on coagulation needs to be reversed when patients undergo an invasive procedure with considerable bleeding risk. A strategy to achieve this is by administering oral vitamin K before a procedure while continuing acenocoumarol. OBJECTIVES: To assess the effect on periprocedural international normalized ratio (INR) values and safety using oral vitamin K as anticoagulant reversal method. METHODS: In this prospective cohort study, consecutive patients using acenocoumarol undergoing elective procedures between 2019 and 2022 were included. According to standard of care in our hospital, patients took 10 mg oral vitamin K 36 to 48 hours before the procedure while continuing their normal use of acenocoumarol. Effectiveness to lower INR to <1.8 preprocedural was assessed. Bleeding and thrombotic complications within 30 days after the procedure were assessed. Periprocedural course of INR was monitored by collecting additional blood samples. RESULTS: Seventy-four patients were included for analysis. On the day of the procedure, an adequate INR of <1.8 was achieved in 99% of patients. One clinically relevant nonmajor bleeding complication and no thrombotic complications were observed during the first 30 days after the procedure. INR gradually restored to therapeutic level during the days after the procedure. CONCLUSION: Using oral vitamin K while patients continue acenocoumarol intake is an effective way to adequately lower INR before an invasive procedure. Low amount of bleeding complications and absence of thromboembolic complications suggest that this is a safe strategy. The INR values returned gradually to therapeutic range after the procedure, probably contributing to the observed low bleeding rate.

A journey through anticoagulant therapies in the treatment of left ventricular thrombus in post-COVID-19 heparin-induced thrombocytopenia: a case report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.

Spontaneous massive pectoral hematoma induced by vitamin K antagonist therapy: a case report.

Vitamin K antagonists (VKA) based oral anticoagulation, is widely used for the prevention and treatment of thromboembolic disease. The major complication of this therapy is bleeding, and sometimes it can occur in unsuspected areas. Spontaneous pectoral hematoma is one of the rare complications due to over anticoagulation by VKA therapy, with only a few cases reported in the literature. Concomitant use of this therapy with commonly used antibiotic, especially in the elderly with multiple comorbidities, can increase the risk of bleeding. Herein, we report a case of a 72-year-old woman under VKA for the treatment of atrial fibrillation, who presented with a spontaneous massive pectoral hematoma, while using antibiotic to treat a respiratory tract infection, who was successfully managed.

Selecting the right anticoagulant for stroke prevention in atrial fibrillation.

OBJECTIVE: The embolization of thrombi formed within the atria can occur in any form of atrial fibrillation (AF), i.e., paroxysmal, persistent, or permanent. Although ischemic stroke is the most frequent embolic event associated with AF, embolization to other sites in the pulmonary and systemic circulations may occasionally occur. To avert the risk of embolization, long-term oral anticoagulation therapy is recommended for all AF patients if the CHA2DS2-VASC score is at least 1 for men and at least 2 for women. Since anticoagulant therapy is associated with an increased risk of bleeding, the choice of oral anticoagulant agent should be made by careful consideration of the benefit-to-risk ratio. The use of a newer class of direct oral anticoagulants (DOACs) as an alternative to the anti-vitamin K (AVK) anticoagulants (warfarin, acenocumarol, etc.) can help mitigate the need for periodic monitoring of International Normalized Ratio (INR) and adverse bleeding events that are commonly associated with the use of AVK anticoagulants. Though the use of DOACs (dabigatran, rivaroxaban, edoxaban, apixaban, etc.) is gaining ground due to their relative safety profile and the low overall cost, quite a few clinicians remain skeptical about their use. PATIENTS AND METHODS: Our objective was to evaluate the risk of thromboembolism, stroke, neuropsychiatric illness, depression, and dementia, in patients with non-valvular atrial fibrillation who have been treated with either acenocumarol or apixaban, as well as to see the inflammatory status (ESR) and levels of fibrinogen. Our team at Municipal Emergency University Hospital, Timisoara, Romania, conducted a retrospective study using the medical records of AF patients who were treated with either apixaban or acenocumarol between 2016-2019. We divided the patients into two groups and compared the groups for the aforementioned outcomes. RESULTS: AF patients who were prescribed apixaban had a lower rate of stroke and psychiatric illness compared to those on acenocumarol. No significant correlation was found in terms of risk of developing depression or dementia between the groups. CONCLUSIONS: Non-valvular AF patients on apixaban had lower rates of thromboembolic events than the patients on acenocumarol. This article will serve as a reminder of the positive health and financial outcomes of apixaban use, especially to those healthcare systems that are still oblivious to the decrease in economic burden and gain in quality-adjusted life years (QALY) by the long-term use of NOACS/ DOACS instead of the AVK anticoagulants.

Acute myocardial infarction in a 41-year-old woman due to elevated factor VIII: a case report.

Myocardial infarction is a life-threatening emergency with a high mortality rate. A high plasma level of factor VIII is an established risk for both arterial and venous thrombotic events. In this mini-review, we report the case of a 41-year-old woman without cardiovascular risk factors or a previous history of thrombotic events, admitted for ST-elevation myocardial infarction, in whom coronary angiography showed a thrombotic occlusion in the left anterior descending artery. The patient underwent primary percutaneous coronary intervention (PCI), with GPIIB-IIIA antagonist, then, a pre-dilation with a semi-compliant balloon-catheter, followed by implantation of 2 stents. The etiological assessment revealed a high level of coagulation factor VIII (FVIII). She underwent anticoagulation therapy (with acenocoumarol) with well-controlled international normalised ratio (INR).

Cost-effectiveness of direct oral anticoagulants versus vitamin K antagonist in atrial fibrillation: A study protocol using Real-World Data from Catalonia (FantasTIC Study).

BACKGROUND: Anticoagulant therapy is used for stroke prevention and proved to be effective and safe in the long term. The study aims to analyse the cost-effectiveness relationship of using of direct-acting oral anticoagulants vs vitamin K antagonists to prevent ischaemic stroke in patients with nonvalvular atrial fibrillation, including all the active ingredients marketed in Spain, prescribed for 2 years in the Primary Care service of the Institut Català de la Salut. METHODS: Population-based cohort study, in which the cost of the 2 treatment groups will be evaluated. Direct costs (pharmacy, primary care, emergency and hospitalization) and indirect costs (lost productivity) will be included from a social perspective. Effectiveness (assessed as the occurrence of a health event, the 1 of primary interest being stroke) will be determined, with a 2-year time horizon and a 3% discount rate. The average cost of the 2 groups of drugs will be compared using a regression model to determine the factors with the greatest influence on determining costs. We will carry out a univariate ('one-way') deterministic sensitivity analysis. DISCUSSION: We hope to provide relevant information about direct and indirect costs of oral anticoagulants, which, together with aspects of effectiveness and safety, could help shape the consensual decision-making of evaluating bodies.

Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain.

Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.

[Intravenous thrombolysis after reversion of acenocoumarol anticoagulation. Report of one case]. / Trombolisis endovenosa post reversión de acenocumarol con complejo de protrombina. Caso clínico.

We report an 89-year-old male under oral anticoagulant therapy with a therapeutic international normalized ratio, presenting at the emergency room with right side hemiparesis and aphasia. Neuroimaging was compatible with an acute middle cerebral artery ischemic stroke. Anticoagulation was reverted with the use of four factor prothrombin complex, followed by thrombolysis with alteplase, with a favorable evolution, returning to his basal functional status.

Oral anticoagulation therapy using acenocoumarol during the month of ramadan: a comparative study between fasting and non-fasting patients.

BACKGROUND AND OBJECTIVES: The effect of Ramadan fasting on anticoagulation by vitamin K antagonists has been previously investigated in small scale studies with controversial results. From this perspective, this study aimed to compare the fluctuations of anticoagulation in fasting and nonfasting patients taking Acenocoumarol and to identify the factors associated with such fluctuations. METHODS: The study, conducted between May and August 2018, was a comparative one. Three study periods were defined: before Ramadan (BR), Ramadan and after Ramadan (AR). Enrolment involved ambulatory patients aged over eighteen, without medical contraindications to fasting (for the fasting group) and whom international normalized ratio (INR) was within the therapeutic target range during the last three months BR. Anticoagulation monitoring consisted in five consecutive INR assays; INR0 (during the 14 days BR), INR1 (between the 1st and the 14th day of Ramadan), INR2 (between the 15th and the 28th day of Ramadan), INR3 (28 days after INR2) and INR4 (28 days after INR3). INR stability was assessed by calculating four percentages of time in therapeutic range (TTR); TTR0 (between INR0 and INR1), TTR1 (between INR0 and INR2), TTR2 (between INR2 and INR3) and TTR3 (between INR3 and INR4). The null hypothesis was the occurrence of an anticoagulation imbalance (evaluated by TTR) in fasting patients in comparison with non-fasting ones. RESULTS: One hundred and twenty-two patients (84 fasting patients), aged 60 ± 19 years, were included. In fasting patients, the average differences of INR1, 2, 3 and 4 compared with INR0 were statistically non-significant and accounted for +0.46, +0.34, +0.28 and +0.30 respectively. Among the three TTRs, only TTR2 significantly decreased in comparison with TTR0 in fasting group (50.3 ± 37.4 vs. 63.6 ± 39.3%, p=0.004). TTR1, 2 and 3 were comparable between fasting and non-fasting patients. CONCLUSIONS: The fluctuations of anticoagulation balance, assessed by TTR, were comparable between fasting and non-fasting patients taking Acenocoumarol.

[A rare and severe complication related to acenocoumarol therapy: intra-alveolar bleeding]. / Une complication rare et grave du traitement par l'acénocoumarol: l'hémorragie intra-alvéolaire.

Intra-alveolar bleeding is a rare and severe medical emergency due to numerous causes. We report the clinical case of a patient who could contribute to extend the literature on this subject. The study included a 62-year old man, with a history of a trial fibrillation, under anti-vitamins K antagonist admitted with dyspnoea of sudden onset associated with haemoptysis and practising self-medication using non-steroidal anti-inflammatory drugs. X-rays and chest scan showed diffuse bilateral alveolar opacities. Haemostatic screening tests on admission showed non-coagulable INR. The diagnosis of intra-alveolar bleeding was clinically and radiologically suspected and then confirmed by bronchial endoscopy with broncho-alveolar lavage (BAL) which detected uniformly hemorrhagic liquid. Previous studies of similar complications occurring after anti-vitamins K antagonists assumption are rare. In conclusion, it seems very important to emphasize the interest of strict and optimal clinico-biological monitoring of patients treated in anti-vitamins K antagonists to avoid an overdose which could contribute to a life-threatening severe haemorrhagic event.

Trombolisis endovenosa post reversión de acenocumarol con complejo de protrombina: caso clínico / Intravenous thrombolysis after reversion of acenocoumarol anticoagulation: report of one case

We report an 89-year-old male under oral anticoagulant therapy with a therapeutic international normalized ratio, presenting at the emergency room with right side hemiparesis and aphasia. Neuroimaging was compatible with an acute middle cerebral artery ischemic stroke. Anticoagulation was reverted with the use of four factor prothrombin complex, followed by thrombolysis with alteplase, with a favorable evolution, returning to his basal functional status.

Extremely low therapeutic doses of acenocoumarol in a patient with CYP2C9*3/*3 and VKORC1-1639A/A genotype.

Vitamin-K antagonists (VKAs) have remained the mainstay of oral anticoagulant therapy for the treatment and prevention of thromboembolism. The management of treatment with VKAs is challenging due to their narrow therapeutic index and the wide interindividual variation in response to therapy. Variants of the CYP2C9 and the VKORC1 gene account for 30-50% of the variability in dosing requirements, and it has been proposed that genotyping of these loci could facilitate management of VKA therapy and minimize risk of overanticoagulation, even in very low doses. We present the first reported case of a patient with the compounded genotype CYP2C9*3*3 and VKORC1-1639A/A under treatment with acenocoumarol, and review of other reported cases with analogous genotypic profiles but under treatment with warfarin.

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Clinical and genetic factors influencing acenocoumarol dosing: a cross-sectional study.

: Coumadin oral anticoagulants are widely used in multiple clinical scenarios. Their narrow therapeutic range and a dosing strategy based on 'a posteriori' algorithms, pose them as an interesting group for prediction modelling research. Extensive literature explaining the association between clinical and genetic variables with the dose of warfarin have been published. Limited information exists regarding these factors and acenocoumarol dosing. The aim of the study is to explain through clinical/genetic variables, the weekly dose of acenocoumarol necessary for achieving stable anticoagulation status. We performed a cross-sectional study enrolling adults under treatment with acenocoumarol with at least three consecutive INRs between 2 and 3. To explain the association between demographic, clinical and genotype data (VKORC1, CYP2C9 and CYP4F2) and the mean weekly dose of acenocoumarol, we performed a multiple linear regression model. In our cohort, a higher age, the presence of atrial fibrillation, chronic renal failure and VKORC1 haplotype A were associated with a lower mean weekly dose of acenocoumarol. On the other side, a higher weight was associated with a higher weekly dose. Amongst anticoagulated adult patients, VKORC1 genotype and baseline clinical factors can explain acenocoumarol dosing, and therefore, help clinicians while deciding the initial anticoagulant dose.

Time to therapeutic range (TtTR), anticoagulation control, and cardiovascular events in vitamin K antagonists-naive patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists (VKAs) reduce cardiovascular events (CVEs) in atrial fibrillation (AF) when a time in therapeutic range (TiTR) >70% is achieved. Factors affecting the time to achieve the TR (TtTR) are unknown. METHODS: Prospective observational study including 1,406 nonvalvular AF patients starting VKAs followed for a mean of 31.3months (3,690 patient/year); TiTR, TtTR, and SAMe-TT2R2 score were calculated, and CVEs were recorded. RESULTS: Median TtTR was 8.0days (interquartile range 5.0-18.0). Patients with high TtTR (ie, >75th percentile) were more likely to be in AF than in sinus rhythm at entry (odds ratio [OR]: 1.423, P=.011). Median TiTR was 60.0%; low TiTR (below median) was associated with SAMe-TT2R2 score (OR: 1.175, P=.001), high TtTR (>75th percentile, OR: 1.357, P=.017), and number of international normalized ratio checks (OR: 0.998, P=.049). We recorded 113 CVEs (3.1%/y), with a higher rate seen in patients with TtTR >75th percentile compared to those below (log-rank test, P=.006). A multivariable Cox regression analysis showed that SAMe-TT2R2 score (hazard ratio [HR]: 1.331, P<.001), TtTR >75th percentile (HR: 1.505, P=.047), TiTR <70% (HR: 1.931, P=.004), number of international normalized ratio checks (HR: 0.988, P<.001), digoxin (HR: 1.855, P=.008), and proton-pump inhibitors (HR: 0.452, P<.001) were independently associated with CVEs. CONCLUSIONS: High TtTR is associated with poorer long-term quality of VKAs therapy. Patients with TtTR >18days or with high SAMe-TT2R2 score should be considered for treatment with non-vitamin K oral anticoagulants.

Effect of CYP2C9, VKORC1, CYP4F2, and GGCX gene variants and patient characteristics on acenocoumarol maintenance dose: Proposal for a dosing algorithm for Moroccan patients.

We investigated the impact of non-genetics factors, and single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP4F2, and GGCX on acenocoumarol dosage in Moroccan adult's patients, in order to develop an algorithm to predict acenocoumarol dose for Moroccan patients. Our study consisted of 217 Moroccan patients taking a maintenance dose of acenocoumarol for various indications. The patients were genotyped for VKORC1 -1639 G>A, VKORC1 1173 C>T, CYP2C9*2, CYP2C9*3, CYP4F2 1347 G>A and GGCX 12970 C>G SNPs. The statistical analysis was performed using the SPSS software. The age and SNPs in VKORC1 and CYP2C9 were significantly associated with the weekly acenocoumarol dose requirement (p = 0.023, p = 0.0001 and p = 0.001 respectively). There was no association found between the weekly acenocoumarol dose and the CYP4F2 or GGCX variants (p-value > 0.05). Non-parametric analysis confirmed the accumulate effect of variant alleles at VKORC1 -1639 G>A, VKORC1 1173 C>T and CYP2C9 SNPs on the acenocoumarol dose requirement. With 90.24% less dose required for one patient carrying homozygote variant at VKORC1 -1173 (TT) and CYP2C9 *x/*x haplotype. The multiple linear regression analysis showed that mutation in VKORC1 -1639, VKORC1 1173 SNPs, or in CYP2C9 haplotype reduces the mean acenocoumarol weekly dose to 25.4%, 23.4% and 6.2%, respectively. The R2 for multiple regression analysis final model was found to be 35.9%. In this work we were able to establish the factors influencing interindividual sensitivity to the anticoagulant therapy that can help physicians to predict optimal dose requirement for long term therapy.