Acenocoumarol Exerts Anti-Inflammatory Activity via the Suppression of NF-κB and MAPK Pathways in RAW 264.7 Cells.

The repurposing of already-approved drugs has emerged as an alternative strategy to rapidly identify effective, safe, and conveniently available new therapeutic indications against human diseases. The current study aimed to assess the repurposing of the anticoagulant drug acenocoumarol for the treatment of chronic inflammatory diseases (e.g., atopic dermatitis and psoriasis) and investigate the potential underlying mechanisms. For this purpose, we used murine macrophage RAW 264.7 as a model in experiments aimed at investigating the anti-inflammatory effects of acenocoumarol in inhibiting the production of pro-inflammatory mediators and cytokines. We demonstrate that acenocoumarol significantly decreases nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß levels in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Acenocoumarol also inhibits the expression of NO synthase (iNOS) and cyclooxygenase (COX)-2, potentially explaining the acenocoumarol-induced decrease in NO and PGE2 production. In addition, acenocoumarol inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun N terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK), in addition to decreasing the subsequent nuclear translocation of nuclear factor κB (NF-κB). This indicates that acenocoumarol attenuates the macrophage secretion of TNF-α, IL-6, IL-1ß, and NO, inducing iNOS and COX-2 expression via the inhibition of the NF-κB and MAPK signaling pathways. In conclusion, our results demonstrate that acenocoumarol can effectively attenuate the activation of macrophages, suggesting that acenocoumarol is a potential candidate for drug repurposing as an anti-inflammatory agent.

Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis.

OBJECTIVES: Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP. METHODS: We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association. RESULTS: Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94-3.20), both for knee (OR=2.34, 95% CI=1.67-3.22) and hip OA (OR=2.74, 95% CI=1.82-4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78-1.33). CONCLUSIONS: These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

Outcomes of long-term anticoagulant treatment for the secondary prophylaxis of splanchnic venous thrombosis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA. METHODS: This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded. RESULTS: Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09). CONCLUSIONS: Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Clinical outcomes of nonvitamin K oral anticoagulants and acenocoumarol for stroke prevention in contemporary practice: A population-based propensity-weighted cohort study.

AIMS: Acenocoumarol is a vitamin-K antagonist (VKA) primarily used in certain countries (e.g. India, Netherlands, Spain). The half-life of acenocoumarol is similar to that of non-VKA oral anticoagulants (NOAC), unlike warfarin, and this could affect comparative effectiveness and safety (CES). However, data on CES for NOAC come almost exclusively from studies using warfarin as the comparator. We aimed to assess outcomes of NOAC and acenocoumarol in people with non-valvular atrial fibrillation (NVAF) in real-world clinical practice. METHODS: This is a population-based retrospective cohort study. All new users of oral anticoagulants from November 2011 to December 2015 with NVAF were included (n = 41,560). Data were obtained by linking several health electronic records of the Valencia region, Spain. Incidence rates were estimated. We used the inverse probability of treatment weighted Cox analysis to control for indication bias when assessing the risk of effectiveness and safety outcomes for each NOAC compared with acenocoumarol. Several sensitivity analyses were performed. RESULTS: We did not find differences in the risk of mortality, ischaemic stroke or any gastrointestinal bleeding. However, we did find a decreased risk of intracranial haemorrhage for dabigatran (HR: 0.34, 95% CI 0.20-0.56) and rivaroxaban (HR: 0.55, 95% CI 0.35-0.85) as compared to acenocoumarol. In subanalyses, apixaban showed a higher risk of ischaemic stroke in high-risk persons (≥75 years and CHA2DS2-VASC score ≥ 2). CONCLUSIONS: No differences in clinical outcomes were found between NOAC and acenocoumarol overall, although dabigatran and rivaroxaban showed a lower risk of intracranial haemorrhage. Findings on the potential inferiority of specific NOAC in high-risk subgroups should be studied further.

RHEDAR study: Determination of the risk of gastrointestinal hemorrhage in treatment with dabigatran, acenocoumarol and rivaroxaban.

BACKGROUND AND AIM: Atrial fibrillation is a major cause of death and disability due to stroke. Vitamin K antagonist drugs are effective for prevention, but they have a narrow therapeutic range and multiple pharmacological interactions. In recent years, new therapeutic alternatives have been searched to minimize complications. The main objective is to evaluate the risk of gastrointestinal bleeding in anticoagulated patients and compare the classic treatment with new anticoagulants. METHODS: We conducted a retrospective cohort study to determine the risk of gastrointestinal bleeding in patients treated with acenocoumarol/dabigatran/rivaroxaban, between 2012 and 2016. We compared the classic with the new anticoagulant group, and a multivariate logistic regression analysis was used to determinate the risk factors of gastrointestinal bleeding. RESULTS: A total of 1213 patients were selected, 52.7% male patients, a mean age of 72.6 years old (± 14.563). 73.6% had atrial fibrilation. 14.5% of patients used acetylsalicylic acid, and 4% clopidogrel. 67.2% had a high-risk CHADS-2 Score, and 36.9% a high-risk HAS-BLED Score. We determined a 5.6% (68) of gastrointestinal bleeding, without differences according to anticoagulant used. The multivariate model showed a greater risk for digestive hemorrhage in patients with a previous hemorrhagic event (odds ratio [OR] = 2.422 95% confidence interval [CI]: 1.101-5.327) and the concomitant therapy with clopidogrel (OR = 2.373 95% CI: 0.996-5.652). CONCLUSIONS: No differences were found in the risk of gastrointestinal bleeding between the different anticoagulants. A previous gastrointestinal bleeding were considered independent risk factor. The HAS-BLED score should be taken into account to make clinical decisions about to prescribe anticoagulant treatment.

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones (p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.

Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol.

PURPOSE: Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients. METHODS: We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group. RESULTS: In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing. CONCLUSION: Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently.

[Anticoagulant efficacy of different pharmacological presentations of vitamin K antagonists]. / Eficacia en el control de la anticoagulación de los diferentes fármacos antagonistas de la vitamina K disponibles en Chile.

BACKGROUND: Vitamin K antagonist medications (VKA) are essential for the prevention of thromboembolic events, but their effectiveness is influenced by multiple factors, such as the type of medication chosen. AIM: To evaluate the efficacy in anticoagulant control of the bioequivalent and non-bioequivalent drugs of acenocoumarol compared to the reference drug. To evaluate the efficacy of warfarin bioequivalents available in Chile. To contrast the overall anticoagulant control efficacy between acenocoumarol and warfarin. MATERIAL AND METHODS: The results of 69333 outpatient oral anticoagulation controls were analyzed. Patient were separated in groups according to the drug that they used. Subsequently, the proportions of controls outside the range for each of acenocoumarol and warfarin bioequivalent drugs were compared. Acenocoumarol non-bioequivalent drugs were also compared with the reference drug. Acenocoumarol was compared with warfarin. RESULTS: Acenocoumarol bioequivalent drugs and the reference drug had a similar proportion of controls outside the range (Odds ratios (OR) 0.812; 0.969; 0.974 and 0.963). Non-bioequivalent drugs had a higher proportion than the reference drug (OR 1.561 and 2.037). Both warfarin brands have a similar proportion of controls outside of the range (OR 1.050). Acenocoumarol compared to warfarin had a significant higher proportion of controls outside the range (OR 1.191). CONCLUSIONS: The pharmacological presentation of vitamin K antagonists could influence anticoagulant control. Therefore, it is not prudent to switch these presentations frequently.

Perioperative bridging of vitamin K antagonist treatment in patients with atrial fibrillation: only a very small group of patients benefits.

AIMS: Bridging anticoagulation in atrial fibrillation (AF) patients who need to interrupt vitamin K antagonists for procedures is a clinical dilemma. Currently, guidelines recommend clinicians to take the stroke and bleeding risk into consideration, but no clear thresholds are advised. To aid clinical decision making, we aimed to develop a model in which periprocedural bridging therapy is compared with withholding anticoagulation in AF patients, for several bleeding and stroke risk groups. METHODS AND RESULTS: A model was developed to simulate both a bridge and a non-bridge cohort, using simulated international normalized ratio (INR) values for patients on warfarin, acenocoumarol, and phenprocoumon. For both clinical strategies, stroke and bleeding risks were included and outcomes were stratified by CHA2DS2-VASc or CHADS2 and HAS-BLED groups. Quality-adjusted life expectancy was the main outcome considered. Our analyses show bridging to only be beneficial for patients with HAS-BLED scores equal or lower to 2 and with CHA2DS2-VASc scores of 6 or higher. For patients using acenocoumarol bridging may be beneficial starting at a CHA2DS2-VASc score of 7. Post-procedural time to therapeutic INR has a significant influence on the results: no significant benefit of bridging was found for patients reaching therapeutic INR values within 5 days. CONCLUSION: When deciding whether to bridge anticoagulation, clinicians should consider the patient's individual stroke and bleeding risk, while also considering the patient's post-procedural INR management. In practice, only a small subset of patients is expected to benefit from bridging anticoagulation treatment.

Effectiveness and Safety of Rivaroxaban Compared to Acenocumarol after Infrainguinal Surgical Revascularization.

BACKGROUND: Optimal antithrombotic therapy after lower limb infrainguinal revascularization remains a controversial topic. The use of anticoagulants, alone or in combination with antiplatelet drugs, can potentially improve patency rate and limb salvage, particularly in patients with risk factors for early thrombosis. Bleeding is the main complication of long-term anticoagulant use. New oral anticoagulants can represent an attractive alternative to the standard vitamin K antagonists. The objective of the study is to evaluate the effectiveness (bypass occlusion and major amputation) and safety (major bleeding and all-cause mortality) of rivaroxaban compared to acenocumarol after infrainguinal lower limb surgical revascularization. MATERIAL AND METHODS: Retrospective cohort study of patients with peripheral arterial disease submitted to lower limb infrainguinal bypass revascularization with vein or expanded polytetrafluoroethylene conduit, who were anticoagulated with acenocumarol or rivaroxaban after hospital discharge. Patients with proximal revascularization, revascularization due to any pathology other than peripheral arterial disease, coagulation disorder, stroke or acute myocardial infarction in less than 30 days, glomerular filtration rate <15 mL/min, or on hemodialysis were excluded. RESULTS: One hundred nine patients were included (78.9% male), with a mean age of 64.8 years. After hospital discharge, 40 patients (36.7%) were medicated with rivaroxaban and 69 patients (63.3%) with acenocumarol. At 1 year of follow-up, patients under rivaroxaban and acenocumarol presented comparable major amputation rates (12.5 % vs. 10.1%, P = 0.756), bypass occlusion (22.5% vs. 24.6 %, P = 0.769), and mortality rate (10% vs. 8.7%, P = 0.756). Major bleeding occurred in 13.8% of patients. Patients with renal dysfunction had significantly higher bleeding risk with acenocumarol (45.5% vs. 0%, P = 0.028) compared to rivaroxaban, while patients with normal renal function presented similar bleeding rates with both anticoagulants (6.1% vs. 6.4%, P = 0.953). CONCLUSIONS: Rivaroxaban has equivalent effectiveness to acenocumarol after infrainguinal bypass revascularization, with similar occlusion, major amputation, and mortality rates. Rivaroxaban has an improved safety profile in patients with moderate renal dysfunction due to a significantly lower incidence of major bleeding. In patients with normal renal function, rivaroxaban and acenocumarol present equivalent major bleeding rates.

Resolution of acenocoumarol-associated calciphylaxis with drug withdrawal.

Calciphylaxis is a syndrome of cutaneous ischaemic necrosis and ulceration due to arteriolar calcification with subsequent thrombosis, which rarely presents in patients without terminal kidney disease. Recently, several reports of coumarins-associated calciphylaxis have stressed the relevance of anticoagulant therapy as an important risk factor for the development of this condition. We report five cases of acenocoumarol-associated, biopsy-proven calciphylaxis in women aged between 64 and 92 years. The drug had been prescribed for atrial fibrillation and was taken without interruption from 14 to 224 months. Lesions were present for months in all cases and were resistant to multiple therapeutic options, but they resolved only with simple wound care measures 6-14 months after changing the anticoagulant therapy.

[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.

New versus Old Oral Anticoagulants: How Can We Set the Scale Needle? Considerations on a Case Report.

Ischemic stroke is a complex multifactorial disorder. Anticoagulation is a growing research area, with the main goal of preventing systemic embolization and stroke. We report the case of a 41-year-old woman with antiphospholipid syndrome who was unsuccessfully treated with Dabigatran, a new oral anticoagulant, as she developed a major stroke involving the right carotid artery, due to deep venous thrombosis with pulmonary embolism. We therefore suggest a closer monitoring of the safety and efficacy of dabigatran. Moreover, in the presence of multifactorial causes of pro-coagulation, we believe that warfarin should remain the mainstay of oral anticoagulation.

Paget-Schroetter syndrome in a teenager after throwing firecrackers - A case report.

Paget-Schroetter syndrome (PSS), or effort thrombosis, refers to axillary and/or subclavian vein thrombosis associated with repetitive effort of the superior limbs, and is rare in the pediatric population. We report the case of a previously healthy 15-year-old boy who presented with a painful and swollen right arm after throwing firecrackers. Doppler ultrasound showed extensive right subclavian and axillary vein thrombosis. Anticoagulation therapy was started and had favorable evolution. We emphasize that PSS must be included in the differential diagnosis of a swollen arm.

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.

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation.

BACKGROUND: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. MATERIAL AND METHODS: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS-BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score "GEN|HAS-BLED." During a median follow-up of 7.6 years (IQR 5.6-8.0), all major bleeding events were recorded. RESULTS: During follow-up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS-BLED or GEN|HAS-BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS-BLED clinical score had better predictive ability than GEN|HAS-BLED (0.660, 95% CI 0.622-0.696 vs 0.645, 95% CI 0.607-0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS-BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification. CONCLUSION: Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS-BLED score does not improve the prediction or discrimination performance for major bleeding.

Acenocoumarol as an alternative anticoagulant in a patient with warfarin-related nephropathy.

ADVERSE EVENT: Warfarin-related nephropathy. DRUG IMPLICATED: Warfarin. THE PATIENT: A 31-year-old female, managed with warfarin for rheumatic heart disease with atrial fibrillation. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: There were no alternative causes of nephropathy that could have caused the adverse event in this patient. MANAGEMENT: Shifting the drug from warfarin to acenocoumarol. MECHANISM: Difference in renal elimination between warfarin and acenocoumarol. IMPLICATION FOR THERAPY: Clinicians should be aware of this rare adverse effect of warfarin, and acenocoumarol can be considered as an alternative therapy for this condition. HYPOTHESES TO BE TESTED: Further prospectively designed studies are needed to consider acenocoumarol as an alternative therapy in warfarin-related nephropathy.

Quality of oral anticoagulation with vitamin K antagonists in 'real-world' patients with atrial fibrillation: a report from the prospective multicentre FANTASIIA registry.

Aims: The efficacy and safety of oral anticoagulation (OAC) using the vitamin K antagonists (VKA) are closely associated with the quality of anticoagulation, reflected by time in therapeutic range (TTR). The SAMe-TT2R2 is a risk score developed to predict the quality of anticoagulation control among VKA users. To analyse the quality of anticoagulation and its clinical determinants based on different methods in a prospective cohort of atrial fibrillation patients on VKA treatment participating in the multicentre Spanish observational registry FANTASIIA. Methods and results: Estimated TTR was calculated from Rosendaal, direct method, international normalized ratio variability, and NICE criteria. Time in therapeutic range values were compared for those patients with a SAMe-TT2R2 score 0-2 and >2. One thousand four hundred and seventy patients were analysed (56.4% male, mean age 74.1 ± 9.5 years). Mean TTR was 61.5 ± 25.1 with Rosendaal and 64.7 ± 24.2 with direct method. There was a high correlation between both methods (ρ = 0.805). The prevalence of poor anticoagulation control was 55%. Diabetes mellitus [odds ratio (OR) 1.38; P = 0.008], peripheral artery disease (PAD, OR 1.62; P = 0.048), and HAS-BLED (OR 1.13; P = 0.022) were independently associated with TTR < 70%. SAMe-TT2R2 score 0-2 had a higher mean TTR than patients with SAMe-TT2R2 >2 (P = 0.044), with a specificity of > 90% for predicting TTR < 70%. Patients with TTR < 70% had higher risk of events (21.7 vs. 16.8%; P = 0.021). Conclusion: In a multicentre prospective registry, 55% of AF patients had poor anticoagulation control with diabetes mellitus, PAD, and HAS-BLED being independently associated with TTR < 70%. A high SAMe-TT2R2 scores had a high specificity for predicting a TTR < 70% as an indicator of poor quality anticoagulation.

Influence of genetic and non-genetic factors on acenocoumarol maintenance dose requirement in a Tunisian population.

PURPOSE: We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients. METHODS: Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD): ((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated. The statistical study was carried out with SPSS V20. RESULTS: A significant correlation was found between age, BMI, and daily AC dose (r = - 0.397; p < 0.001 and r = 0.215; p = 0.001, respectively). The carriers of mutated alleles CYP2C9*2 or CYP2C9*3 or VKORC1 haplotypes (H1 and H7) were associated with AC hyper-sensibility. After adjustment to potential covariates, these patients presented supra-therapeutic INR during treatment period and needed low AC dose (ORs* = 0.28 [0.06-0.60], p = 0.004; ORs* = 0.12 [0.04-0.05], p < 0.001; ORs* = 0.45 [0.24-0.84], p = 0.01; and ORs* = 0.28 [0.06-0.98], p = 0.049, respectively). However, carriers of VKORC1 haplotypes (H3 and H12) or mutated alleles CYP4F2 (rs2108622) or CALU (rs1043550) tend to resist to treatment, hence long period of therapy initiation, and must be treated with high AC dose (ORs* = 2.67 [81.12-5.91], p = 0.013; ORs* = 8.76 [1.07-76.26], p = 0.019; ORs* = 3.12 [1.01-9.63], p = 0.047; and ORs* = 3.96 [1.41-11.09], p = 0.009, respectively). A final multivariate regression model explained 48.1% of the global interindividual variability in AC dose requirement. CONCLUSION: The PA demonstrated that VKORC1 and CYP2C9 polymorphisms contribution was more important than clinical factors. Applying the PA would allow dose adjustment to treat patients in a personalized manner.

Ocular Myasthenia Induced by Rivaroxaban in Patient with Deep Vein Thrombosis.

The non-vitamin K antagonist oral anticoagulant rivaroxaban is indicated in prevention and treatment of venous thromboembolism (VTE). A 60-year-old male patient complained of bilateral ptosis after administration of rivaroxaban for deep vein thrombosis (DVT). Myasthenia gravis (MG) was confirmed by positive serum antiacetylcholine receptor antibody test. No mediastinal thymoma was found. The ocular myasthenia reversed after discontinuing rivaroxaban treatment. Nevertheless, ptosis recurred and chronic oral pyridostigmine bromide treatment was necessary. The mechanism of MG development by rivaroxaban therapy is not completely understood. The development of rivaroxaban-induced autoimmune disease could be based on cross-reactivity between antibodies against rivaroxaban-derived antigens or by T-cell activation. To our knowledge, this report of ocular myasthenia by rivaroxaban administration is the first in the literature. Despite the benefits of rivaroxaban, it is important to recognize unexpected immune-related adverse events.