Vitamin K Antagonists Monitoring Research Articles

Thrombosis centres and AVKs monitoring in COVID-19 pandemic.

Vitamin K-Antagonists (VKAs) are the treatment of choice in patients with indications other than atrial fibrillation and venous thromboembolism. Moreover, some patients still assume VKAs refusing to change their therapy when direct oral anticoagulants (DOACs) are properly indicated. The COVID-19 pandemic has completely changed our lives, nullifying inter-personal relationships to avoid contagion, making difficult the VKAs monitoring. We describe the re-organization of our thrombosis centre (TC) as an example on how to face the emergency due to the COVID-19 pandemic. In the first phase, to avoid overcrowding at the TC, we planned to increase the interval time between INRs checks and to encourage blood sampling at home, especially for elderly patients. Moreover, precise scheduled blood sampling was also organized while telephone and email counselling were guaranteed by two doctors of the TC. In the second phase, to reduce the number of patients who daily attended our TC a switch from VKAs to DOACs was carried out, if no contraindications were identified. In the third phase, to protect patients, healthcare staff and hospital from COVID-19 widespread, telemedicine was strengthened. We tried to extend self-testing at home by means of portable coagulometers to as more patients as possible. To avoid patients staying or coming back to the TC an ad hoc web platform for sending the therapeutic dose adjustment and the next scheduled appointment was developed. The TC re-organization allowed us to monitor anticoagulated patients respecting personal isolation and security measures to avoid possible COVID-19 contagion.

Replacing PT-INR Monitoring of Warfarin with Fiix-NR in Clinical Practice Reduces Thromboembolism without Increasing Bleeding Despite Reduced Number of Dose Adjustments

Background: Traditional prothrombin time (PT) based international normalized ratio (INR) is often highly variable. Often this is caused by rapid factor VII reductions due to its short (4 hour) half-life. Thus, factor VII variation is an important confounder during vitamin K antagonist (VKA) dosing. Furthermore, prior studies have demonstrated that factor VII reductions only minimally influence the antithrombotic effect and bleeding risk of VKA, the clinical effect depending mainly on controlled reduction of factors II and X. Therefore, ignoring the influence of FVII during VKA monitoring has the potential to simplify management and outcome.The Fiix prothrombin time (Fiix-PT) is a new modified PT that is only affected by reduced factors II and X. The Fiix-PT is not affected by variations in factor VII. Hence, the Fiix normalized ratio (Fiix-NR) fluctuates less than the standard standard PT-INR. In the double-blind randomized clinical Fiix-trial, published in 2015, monitoring of warfarin with with Fiix-PT (Fiix-NR) was compared to standard high time-in-range PT-INR monitoring. Fiix-NR monitoring led to improved time-in-range, reduced testing frequency, reduced dose-adjustment need and a 50% reduction in thromboembolism (TE). Bleeding did not increase and it occurred at a low rate in both trial arms. Subsequently starting on July 1st 2015 we replaced the PT-INR with Fiix-NR in our anticoagulation monitoring practice.Aim: We compared anticoagulation outcome and dosing frequency during 12 months prior to switching from PT-INR based management (Pre-Fiix monitoring period) and during 12 months following switch to Fiix-NR monitoring (Fiix monitoring period).Methods: This is a retrospective before and after study involving unselected patients managed at a single anticoagulation management service at the Landspitali University Hospital in Reykjavik, Iceland. All patients on warfarin during two consecutive twelve month periods were analysed irrespective of indication or anticoagulation target range. Pre-Fiix patients analysis was based on events occuring during months -12 to -1 before replacing the PT with Fiix PT and the Fiix patients´outcome was analysed during months +4 to +15. Three transitional months were excluded. All patients were dosed by specialized staff using the DAWN anticoagulation software®. Hospital chart diagnostic codes were reviewed for occurrence of TE or major bleeding (MB) during the two separate monitoring periods.Surrogate assessments included the number of tests, testing intervals and dose adjustment frequencies and will be analyzed later.Results: During the Pre-Fiix period 2,345 patients were managed with PT-INR for 1,984 patient years (0.85 years/patient) and during the Fiix period 1,909 patients were managed with Fiix-NR for 1,643 patient years (0.86 y/pt). Indications for warfarin were identical during both periods (atrial fibrillation 57%, venous thromboembolism 26%, prosthetic heart valves 5% and other 12%). The INR target range during both periods was 2.0-3.0 in 92% and 2.5-3.5 in 6%. Clinical outcome with respect to TE and MB is shown in the figure. Overall the point estimates were suggestive of a 34-52% reduction of TE with Fiix-NR monitoring whereas major bleeding was similar. The reduction in untoward events in the Fiix group was statistically significant for composite new TE (OR 0.63;0.41-0.97) and total stroke (ischemic and hemorrhagic, OR 0.57;CI 0.33-0.98), mainly driven by reduced cerebral infarction. Intracranial bleeding occurred in 0.76% in the Pre-Fiix group and in 0.37% in the Fiix montoring group (n.s., OR 0.51;0.19-1.32). The median time-within-Target-range (TTR, Rosendaal method) was similar in both groups (75 vs 76%, respectively), despite dose adjustment frequency being reduced by 18% in the Fiix monitoring group (OR 0.82;CI 0.79-0.85, p <0.0001).Conclusions: These results are in agreement with the results of the Fiix-trial and show that ignoring factor VII during VKA monitoring is safe and leads to reduction in thromboembolism without increasing bleeding. Although TTR was identical in both groups, the dose adjustment need was reduced possibly indicating that less anticoagulation variability in the Fiix-NR group explains reduced thromboembolism. [Display omitted] DisclosuresGudmundsdottir:Hart Biologicals Ltd: Consultancy, Patents & Royalties: Hart Biologicals Ltd is commercializing the Fiix-PT which will be ready for marketing in Europe in the beginning of year 2019 and possibly later that year in the USA. Patent fees will be paid to Fiix Diagnostics Ltd once the test is commercialized.; Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: The Fiix prothrombin time (Fiix-PT) is a patented invention of P. T. Onundarson and B.R. Gudmundsdottir that is owned by Fiix Diagnostics Ltd, a start-up company founded by the inventors. . Onundarson:Hart Biologicals Ltd: Consultancy, Other: Hart Biologicals Ltd is commercializing the Fiix-PT which will be ready for marketing in Europe in the beginning of year 2019 and possibly later that year in the USA. Patent fees will be paid to Fiix Diagnostics Ltd once the test is commercialized.; Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: The Fiix prothrombin time (Fiix-PT) is a patented invention of P. T. Onundarson and B.R. Gudmundsdottir that is owned by Fiix Diagnostics Ltd, a start-up company founded by the inventors. .

Monitoring of treatment with vitamin K antagonists: recombinant thromboplastins are more sensitive to factor VII than tissue‐extract thromboplastins

Background Differences regarding sensitivity to factor VII have been suggested for recombinant human and tissue-extract thromboplastins used for International Normalized Ratio (INR) measurement, but the evidence is scarce. Differences in FVII sensitivity are clinically relevant, as they can affect INR stability during treatment with vitamin K antagonists (VKAs). Objectives To determine whether commercial thromboplastins react differently to changes in FVII. Methods We studied the effect of addition of FVII on the INR in plasma by using three tissue-extract (Neoplastin C1+, Hepato Quick, and Thromborel S) and three recombinant human (Recombiplastin 2G, Innovin, and CoaguChek XS) thromboplastins. Three different concentrations of purified human FVII (0.006, 0.012 and 0.062 μg mL-1 plasma), or buffer, were added to five certified pooled plasmas of patients using VKAs (INR of 1.5-3.5). Changes in FVII activity were measured with two bioassays (Neoplastin and Recombiplastin), and relative INR changes were compared between reagents. Results After addition of 0.062 μg mL-1 FVII, FVII activity in the pooled plasmas increased by approximately 20% (Neoplastin) or 32% (Recombiplastin) relative to the activity in pooled normal plasma. All thromboplastins showed dose-dependent INR decreases. The relative INR change in the pooled plasmas significantly differed between the six thromboplastins. No differences were observed among recombinant or tissue-extract thromboplastins. Pooled results indicated that the FVII-induced INR change was greater for recombinant than for tissue-extract thromboplastins. Conclusions Differences regarding FVII sensitivity exist between various thromboplastins used for VKA monitoring. Recombinant human thromboplastins are more sensitive to FVII than tissue-extract thromboplastins. Therefore, thromboplastin choice may affect FVII-mediated INR stability.

Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data.

BackgroundVitamin-K antagonists (VKAs) present an effective anticoagulant treatment in deep venous thrombosis (DVT). However, the use of VKAs is limited because of the risk of bleeding and the necessity of frequent and long-term laboratory monitoring. Therefore, new oral anticoagulant drugs (NOACs) such as dabigatran, with lower rates of (major) intracranial bleeding compared to VKAs and not requiring monitoring, may be considered.ObjectivesTo estimate resource utilization and costs of patients treated with the VKAs acenocoumarol and phenprocoumon, for the indication DVT. Furthermore, a formal cost-effectiveness analysis of dabigatran compared to VKAs for DVT treatment was performed, using these estimates.MethodsA retrospective observational study design in the thrombotic service of a teaching hospital (Deventer, The Netherlands) was applied to estimate real-world resource utilization and costs of VKA monitoring. A pooled analysis of data from RE-COVER and RE-COVER II on DVT was used to reflect the probabilities for events in the cost-effectiveness model. Dutch costs, utilities and specific data on coagulation monitoring levels were incorporated in the model. Next to the base case analysis, univariate probabilistic sensitivity and scenario analyses were performed.ResultsReal-world resource utilization in the thrombotic service of patients treated with VKA for the indication of DVT consisted of 12.3 measurements of the international normalized ratio (INR), with corresponding INR monitoring costs of €138 for a standardized treatment period of 180 days. In the base case, dabigatran treatment compared to VKAs in a cohort of 1,000 DVT patients resulted in savings of €18,900 (95% uncertainty interval (UI) -95,832, 151,162) and 41 (95% UI -18, 97) quality-adjusted life-years (QALYs) gained calculated from societal perspective. The probability that dabigatran is cost-effective at a conservative willingness-to pay threshold of €20,000 per QALY was 99%. Sensitivity and scenario analyses also indicated cost savings or cost-effectiveness below this same threshold.ConclusionsTotal INR monitoring costs per patient were estimated at minimally €138. Inserting these real-world data into a cost-effectiveness analysis for patients diagnosed with DVT, dabigatran appeared to be a cost-saving alternative to VKAs in the Netherlands in the base case. Cost savings or favorable cost-effectiveness were robust in sensitivity and scenario analyses. Our results warrant confirmation in other settings and locations.

General Practitioners' vitamin K antagonist monitoring is associated with better blood pressure control in patients with hypertension--a cross-sectional database study.

BackgroundPatients requiring anticoagulation suffer from comorbidities such as hypertension. On the occasion of INR monitoring, general practitioners (GPs) have the opportunity to control for blood pressure (BP). We aimed to evaluate the impact of Vitamin-K Antagonist (VKA) monitoring by GPs on BP control in patients with hypertension.MethodsWe cross-sectionally analyzed the database of the Swiss Family Medicine ICPC Research using Electronic Medical Records (FIRE) of 60 general practices in a primary care setting in Switzerland. This database includes 113,335 patients who visited their GP between 2009 and 2013. We identified patients with hypertension based on antihypertensive medication prescribed for ≥6 months. We compared patients with VKA for ≥3 months and patients without such treatment regarding BP control. We adjusted for age, sex, observation period, number of consultations and comorbidity.ResultsWe identified 4,412 patients with hypertension and blood pressure recordings in the FIRE database. Among these, 569 (12.9 %) were on Phenprocoumon (VKA) and 3,843 (87.1 %) had no anticoagulation. Mean systolic and diastolic BP was significantly lower in the VKA group (130.6 ± 14.9 vs 139.8 ± 15.8 and 76.6 ± 7.9 vs 81.3 ± 9.3 mm Hg) (p < 0.001 for both). The difference remained after adjusting for possible confounders. Systolic and diastolic BP were significantly lower in the VKA group, reaching a mean difference of −8.4 mm Hg (95 % CI −9.8 to −7.0 mm Hg) and −1.5 mm Hg (95 % CI −2.3 to −0.7 mm Hg), respectively (p < 0.001 for both).ConclusionsIn a large sample of hypertensive patients in Switzerland, VKA treatment was independently associated with better systolic and diastolic BP control. The observed effect could be due to better compliance with antihypertensive medication in patients treated with VKA. Therefore, we conclude to be aware of this possible benefit especially in patients with lower expected compliance and with multimorbidity.

The Ottawa Hospital Regional Warfarin Anticoagulation Management Service. Efficacy and a Patient Satisfaction Survey

Background: 5% of the population over 65 is on oral anticoagulant therapy. The indications for anticoagulation therapy are wide, not limited to but including treatment of arterial and venous thrombosis, and primary stroke prophylaxis is patients with atrial fibrillation and mechanical cardiac valves. While new oral anticoagulants not requiring monitoring are being more widely prescribed, vitamin K antagonists (VKA) are still being used for many patients in whom the novel agents are contra-indicated (renal failure), not available (funding), or patient/physician preference. Most patients on VKA have their family physicians manage their oral anticoagulants. On average, the time in therapeutic range achieved by family physicians is low (50-55%). There is also a number of patients who have no family physician and are either taking VKA without monitoring, or are having their anticoagulants monitored routinely though emergency room physicians/visits. The Ottawa Hospital (TOH) anticoagulation management service is an e-health solution that offers patients world beating time in therapeutic range (TIR). TOH uses a pharmacy managed DAWN software package (computer-assisted warfarin dosing program). Maintaining patients in therapeutic range for a high percentage of time (greater than 70%) can reduce the risk or recurrent thrombosis (venous or arterial) from under-anticoagulation and the risk of bleeding complications from over-anticoagulation. Well managed VKA therapy has also been suggested to be as safe as therapy with novel oral anticoagulants in some subgroup analysis of studies investigating the novel oral anticoagulants. Objectives/Methods: The purpose of this study was to bring the benefits of the TOH experience to provide a Regional Anticoagulation Management Service across a wide region of eastern Ontario, Canada. This service includes remote blood testing (at a lab near the patient’s home), integrated LIS link to a computerized dosing system (possible through a commercial lab partnership), and communication of dosing and testing instructions via interactive voice recognition (IVRS), email, or live (pharmacist/pharmacist assistant). We administered a patient satisfaction survey to a sample of 111 patients enrolled in the service as well as reported TIR for patients enrolled in our service during the study period (2009-2011). Results: At the beginning of the study, 1400 patients were enrolled in the program. After 2 years, the number has increased to by 66% to 2325. The average TIR for patients in the program as of October 2011 was 76.3% (overall), 77.8% (IVRS), 76.8% (email), and 73.3% (live). The patient satisfaction survey demonstrated that 94% patients prefer VKA anticoagulation monitoring through TOH service compared to their previous experience. 84% patients either satisfied or very satisfied with VKA anticoagulation care through TOH service (compared to 53% satisfaction with anticoagulant care prior to enrolling in our program). Conclusions: The TOH model of anticoagulation management service results in excellent VKA monitoring (high TIR) for a large number of patients across a wide geographical area, as well as a high level of patient satisfaction. This service allows for the safe and efficient management of VKAs in patients in whom VKA therapy is indicated. Disclosures No relevant conflicts of interest to declare.

Interpretation and management of INR results: A case history based survey in 13 countries

IntroductionStandardisation of treatment with vitamin K antagonists (VKAs) is still an issue after 60years of use. The study aimed to explore aspects of VKA monitoring in primary and secondary care. MethodsTwo case histories were distributed to physicians in 13 countries. Case history A focused on a patient with atrial fibrillation on stable anticoagulation (latest INR 2.3). Physicians were asked about frequency of INR measurement, when to change the VKA dose, and the patient's annual risk of ischemic stroke and bleeding. Case history B focused on a patient with an unexpected INR of 4.8, asking for the patient's 48-hour bleeding risk, the immediate dose reduction and time until a repeat INR. ResultsAltogether, 3016 physicians responded (response rate 8 – 38%), of which 82% were from primary care and 18% from secondary care. Answers varied substantially within and between countries regardless of level of care and VKA used. Median number of weeks between INR measurements was 4 – 6weeks. Median threshold INR for increasing or decreasing the VKA dose was 1.9 and 3.1, respectively. Risk of ischemic stroke and bleeding were overestimated 2 – 3 times. In case history B, the median dose reduction the two first days was 75% for GPs and 55% for specialists, irrespective of estimates of bleeding risk; with one week to a repeat INR. ConclusionVariation in VKA monitoring is substantial implying clinical consequences. Guidelines seem either unknown or may be considered impracticable. Further efforts towards standardisation of VKA management are needed.

Anticoagulation Monitoring by an Anticoagulation Service is More Cost-effective than Routine Physician Care

Vitamin K antagonists (VKA) are the mainstay of long-term anticoagulation but require careful monitoring for effectiveness and safety. Most patients are treated by physicians, although anticoagulation services (AS) are becoming increasingly popular. A new AS run by nurses and overseen by a physician was established, and the insurance carrier independently assessed its effectiveness vs usual physician care. We report the independent analysis of anticoagulation morbidity reflected by emergency department (ED) visits and hospitalizations observed by these two paradigms of VKA monitoring.