Pharmacology And Management Of The Vitamin K Antagonists Pdf

pharmacology and management of the vitamin k antagonists pdf

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Map of the literature search and selection process.

Metrics details. Vitamin K antagonists VKAs are effective oral anticoagulants that are titrated to a narrow therapeutic international normalized ratio INR range.

New Oral Anticoagulants: Comparative Pharmacology with Vitamin K Antagonists

Metrics details. Vitamin K antagonists VKAs are effective oral anticoagulants that are titrated to a narrow therapeutic international normalized ratio INR range. We reviewed published literature assessing the impact of INR stability - getting into and staying in target INR range - on outcomes including thrombotic events, major bleeding, and treatment costs, as well as key factors that impact INR stability. There are many factors associated with poor INR control. Clinicians caring for patients who require anticoagulation are encouraged to intensify diligence in INR management when using VKAs and to consider appropriate use of newer anticoagulants as a therapeutic option.

Vitamin K antagonists VKAs such as warfarin inhibit the enzyme vitamin K epoxide reductase and consequently the recycling of inactive vitamin K epoxide back to its active, reduced form [ 1 ].

Vitamin K in its active form is required for the synthesis of various clotting factors II, VII, IX and X involved in the coagulation cascade as well as the anti-clotting proteins C and S ; and thus, VKAs result in the depletion of these factors within 72—96 h after dosing and an anticoagulated state.

VKAs are indicated for the prevention of thrombotic events in patients with atrial fibrillation AF and following venous thromboembolism VTE [ 2 , 3 ]. In patients suffering an acute VTE either deep vein thrombosis DVT or pulmonary embolism PE , adjusted-dose VKA use preceded by a parenteral anticoagulant significantly reduces the risk of recurrence of thrombotic events [ 3 , 5 , 6 ].

The red, green, purple, and orange boxes display the percent of people who ever achieved a level of 3. The same individual could be represented in multiple categories given their INRs achieved over time including being below 2.

The literature from clinical trials and observational studies substantiate that INR stability is not readily attainable and when it occurs, is rarely sustainable over time. The consequences of INR instability are multifaceted. INR instability was associated with clinical events, higher level of medication non-persistence and discontinuation, utilization of more healthcare resources, and therefore, higher costs.

While most of these events were stroke associated with sub-therapeutic values, increased bleeding events were also observed. While only speculative and we could not identify supportive literature it is possible the increased bleeding associated with sub-therapeutic INRs is due a lag in time between the actual event and the true INR value.

This emphasizes the need for close INR monitoring to prevent subtherapeutic warfarin dosing. Adapted from data from an observational study using the Veterans Health Administration dataset [ 38 ] showing the relative risk RR of adverse thrombotic or embolic events in patients with subtherapeutic INRs versus normal INRs and then major bleeding vents with supertherapeutic INRs versus normal INRs.

Further evidence showed the link between INR instability and clinical events. In meta-analyses that examine the relationship between TTR and the prediction of adverse events, a significant negative relationship has been observed [ 19 ].

The TTR of patients with a major hemorrhage was 7. Of note, ACTIVE W also found that patients spent a greater amount of time out of range in the 1—2 months preceding a major bleeding event or stroke which suggests even a temporary period out of range can lead to a bleeding event or stroke. Inability to achieve high TTR in clinical practice is associated with non-persistence and medication discontinuation [ 40 ].

Continued protection by anticoagulation is particularly important for patients with NVAF, since the risk of stroke is expected to increase with age and additional comorbidities [ 43 ].

INR instability was associated with higher healthcare utilization and costs. In an observational study using the Premier Perspective Comparative Hospital Database, hospital length of stay was 5. These findings remained robust in a sensitivity analysis with a more stringent definition of the cohort. The substantial cost difference between in-range and out-of-range time is significant across a broad warfarin population with atrial fibrillation.

Adapted from data from a US Veterans Administration dataset [ 46 ] where the total costs are displayed in blue and the constituent costs of inpatient, outpatient, and outpatient pharmacy costs are in red, green, and purple, respectively.

The total costs in the therapeutic INR group is significantly lower than those with abnormally low or high INR groups. Note that the highest costs were associated with suboptimal INR values i. The literature suggests that INR instability has important clinical and financial consequences which underscore the need for greater vigilance on achieving INR stability or the use of a novel oral anticoagulant which provides more consistent pharmacologic effects.

Therefore, a broad understanding of factors predicting INR instability is beneficial for clinical practice.

Two of the most extensive studies were conducted by Apostolakis et al. VARIA [ 48 ] and provided insight into factors affecting anticoagulation control. The VARIA investigators also created a clinical prediction tool but eliminated race because they did not wish to perpetuate disparities in care, eliminated poverty and distance to drive to receive care because they felt it was hard to assess, and eliminated other factors to simplify the model.

In addition to the factors in the SAMeTT2R2 score, this tool also assesses the indication for use, total number of chronic medications, substance abuse, mental illnesses, number of hospitalizations, and the general quality of TTR attainment in other patients within that healthcare setting.

Even with all of these additional factors, the R-squared value only ranged from 3. Furthermore, while the study assessed TTR at therapy initiation and after chronic therapy, the authors stated that the prediction tool is not to be used as a means to assess long term control, and that clinical experience from past VKA therapy is the preferred method [ 48 ].

Two reasons why the clinical prediction tools are inadequate may be related to genetics and adherence to therapy. Patient genotype plays an important role in INR stability [ 12 , 50 — 52 ].

At least 30 genes contribute to the anticoagulant effects of VKAs, with one third of the variance in warfarin dosing related to mutations in genes leading to the synthesis of CYP2C9 and vitamin K epoxide reductase VKORC1 [ 12 , 50 — 52 ].

VKORC1 polymorphisms can result in either a heightened group A haplotype or reduced effect group B haplotype of warfarin which alters the risk of thromboembolism and bleeding accordingly [ 12 ]. Based on this data, the Food and Drug Administration altered the package insert recommending clinicians consider genetic testing before initiating warfarin therapy [ 56 ]. Identified predictors of VKA nonadherence include not being married, not having a vehicle for transportation, education levels beyond high school, currently employed, lower levels of mental health functioning, poor cognitive functioning, and greater drug regimen complexity [ 58 , 59 ].

In addition, studies have identified patient dissatisfaction with care as a cause of medication non-adherence in patients with cardiovascular disease states [ 60 ].

This is noteworthy since patient satisfaction with warfarin therapy has been shown to be poor in recent studies of AF [ 61 ] and VTE patients [ 62 ]. Existing research provided good understanding of the drivers behind poor INR control. The research findings indicate that many of the patient factors are not modifiable and are also not sufficiently reliable to predict whether VKA will perform well for a particular patient. There are several modalities to improve the clinical management of patients on VKAs including computer assisted dosing and patient self-testing or management.

In a randomized study of 13, patients conducted in 32 centers around the world, the impact of software program guided VKA therapy was compared with experienced clinician dosing [ 64 ]. Point of care testing by the patient or clinician allow rapid determination of the INR without the need for a centralized laboratory to acquire and analyze the samples. The CoaguChek system was the most commonly assed and yielded a coefficient of variation that ranged from 1.

The other systems have coefficients of variation ranging from 3. In general, point of care testing is accurate and can facilitate patient self-testing where the patient self-tests the INR but clinician doses or patient self-management where the patient self-tests and self-adjusts VKA therapy based on the INR.

Patients were trained and given an algorithm to follow that specified the new dose and the timeframe for which to reassess the INR. No calls or visits were made to the physician regarding dose adjustment during the patient self-management period. There were no episodes of major bleeding or thromboembolic events. Studies like this are promising but preliminary and it is unclear whether this is an effective therapy for highly motivated and intelligent patients or patients with health disparities or care barriers.

A more common pattern — based on the literature — is that there is high variability, and even the patients who achieve target INR range do not remain in this target range for long. Patients are more likely to have INR below the therapeutic range, exposing them to significant risk of adverse clinical events. Not achieving a high TTR can result in thrombotic and major bleeding events, inability to remain on therapy, and higher cost of care.

To avoid the adverse consequences of unstable INR, careful evaluation of patients prior to initiating therapy is important. Clinicians caring for patients who require anticoagulation are encouraged to apply intensified diligence in INR management when using VKAs. Coumadin warfarin sodium tablets prescribing information.

Meta-Analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med.

Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. J Am Coll Cardiol. Measures of vitamin K antagonist control reported in atrial fibrillation and venous thromboembolism studies: a systematic review.

BMJ Open. A systematic review of outcome measures reported for the therapeutic effectiveness of oral anticoagulation. J Clin Pathol.

A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT 2 R 2 score.

Identifying potential predictors of high-quality oral anticoagulation assessed by time in therapeutic international normalized ratio range: a prospective, long-term, single-center, observational study. Clin Ther.

Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression. Thromb J. Meta-analysis to assess the quality of international normalized ratio control and associated outcomes in venous thromboembolism patients. Thromb Res. Benchmark for time in therapeutic range in venous thromboembolism: a systematic review and meta-analysis. PLoS One. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review.

Circ Cardiovasc Qual Outcomes. Evaluating the impact of study-level factors on warfarin control in U. Am J Health Syst Pharm. Effect of study setting on anticoagulation control: a systematic review and metaregression. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Dabigatran versus warfarin in patients with atrial fibrillation. Edoxaban versus warfarin in patients with atrial fibrillation. Apixaban versus warfarin in patients with atrial fibrillation. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.

Management of Non-Vitamin K Antagonist Oral Anticoagulants in the Perioperative Setting

Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Ansell and J. Hirsh and E. Hylek and A.

Anticoagulant therapy with vitamin K antagonists is an effective treatment for both primary and secondary prevention of venous and arterial thrombosis. In recent years it has become clear that diet, and especially the intake of vitamin K 1 , plays an important role as a cause of the variability of the INR. Several scientific studies did indeed show that vitamin K 1 supplementation improved anticoagulant control, both in healthy volunteers,10 and in patients on anticoagulant therapy11—13 without necessitating a large increase of the dose of vitamin K antagonists required to maintain a therapeutic INR. A difference of 3. First, it is unclear whether all patients benefit from vitamin K 1 supplementation or only a subgroup of patients with unstable anticoagulation control.

Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Ansell and J. Hirsh and L.

A challenge in the use of vitamin K antagonists VKAs is the potential for drug-drug interactions, resulting in insufficient or excessive anticoagulation. Solid data are lacking for most alleged interactions. In case reports, 1 - 3 the commonly used antibiotic dicloxacillin has been reported to lower the anticoagulant effect of warfarin, the most used VKA. All international normalized ratios INRs are recorded.

Warfarin , sold under the brand name Coumadin among others, [1] is a medication that is used as an anticoagulant blood thinner. The common side effect is bleeding. Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K 1. Warfarin first came into commercial use in as a rat poison.

The field of oral anticoagulation has evolved with the arrival of non-vitamin K antagonist oral anticoagulants NOACs including an anti-IIa agent dabigatran etexilate and anti-Xa agents rivaroxaban and apixaban. The main specificities of these drugs are predictable pharmacokinetics and pharmacodynamics but special attention should be paid in the elderly, in case of renal dysfunction and in case of emergency. In addition, their perioperative management is challenging, especially with the absence of specific antidotes. Effectively, periods of interruption before surgery or invasive procedures depend on half-life and keeping a permanent balance between bleeding and thromboembolic risks. In addition, few data regarding the link between plasma concentrations and their effects are provided. Routine laboratory tests are altered by NOACs and quantitative measurements are not widely performed. This paper provides a review on the management of NOACs in the perioperative setting, including the estimation of the bleeding and thrombotic risk, the periods of interruption, the indication of heparin bridging, the usefulness of laboratory tests before surgery or invasive procedure, and the time of resuming.

PDF | This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the Seventh American.

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New oral anticoagulants OACs that directly inhibit Factor Xa FXa or thrombin have been developed for the long-term prevention of thromboembolic disorders.

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Vitamin K antagonists VKA are used in human medicine as well as for the management of rodent populations.

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Key words: anticoagulation; pharmacogenetics; pharmacology; quality of care; vitamin K antagonists; warfarin. Abbreviations: AMS anticoagulation management.