Determination of the lack of a drug interaction between azithromycin and warfarin

STUDY OBJECTIVE: To determine the effect on the international normalized ratio (INR) of adding azithromycin to patients receiving stable dosages of warfarin. DESIGN: Retrospective chart review. SETTING: Outpatient clinic. PATIENTS: Ambulatory patients receiving warfarin and azithromycin concurrently who had a documented therapeutic INR value before the start of azithromycin therapy (pre-INR) and a documented INR value within 30 days after the start of azithromycin therapy (post-INR). MEASUREMENTS AND MAIN RESULTS: Patients given felodipine during long-term warfarin therapy formed a comparative control group. Patient demographics were similar in both treatment groups. Mean age of the azithromycin group (17 patients) was 59 +/- 13 years and of the control group (20 patients) 65 +/- 12 years. All 17 patients in the azithromycin group and 16 of the controls were women. Mean change from pre-INR to post-INR in the azithromycin and control groups, respectively, was 0.14 +/- 0.64 (pre-INR 2.46, post-INR 2.61) and 0.19 +/- 0.54 (pre-INR 2.46, post-INR 2.66) (p = 0.74). A post hoc power analysis based on a pooled standard deviation of 0.60 revealed that the study had 68% power to detect a 0.5 change in the INR value. CONCLUSION: No interaction between azithromycin and warfarin was observed in ambulatory patients with therapeutic baseline INR values.     

Retrospective evaluation of a possible interaction between warfarin and levofloxacin

STUDY OBJECTIVES: In order to clarify the clinical significance of a suspected drug interaction, we sought to determine if the international normalized ratio (INR) is affected when levofloxacin is administered in patients receiving long-term warfarin therapy. DESIGN: Retrospective cohort study using pharmacy and medical records. SETTING: Outpatient clinic. PATIENTS: Forty-three patients receiving long-term warfarin therapy who subsequently were prescribed either levofloxacin (22 patients) or felodipine (21 controls); felodipine was chosen as it has been shown not to interact with warfarin. Patients in both groups were required to have a documented INR before the start of levofloxacin or felodipine (pre-INR) and either during levofloxacin or felodipine therapy or within 15 days after the drug had been started (post-INR). MEASUREMENTS AND MAIN RESULTS: Patient demographics were similar between the two treatment groups. The mean +/- SD age of the patients in the levofloxacin and control groups was 59.5 +/- 8.7 and 65.3 +/- 11.5 years, respectively (p=0.07). The mean change between the pre- and post-INR (primary outcome measure) was 0.31 +/- 0.82 (pre-INR 2.46, post-INR 2.76) and 0.21 +/- 0.54 (pre-INR 2.46, post-INR 2.67) in the levofloxacin and felodipine groups, respectively (p=0.65). A post hoc power analysis, based on a sample-derived, weighted standard deviation of 0.68, revealed that the study had 66% power to detect a change of 0.5 in the INR value. The percentage of patients who required a warfarin dosage adjustment based on the post-INR (secondary outcome measure) was 41% (9 of 22 patients) in the levofloxacin group and 33% (7 of 21 patients) in the felodipine group. CONCLUSION: Although our primary analysis did not detect a warfarin-levofloxacin interaction, the potential for such an interaction, especially in idiosyncratic cases, cannot be ruled out. Clinicians should closely monitor INR values when levofloxacin is administered jointly with warfarin.     

Does heart failure exacerbation increase response to warfarin?A critical review of the literature

ABSTRACT

Background: Numerous factors, such as other drugs, diet, and age, are well documented as altering response to warfarin. Less attention has been focused on the effect of disease states on the response to oral anticoagulants. Decompensated heart failure is reported to increase response to warfarin, but documentation is limited.

Objective: The purpose of this review is to critically examine the evidence of a possible effect of heart failure exacerbations on response to warfarin.

Research design and methods: A literature search was completed of the last 60 years using several databases, including PubMed, MEDLINE, EMBASE, and SCOPUS. Key terms in our search included ‘warfarin’ AND ‘heart failure’ and ‘heart failure exacerbation’ (or ‘decompensated heart failure’) AND ‘effect on warfarin’. When relevant citations were found, the references cited by those authors were checked.

Results: Several reports from 1946–1989 suggested that decompensated heart failure increases response to oral anticoagulants. Unfortunately, these early reports have important limitations. More recent reports, since the widespread use of the international normalized ratio (INR), also suggest that heart failure exacerbations are associated with increased response to warfarin. Patient populations are small in these reports.

Conclusions: Heart failure exacerbations may be associated with an increased response to warfarin and other vitamin K antagonists, but many reports are inadequate, and it appears that not all patients are susceptible to this effect. More frequent monitoring of INR in patients with decompensated heart failure is warranted. It is prudent to initiate warfarin at lower doses in patients with a history of heart failure and to monitor INR every 1–2 weeks during times of instability in ambulatory patients, and daily INRs in hospitalized patients. Given the large number of variables that impact on warfarin dose requirement, it is difficult to clearly establish the effect of decompensated heart failure on response to warfarin. Further studies must take all of these variables into account.     

Dietary implications for patients receiving long-term oral anticoagulation therapy for treatment and prevention of thromboembolic disease

Introduction: The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin.

Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability.

Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.     

Anticoagulation in patients with non-valvular atrial fibrillation: an evaluation of stability and early factors that predict longer-term stability on warfarin in a large UK population

ABSTRACT

Objective: To determine the proportion of patients with non-valvular atrial fibrillation (NVAF) treated with warfarin that achieved a 6‐month period within the target INR range (stability). To then evaluate any associations between stability and outcome and to determine whether stability can be predicted by clinical factors at an early stage in warfarin treatment.

Methods: This study was a record linkage study in 1513 patients with NVAF treated with warfarin for a minimum of 6‐months, carried out in a large UK population. The main outcome measures were stability (defined as six months within the target INR range [2.0–3.0]), thromboembolic and bleeding event rates and mortality. Secondary outcome measures were the predictive value of baseline characteristics and other treatment variables.

Results: Stability was achieved in 52% of the study group. Standardised mean survival was significantly higher in the group who achieved stability (? = 16.91 months, p < 0.001) with a hazard ratio of 4.36 (?p < 0.001). The stable group had a lower rate of both thromboembolic events (0.8% vs. 2.3% per patient year) and bleeds recorded on inpatient diagnoses (0.4% vs. 1.2% per patient year). Failure to achieve stable control was associated with age (Odds Ratio [OR] 1.011 (95% Confidence Interval [CI] 1.001–1.021)) and morbidity at baseline (OR 1.015; 95% CI 1.007–1.022). An increase in mean time between visits (OR 0.939; 95% CI 0.926–0.952) and the percentage time in range (OR 0.889; 95% CI 0.879–0.900) was associated with a decrease in the chance of instability. Greater variability in INR was also associated with a failure to achieve stability (OR 1.518; 95% CI 1.427–1.615). Receiver Operator Characteristic (ROC) analysis using data from the first three months of treatment demonstrated good discrimination of stability using age and morbidity at baseline and percentage time in range and frequency of visits during the first three months of treatment (area under curve [AUC] 0.780; standard error [SE] 0.012; 95% CI 0.757–0.803).

Conclusions: Many patients never achieved a period of 6‐months stability and were at increased risk of thromboembolic events and bleeds. Age, morbidity at baseline and variability of INR control in the first three months could be used to predict instability using warfarin. This study infers that patients should be treated more intensively in the early stages of warfarinisation in order to improve outcome.     

Effect of CYP2C9 and VKORC1 genetic variations on warfarin dose requirements in Indian patients

BackgroundWarfarin, an oral anticoagulant is used in patients who are at increased risk of developing blood clots. The management of warfarin therapy is challenging because it shows large inter and intra individual variability in patient response due to factors like age, gender, diet, concurrent drug interactions and variations in CYP2C9 and VKORC1 genes. Studies implicate that polymorphisms in VKORC1 and CYP2C9 genes are associated with reduced doses of warfarin. The aim of our current study was to characterize the effects of VKORC1 and CYP2C9 gene variations that contribute to variability in warfarin dosing in Indian patients.MethodsGenomic DNA was extracted from 103 patients undergoing warfarin therapy. Their mean daily warfarin dose, INR and demographics were recorded and genotyping of VKORC1 and CYP2C9 gene was performed by PCR-RFLP method.ResultsIndividuals with wild type genotypes required highest mean warfarin dosage of 4.72 mg/day while VKORC1 variants required 3.6 mg/day to maintain their therapeutic INR. CYP2C9*2 genotype was not found to affect the warfarin maintenance dosages. The odds ratio for developing supra therapeutic INR in patients carrying VKORC1 variant allele when compared to wild types was 13.96 (95% CI; 4.85 – 44.65. Other factors affecting warfarin dosages were age and weight.ConclusionInclusion of pharmacogenetic data along with clinical parameters would help better predict warfarin doses in Indian patients.     

Evaluation of an Initiation Regimen of Warfarin for International Normalized Ratio Target 2.0 to 3.0

Background: he number of patients on warfarin therapy is rising steadily. Although warfarin is beneficial, it carries a high risk of bleeding, especially if the international normalized ratio (INR) values exceed 3.0. Currently, no warfarin initiation regimens have been developed for the Asian population, especially for Malaysians. Objective: This article describes the efficacy and safety of a new initiation regimen for warfarin among warfarin-naive patients. Method: Data were retrospectively collected from the ambulatory and inpatient settings. Results: A total of 165 patients who each had a target INR of 2.0 to 3.0 were included in the study. The mean age was 57.2 years and 94 patients were male. A total of 108 patients used Regimen 1 (5 mg/5 mg/3mg) and the rest of the patients used Regimen 2 (5 mg/3 mg/3 mg). Most patients used warfarin either for atrial fibrillation (52.1%) or for venous thromboembolism (29.7%). Overall, 88 of the patients had INR values above 50% from the baseline on Day 4. Additionally, 13 patients had INR values of >3.2, which required withholding and lower dose of warfarin. The predicted weekly maintenance warfarin dose (23 ± 0.5 mg/week) was found to have correlated closely with the actual maintenance dose (22.8 ± 0.5 mg/week; r² = 0.75). Nearly two thirds (70.3%) of the patients achieved the target INR on Day 11. Conclusion: The warfarin initiation regimens in this study was simple, safe, and suitable to be used in both ambulatory and inpatient settings for managing warfarin therapy.     

参松养心胶囊致INR值降低2例及文献回顾

目的 探讨参松养心胶囊对华法林抗凝作用的影响、作用机制和处理方法。方法 采用病例回顾方式,1例62岁非瓣膜病房颤女性服用华法林抗凝治疗后INR>2,加用参松养心胶囊4 d后INR降至1.68,停用参松养心胶囊4 d后INR值升至2以上;另1例57岁非瓣膜病房颤男性服用稳定剂量（4.0 mg·d^-1）的华法林抗凝治疗,服用参松养心胶囊后INR值降至1.56,后增加华法林剂量至4.5 mg·d^-1,INR值升至2以上。结果 患者在稳定的华法林治疗剂量基础上加用参松养心胶囊（含有人参）后,减弱了华法林的抗凝效果。可能的机制是人参轻度诱导了CYP2C9,但是尚不能排除人参的血小板抑制作用等其他可能的机制。结论 服用华法林期间应尽可能避免服用人参等草药,如果坚持加用人参及含人参药物后,建议持续监测INR值,并根据INR值调整剂量。     

Warfarin time in therapeutic range and its impact on healthcare resource utilization and costs among patients with nonvalvular atrial fibrillation

Background:

Warfarin is efficacious for reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF). However, the efficacy and safety of warfarin are influenced by its time in therapeutic range (TTR).

Objective:

To assess differences in healthcare resource utilization and costs among NVAF patients with low (<60%) and high (≥60%) warfarin TTRs in an integrated delivery network (IDN) setting.

Methods:

Patients with NVAF were identified from an electronic medical record database. Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests. NVAF patients were grouped into two cohorts: those with warfarin TTR <60% (low TTR) and those with warfarin TTR ≥60% (high TTR). Healthcare resource utilization and costs were evaluated during a 12 month follow-up period. Multivariable regressions were used to assess the impact of different warfarin TTRs on healthcare costs.

Results:

Among the study population, greater than half (54%, n?=?1595) had a low TTR, and 46% (n?=?1356) had a high TTR. Total all-cause healthcare resource utilization was higher among patients in the low TTR cohort vs. the high TTR cohort (number of encounters: 70.2 vs. 56.1, p?<?0.001). After adjusting for patient characteristics, total all-cause healthcare costs and stroke-related healthcare costs were $2398 (p?<?0.001) and $687 (p?=?0.02) higher, respectively, for patients in the low TTR cohort vs. the high TTR cohort.

Limitations:

In this retrospective study, we were only able to evaluate the association and not the causality between healthcare resource utilization and costs with the different warfarin TTRs.

Conclusion:

Many warfarin-treated NVAF patients have a low warfarin TTR. NVAF patients with low vs. patients with high warfarin TTR used healthcare resources to a greater extent, which was reflected in higher healthcare costs.     

Direct costs of warfarin treatment among patients with atrial fibrillation in a Finnish health care setting

ABSTRACT

Objective: The main objective was to estimate the mean direct costs of warfarin treatment for atrial fibrillation (AF) patients. Secondly, the costs of initiating warfarin treatment during a 60-day period and the impact of International Normalized Ratio (INR) and co-morbidities on costs were estimated.

Design and data: The study was performed as a retrospective cohort study over a 12‐month period in a Finnish communal health care setting. All AF patients aged 65 years or older (n = 250) with warfarin treatment were identified from the database of the health service district of an urban area. Patient specific information related to co-morbidities, INR-control, complications and health care resource use were collected. Cost information was obtained from the Finnish national health care unit cost list.

Methods: The effect of treatment balance and other background variables on treatment costs were evaluated using ordinary least squares regression (OLS), log-transformed OLS and generalized linear model (GLM). The mean costs were calculated on the basis of the different models and bias corrected and accelerated (BCa) bootstrap confidence intervals (CIs) were calculated for the mean costs.

Results: The best fitting cost model was log-transformed OLS. The costs of warfarin treatment on the basis of the log-transformed model were 589.82 euros (BCa 95% CI: 586.68–591.99) per patient compared to 616.00 euros (BCa 95% CI: 579.98–652.96) obtained with the OLS-model. For the treatment initiation period, the mean costs were 263 euros (BCa 95% CI: 218.90–314.71). Depending on the way that INR-control was defined, the mean costs were 95.27 euros or 166.92 euros higher for patients who were not in the defined INR-balance.

Conclusions: The INR-control has a significant impact on the warfarin treatment costs. The choice of model influences the estimated mean costs. In addition, different models identify statistically significant effects between different background variables and costs.     

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACT

Objective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome.

Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3?±?10.7 years, mean BP: 158.8?±?14.2/93.4?±?10.0?mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5?mg OD. BP control was defined as <140/90?mmHg for all patients and <130/80?mmHg for those with diabetes mellitus or chronic nephropathy.

Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8?±?9.7/80.5?±?6.9?mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n?=?477), 74.8% of those with diabetes (n?=?214), 75.6% of those with chronic nephropathy (n?=?82), and 85.1% of patients with metabolic syndrome (n?=?745). No case of hypokalemia was reported.

Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.     

Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls

Introduction: Devastating thromboses can complicate heparin-induced thrombocytopenia (HIT) and disseminated intravascular coagulation (DIC). In these disorders, acquired abnormalities of the partial thromboplastin time (PTT) and international normalized ratio (INR) can confound monitoring of PTT- and INR-adjusted anticoagulant therapies, contributing to treatment failure.

Areas covered: Illustrative patient cases of anticoagulant failure due to PTT and INR confounding are discussed. Four different scenarios of thrombosis progression associated with inappropriate anticoagulant interruption/underdosing, contributing to ischemic limb necrosis, are presented: i) PTT confounding of heparin therapy of warfarin-associated microthrombosis complicating cancer hypercoagulability; ii) PTT confounding of direct thrombin inhibitor (DTI) therapy complicating HIT-associated DIC; iii) INR confounding during argatroban–warfarin overlap of HIT-associated deep-vein thrombosis; and iv) PTT confounding of anticoagulant therapy during acute DIC/hepatic necrosis–ischemic limb necrosis syndrome.

Expert opinion: Abnormal coagulation test results at pre-treatment baseline can provide an important clue regarding the risk of subsequent anticoagulant failure due to PTT or INR confounding. Greater awareness of the potential for anticoagulant failure due to PTT and INR confounding could assist clinicians in management of prothrombotic coagulopathies, for example, by choosing alternative anticoagulants (e.g., fondaparinux, danaparoid) that are not monitored by global coagulation assays, or by obtaining specific drug levels (anti-factor Xa levels, DTI levels).     

A general practice assessment of mefruside (‘Baycaron’) in the treatment of oedema and hypertension

Summary

In this multi-centre general practice study 2,557 patients requiring a diuretic for the treatment of oedema and/or hypertension received a mean daily dose of 37.5mg. mefruside for a mean of 67 days, either alone or in addition to other therapy. Mefruside was substituted in those patients already receiving diuretics.

A satisfactory clinical response was shown by 91.1% of patients, 4.1% complained that the diuresis inconvenienced them, and only 1.0% were unable to tolerate the drug. Mild to moderate side-effects were reported in 8.8%.     

Impact of patient attitudes and beliefs to insulin therapy upon initiation,and their attitudinal changes after initiation: the DAWN Japan study

Objective As a part of the Diabetes Attitudes, Wishes and Needs (DAWN) Japan study, a multi-center, questionnaire-based survey conducted between 2004 and 2005, this analysis aimed to (1) explore patients’ attitudes and beliefs contributing to their decision to start insulin therapy, and (2) assess the changes in their attitudes and beliefs after actual initiation.

Methods Insulin-naive patients with type 2 diabetes who were recommended to start insulin therapy (n?=?149) were invited to answer a 21-item questionnaire consisting of five clusters assessing their attitudes and beliefs toward insulin therapy. The questionnaire was administered twice: first upon insulin recommendation, and then 1 month after insulin initiation for those who started and 4 months after for those who did not.

Results Of 130 patients included in the analysis, 74 patients (56.9%) started insulin therapy. ‘Negative image of injections’ and ‘Positive image toward insulin therapy’ were significantly associated with patient decision to start insulin therapy (odds ratios [95% CI]: 0.49 [0.32–0.76] and 2.58 [1.51–4.42], respectively). After insulin initiation, ‘Negative image of injections’, ‘Positive image toward insulin therapy’, ‘Feelings of guilt regarding diabetes self-management’, and ‘Negative image toward insulin therapy’ decreased significantly (P?<?0.001 for all). ‘Social/interpersonal effects’ did not change after insulin initiation.

Conclusions This study demonstrated that patients who started insulin therapy were less likely to have negative images of injections and more likely to have positive images toward insulin therapy. Starting insulin therapy did not deteriorate the patient’s overall impression of therapy. The key limitation is the relatively small sample size (n?=?130). The results suggest that education about the benefits of insulin therapy may help patients who are not ready to initiate insulin overcome their barrier to early insulin initiation and practical support may help those who have already started therapy to maintain its use.     

Dabigatran etexilate,a new oral direct thrombin inhibitor,for stroke prevention in patients with atrial fibrillation

Importance of the field: Warfarin is the only oral anticoagulant recommended for the prevention of ischemic stroke in atrial fibrillation. A newer and safer anticoagulant is needed because of increased hemorrhagic risks with warfarin, difficult-to-maintain therapeutic levels, and higher drug to drug and food interactions.

Areas covered in this review: Dabigatran etexilate is a new, effective, reversible, rapid-acting, oral direct inhibitor of thrombin. This review focuses on the results of major Phase II and III trials conducted to evaluate the use of dabigatran in prevention of stroke in atrial fibrillation.

What the reader will gain: The objective of this paper is to discuss the use of dabigatran for prevention of stroke in patients with atrial fibrillation and to review its major advantages and disadvantages over warfarin.

Take home message: After the recent publication of Phase III trial RE-LY (randomized evaluation of long-term anticoagulation therapy), the use of dabigatran in atrial fibrillation is more clearly defined. A higher dose of dabigatran may be beneficial in patients who have recurrent ischemic events, despite therapeutic levels of warfarin. A lower dose is potentially safer than warfarin because of fewer hemorrhagic complications. Disadvantages include twice-daily dosing, dyspepsia and higher cost.     

Diuretics in clinical practice. Part I: mechanisms of action,pharmacological effects and clinical indications of diuretic compounds

Importance of the field: Diuretics are among the most important drugs of our therapeutic armamentarium and have been broadly used for >?50 years, providing important help towards the treatment of several diseases. Although all diuretics act primarily by impairing sodium reabsorption in the renal tubules, they differ in their mechanism and site of action and, therefore, in their specific pharmacological properties and clinical indications. Loop diuretics are mainly used for oedematous disorders (i.e., cardiac failure, nephrotic syndrome) and for blood pressure and volume control in renal disease; thiazides and related agents are among the most prescribed drugs for hypertension treatment; aldosterone-blockers are traditionally used for primary or secondary aldosteronism; and other diuretic classes have more specific indications.

Areas covered in this review: This article discusses the mechanisms of action, pharmacological effects and clinical indications of the various diuretic classes used in everyday clinical practice, with emphasis on recent knowledge suggesting beneficial effects of certain diuretics on clinical conditions distinct from the traditional indications of these drugs (i.e., heart protection for aldosterone blockers).

What the reader will gain: Reader will gain insights into the effective use of diuretic agents for various medical conditions, representing their established or emerging therapeutic indications.

Take home message: Knowledge of the pharmacologic properties and mechanisms of action of diuretic agents is a prerequisite for the successful choice and effective clinical use of these compounds.     

Effect of setting,monitoring intensity and patient experience on anticoagulation control: a systematic review and meta-analysis of the literature

ABSTRACT

Objectives: To investigate the relationship between time spent in the recommended target International Normalised Ratio (INR) range and the setting and intensity of anti­coagulant monitoring, in both treatment-experienced and treatment-naïve atrial fibrillation (AF) patients receiving oral anticoagulation (OAC) therapy for the prevention of ischaemic stroke.

Research design and methods: Systematic review of published studies on participants with atrial fibrillation on anticoagulation therapy. We compared frequent monitoring (well-controlled, according to a strict protocol) versus infrequent monitoring (frequency representative of routine clinical practice), specialised care versus usual care, and naïve versus prior anticoagulant use. Meta-analysis was performed using a random effects model.

Results: 36 studies were included, 22 (primary data) of AF patients managed in line with the consensus guidelines target INR range of 2.0–3.0, and 14 studies (secondary data) of mixed patient groups, including AF, with an INR target of 2.0–3.5. Both data sets were combined for sensitivity analysis. Pooled mean time in INR range was 59.1% (95% CI: 55.5, 62.8%) and 64.3% (95% CI: 60.5, 68.0%) for infrequent monitoring and frequent monitoring, respectively. Significantly more time was spent in range in specialist care settings compared to usual care: +11.3% (95% CI: 0.1–21.7%). Naïve OAC users spent less time in range 56.5% (95% CI: 45.5–67.5%) than existing users 61.2% (95% CI: 57.2–65.2%). All of these differences were found to be significant in the sensitivity analyses.

Conclusions: INR control is variable and dependent on monitoring intensity and duration of anticoagulant therapy.     

Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study

STUDY OBJECTIVE: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin. DESIGN: Retrospective, matched cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age. MEASUREMENTS AND MAIN RESULTS: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05). CONCLUSION: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.     

基于人工神经网络模型预测华法林服药者国际标准化比值

目的 探究CYP2C9*2、CYP2C9*3、CYP4F2、VKORC11173C>T基因多态性与华法林维持剂量之间的相关性,建立华法林服用者用药后国际标准化比值(international normalized ratio,INR)的人工神经网络预测模型,提高稳定剂量预测准确性。方法 回顾性研究2019—2021年收集的214例服用华法林达到稳定抗凝患者的临床资料与华法林药物基因数据,分析临床因素与各基因型对患者华法林稳态剂量的影响;建立机器学习预测模型,采用模拟输入患者华法林剂量计算INR靶值的方式来预测稳态剂量,与直接剂量预测方法以及多元回归模型对比准确性。结果 多元回归模型对数据集中患者稳态剂量的预测最佳准确度56.4%,机器学习的预测模型输入稳态剂量预测INR值时的平均绝对误差(mean absolute error, MAE)为0.40,R2为0.81,直接预测剂量时MAE为0.52,R2为0.68,在进行分组训练后误差能够降低20.4%,准确率提高7.3%。结论 通过模拟输入药物剂量预测INR的人工神经网络华法林模型能够更准确地预测患者稳态剂量,有利于实现个体化给药...     

Low-dose vitamin K to augment anticoagulation control

STUDY OBJECTIVES: To determine the effect of daily low-dose oral vitamin K supplementation on reducing variations in the international normalized ratios (INRs) in patients taking warfarin. DESIGN: Retrospective analysis. SETTING: Anticoagulation clinic in a large, private-practice hematology group. PATIENTS: Eight motivated patients (three men, five women), aged 45-79 years, receiving anticoagulant therapy with warfarin, whose INRs had been fluctuating for reasons not associated with identifiable changes in diet, warfarin dosage, activity level, illness, or changes in drug therapy. INTERVENTION: Daily supplementation with oral vitamin K, starting with 100 microg/day MEASUREMENTS AND MAIN RESULTS: Anticoagulation providers monitored INR responses; all documented INR values were included in the analysis, even those intentionally allowed outside the therapeutic range when dosages were adjusted for procedures. After dietary vitamin K supplementation, INR fluctuations diminished in nearly all patients. Overall, a significant decrease was noted in the INR standard deviation (p<0.05), and more INRs were in the therapeutic range after the start of supplementation. Allowing for small fluctuations on either side of the target range, the number of INRs within 0.2 units of the target range increased from 32% to 57% (relative increase 76%). Time in range also increased by a similar degree. CONCLUSION: Supplementation with daily low-dose oral vitamin K significantly increased the number of INRs in range as well as the time in range, and decreased INR fluctuation in this small series of selected patients.