Anticoagulation Stability Research Articles

Stability of Anticoagulation Following Acenocoumarin in Stroke Patients: Role of Pharmacogenomics and Acquired Factors.

Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and cerebral venous sinus thrombosis (CVST). We report the role of cytochrome P450 (CYP2C9*2/*3) and vitamin K epoxide reductase subunit 1 (VKORC1) genotypes and acquired causes in maintaining stability of anticoagulation following acenocoumarin in cardioembolic stroke and CVST. The study comprised 157 individuals with cardioembolic stroke and CVST who were on acenocoumarin. Their comorbidities, comedication, and dietary habits were noted. Prothrombin time and international normalized ratio (INR) were measured during follow-up, and the coagulation status was categorized as stable (>50% occasions in therapeutic range) and unstable (>50% below and above therapeutic range). Genotyping of VKORC1, CYP2C9*2, and CYP2C9*3 was done by polymerase chain reaction-restriction fragment length polymorphism. Bleeding and embolic complications were noted. The predictors of unstable INR were evaluated using multivariate analysis. INR was stable in 47.8% and unstable in 52.2% of patients. Patients with mutant genotypes required low dose of acenocoumarin. The predictors of unstable INR were metallic valve (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.23-13.49, P = 0.02), use of digoxin (OR 0.031, 95% CI 0.13-0.74, P = 0.09), proton pump inhibitor (OR 0.23, 95% CI 0.06-0.91, P = 0.037), sodium valproate (OR 0.22, 95% CI 0.05-0.85, P = 0.029), and CYP2C9*2 genotype (OR 5.57, 95% CI 1.19-26.06, P = 0.02). Variant genotypes of VKORC1, CYP2C9*2, and CYP2C9*3 required lower dose of acenocoumarin, and CYP2C9*2 was associated with unstable INR. Comedication is a modifiable risk factor that needs attention.

Risk factors for serious adverse events related to vitamin K antagonists in children with congenital or acquired heart disease: a prospective cohort study

ObjectivesTo assess the occurrence of thrombosis and major bleeding in children with congenital or acquired heart disease (CAHD) treated with VKA and to identify risk factors for these serious adverse events (SAE). Study designAll children enrolled in our VKA dedicated educational program between 2008 and 2022 were prospectively included. The time in therapeutic range (TTR) was calculated to evaluate the stability of anticoagulation. Statistical analysis included Cox proportional hazard models. ResultsWe included 405 patients. Median follow-up was 18.7 (9.3–49.4) months. The median TTR was 83.1 % (74.4 %–95.3 %). No deaths occurred because of bleeding or thrombotic events. The incidences of thrombotic and major bleeding events were 0.9 % (CI95 % [0.1–1.8]) and 2.3 % (CI95 % [0.9–3.8]) per patient year, respectively. At 1 and 5 years, 98.3 % (CI95 % [96.2 %–99.2 %]) and 88.7 % (CI95 % [81.9 % 93.1 %]) of patients were free of any SAE, respectively. Although the mechanical mitral valve (MMV) was associated to major bleeding events (HR = 3.1 CI95 % [1.2–8.2], p = 0.02) in univariate analysis, only recurrent minor bleeding events (HR = 4.3 CI95 % [1.6–11.7], p < 0.01) and global TTR under 70 % (HR = 4.7 CI95 % [1.5–15.1], p < 0.01) were independent risk factors in multivariable analysis. In multivariable analysis, giant coronary aneurysms after Kawasaki disease (HR = 7.8 [1.9–32.0], p = 0.005) was the only risk factor for thrombotic events. ConclusionOverall, VKA therapy appears to be safe in children with CAHD. Suboptimal TTR, regardless of the indication for VKA initiation, was associated with bleeding events.

DOES THE TIMING OF WARFARIN INGESTION AFFECT THE TIME IN THERAPEUTIC RANGE IN PATIENTS WITH METALLIC PROSTHETIC VALVE?

Aim: Warfarin , a vitamin K antagonist, is the only approved oral agent to provide anticoagulation in patients with metallic prosthetic valves. Since effectively initiating and maintaining anticoagulation is challenging due to various factors , those patients undergo frequent periodic INR testing. The aim of this study was to investigate the effect of the timing of warfarin ingestion on the stability of anticoagulation.&#x0D; Materials and Methods: A total of 60 patients with metallic prosthetic valves were included in the study. First, all the patients were informed to take warfarin between 19:30 and 20:00 during the first month, then to take warfarin between 09:30 and 10:00 during the second month. All the patients underwent INR monitoring once every 15 days during the follow-up period. The time in therapeutic range (TTR) values for the first month and second month ( referred to as ‘first TTR’ and ‘second TTR’, respectively) were calculated separately using the Rosendaal method. &#x0D; Results: The mean age ( ± SD) of the patients was 59.6 ± 9.6 years and 36.7% (n=22) were male. There was no significant difference between the first TTR and second TTR values of the patients (66.23 ± 40.7% vs 64.12 ± 41.13%, p=0.783). The mean INR value in the first month was found to be significantly lower than in the second month (2.73 ± 0.53 vs 3.06 ± 0.47, p=0.001). &#x0D; Conclusion:.The study results showed that the timing of warfarin ingestion did not affect the stability of anticoagulation although taking the warfarin in the morning provided higher INR values.

The effect of COVID-19 vaccination on anticoagulation stability in adolescents and young adults using vitamin K antagonists

IntroductionThe European Medicine Agency has authorized COVID-19 vaccination in adolescents and young adults (AYAs) from 12 years onwards. In elderly vitamin K antagonist (VKA) users, COVID-19 vaccination has been associated with an increased risk of supra- and subtherapeutic INRs. Whether this association is also observed in AYAs using VKA is unknown. Our aim was to describe the stability of anticoagulation after COVID-19 vaccination in AYA VKA users. Materials and methodsA case-crossover study was performed in a cohort of AYAs (12–30 years) using VKAs. The most recent INR results before vaccination, the reference period, were compared with the most recent INR after the first and, if applicable, second vaccination. Several sensitivity analyses were performed in which we restricted our analysis to stable patients and patients without interacting events. Results101 AYAs were included, with a median age [IQR] of 25 [7] years, of whom 51.5 % were male and 68.3 % used acenocoumarol. We observed a decrease of 20.8 % in INRs within range after the first vaccination, due to an increase of 16.8 % in supratherapeutic INRs. These results were verified in our sensitivity analyses. No differences were observed after the second vaccination compared to before and after the first vaccination. Complications after vaccination occurred less often than before vaccination (9.0 vs 3.0 bleedings) and were non-severe. Conclusionsthe stability of anticoagulation after COVID-19 vaccination was decreased in AYA VKA users. However, the decrease might not be clinically relevant as no increase of complications nor significant dose adjustments were observed.

Anticoagulation Stability With Bivalirudin: Positioning the Horse Before the Cart.

To the Editor: We thank Dr. Seelhammer and colleagues for their interest in our article1 and for the opportunity to expound upon on several key points. With significantly increased use of bivalirudin over the past decade, we acknowledge the need for larger, multicenter collaboration to generate more definitive conclusions in the superiority of bivalirudin used in pediatric Berlin Heart recipients versus unfractionated heparin (UFH). The preferred use of bivalirudin has occurred largely in the absence of robust published evidence. It is our hope that the article is one of many that provides support of this change. We agree that anti-Xa monitoring should be considered over activated partial thromboplastin time (aPTT) in patients anticoagulated on UFH secondary to the impact of inflammation and disseminated intravascular coagulopathy on aPTT. Significant assay variability and center-specific ranges make application across centers challenging. Although inter-reagent differences in anti-Xa have been described,2 we expect more consistent results given that Berlin Hearts (over time) have more pronounced proinflammatory activation compared to other mechanical support devices—translating into greater difficulties with anticoagulation interpretation. This explains some of the discordance of our concurrently drawn aPTT and anti-Xa values, and the difference in our anticoagulation stability findings. We also recognize the limitation of aPTT with bivalirudin use as well and like many centers are working towards access to dilute thrombin time monitoring. We appreciate the request for additional information regarding renal impairment in the bivalirudin group, and have attached Figure 1 which displays the first 21 days of bivalirudin initiation with the infusion rates (mg/kg/hour) plotted alongside estimated glomerular filtration rate (eGFR)-normalized infusion rates for review.Figure 1.: Bivalirudin infusion rates over first 21 days of anticoagulation initiation.Regarding VAD-itis, compared to other devices, Berlin Hearts have a greater perturbation of immune homeostasis, translating into elevated risk for adverse events such as thromboembolism.3,4 These patients are accounted for by the action of treatment with corticosteroids used to attenuate the immune response, and the judgment of the multidisciplinary heart failure team based on elevated laboratory values as recommended by Advanced Cardiac Therapies Improving Outcomes Network’s harmonized protocol rather than any isolated immunologic variable. We are in agreement with Seelhammer et al. that differences in aspirin dosing intensity confers confoundment in thrombotic outcomes, and is accounted for within our limitations. As discussed, higher aspirin utilization with bivalirudin was secondary to the later adoption of the modified Stanford protocol5 and not due to the prevalence of VAD-itis. It is plausible that the UFH patients experienced the same phenomenon of VAD-itis, under-recognized during that era of management, and thus undertreated leading to a greater procoagulant milieu in those patients. At present, this is the only study to compare the use of bivalirudin to UFH in this patient population. Our hypothesis is that greater anticoagulation stability may translate into improved patient outcomes—the former of which we identified in our study. The latter will have to wait for larger, multicenter collaboration. We encourage other centers to publish their experiences in order to reposition the data in front of the practice at-large.

The Relationship Among Intestinal Bacteria, Vitamin K and Response of Vitamin K Antagonist: A Review of Evidence and Potential Mechanism.

The vitamin K antagonist is a commonly prescribed effective oral anticoagulant with a narrow therapeutic range, and the dose requirements for different patients varied greatly. In recent years, studies on human intestinal microbiome have provided many valuable insights into disease development and drug reactions. A lot of studies indicated the potential relationship between microbiome and the vitamin K antagonist. Vitamin K is absorbed by the gut, and the intestinal bacteria are a major source of vitamin K in human body. A combined use of the vitamin K antagonist and antibiotics may result in an increase in INR, thus elevating the risk of bleeding, while vitamin K supplementation can improve stability of anticoagulation for oral vitamin K antagonist treatment. Recently, how intestinal bacteria affect the response of the vitamin K antagonist remains unclear. In this review, we reviewed the research, focusing on the physiology of vitamin K in the anticoagulation treatment, and investigated the potential pathways of intestinal bacteria affecting the reaction of the vitamin K antagonist.

Time in therapeutic range is lower in women than in men and is not explained by differences in age or comorbidity

BackgroundTime in therapeutic range (TTR) measures the stability of the international normalized ratio in patients on vitamin K antagonists (VKA). Low values are associated with poor outcomes. Women were shown to have lower TTR than men, but the causes are poorly defined. It was suggested that women on VKA are older and more morbid than men, and this could affect the stability of anticoagulation. We aimed to identify variables that affect TTR differently in women and men. Materials and methodsThis is a retrospective study in patients referred to a University hospital anticoagulant clinic. Age, sex, comorbidities, number of daily medications, indication and type of anticoagulant, weekly dosage and distribution, were derived from electronic records. Differences by sex and regression analysis to identify significant modulators of TTR were computed. Results1182 women and 1281 men on VKA were studied. Women were older than men (81.5 yrs. ± 11.2 vs 78.4 yrs. ± 12.2), and had lower TTR (65% ± 20.3 vs 69% ± 19.8). Comorbidity was similar between sexes and negatively affected TTR in both. Mechanical valves as an indication to anticoagulation and acenocoumarol as an anticoagulant as opposed to warfarin had a strong negative influence on TTR, while age increased TTR. Being a man rather than a woman afforded more than three TTR points. Number of medications and average anticoagulant dose were equal between sexes. DiscussionWomen have a lower TTR than men, on average below the safety threshold. They were indeed older, but age positively influenced TTR. Since women and men were equally comorbid, neither age nor disease explains differences in TTR. None of the other variables included in the study could explain the gender gap in TTR. Since women are at increased risk of cardioembolic stroke in atrial fibrillation, an effort at defining other causes for the observed differences, closer monitoring and switching to direct anticoagulants whenever possible is warranted.

The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial.

Without supporting evidence, clinicians commonly recommend that warfarin be taken in the evening. We conducted a randomized controlled trial to evaluate the effect of administration time (morning vs evening) on the stability of warfarin's anticoagulant effect. A total of 236 primary care physicians serving 54 western Canadian communities mailed letters of invitation to all their warfarin-using patients. Eligible patients were community-dwelling warfarin users (any indication) with at least 3 months of evening warfarin use and no plans for discontinuation. Participants were randomized (by web-based allocation) to morning vs continued evening warfarin ingestion. We used the Rosendaal method to determine the proportion of time within therapeutic range (TTR) of the international normalized ratio (INR) blood test month 2 to 7 postrandomization vs the 6 months prerandomization. The primary outcome was the percent change in proportion of time outside target INR range (with an a priori minimum clinically important difference of ±20%). All analyses were intention to treat. Between March 8, 2015 and September 30, 2016, we randomized 109 participants to morning and 108 to evening warfarin use. TTR rose from 71.8% to 74.7% in the morning group, and from 72.6% to 75.6% in the evening group, for a change in TTR of 2.9% in the former vs 3.0% in the latter (difference, -0.1%; P = .97; 95% CI for the difference, -6.1% to 5.9%). The difference in percent change in proportion of time outside the therapeutic INR range (obtained via Hodges-Lehmann estimation of the difference in medians) was 4.4% (P = .62; 95% CI for the difference, -17.6% to 27.3%). Administration time has no statistically significant nor clinically important impact on the stability of warfarin's anticoagulant effect. Patients should take warfarin whenever regular compliance would be easiest.

Increasing Dietary Vitamin K Intake Stabilizes Anticoagulation Therapy in Warfarin-Treated Patients with a History of Instability: A 24-week Randomized Controlled Trial (OR36-04-19)

ObjectivesWarfarin (W) is a highly prescribed anticoagulant for the treatment and prevention of thromboembolic diseases. However, anticoagulation stability is often a challenge due to the narrow therapeutic range of the drug. In recent years, dietary vitamin K (VK) has emerged as an important modulator of long-term anticoagulation stability. In trials, patients receiving small doses of supplemental VK (100–150 mg/d) spend significantly more time in the therapeutic range (%TTR) and present fewer bleeding and thrombotic complications. Whether similar beneficial effects can be achieved through diet remains unknown. We determined whether increasing dietary VK intake by ≥150 μg/day improves anticoagulation stability of W-treated patients with a history of INR instability. MethodsWe conducted a 24-week randomized controlled trial at the Anticoagulation Clinics of the Montreal Heart Institute and the Jewish General Hospital (Montreal). The main inclusion criteria were: 1) be anticoagulated for >6 months with a target international normalized ratio (INR) range of 2.0–3.0 or 2.5–3.5, and 2) present a %TTR <50% in the previous 6 months. Patients randomized to the intervention group (VK) received dietary counsel to increase their VK intake by ≥150 μd/day through specific food choices, recipes and cooking strategies. Patients from the control (C) group received general dietary information of similar intensity. Warfarin therapy was monitored weekly by INR. The primary clinical outcome was anticoagulation stability as defined by %TTR > 70% during weeks 4 through 24. Groups were compared in an intention-to-treat method using the exact Fisher test. ResultsIn total, 49 patients aged 32–85 years completed the study. Mean (±SEM) %TTR over the assessment period were 67.7 ± 3.4 and 61.4 ± 3.5 for the VK and C groups, respectively (ns). Increasing dietary VK intakes resulted in a greater proportion of patients with %TTR > 70% over the assessment period. Specifically, 14 of the 28 patients (50%) from the VK group met the criteria versus 4 of the 21 patients (19%) from the C group (P = 0.026). ConclusionsIncreasing VK intake ≥150 μd/day through diet strategies improves anticoagulation stability of W-treated patients with a history of anticoagulation instability. Funding SourcesThis study was funded by the CIHR.

Oral anticoagulant monitoring: Are we on the right track?

Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.

The Role of Clinical Variables and VKORC1 Polymorphism in Efficacy and Stability of Acenocoumarol in Neurological Patients.

Objective:To analyze the clinical importance of VKORC1 polymorphism and its correlation with stability of oral anticoagulation.Patients and Methods:In a hospital-based study, the patients on oral anticoagulant (OAC) were included during 2013–2016. The patients received OAC for cardioembolic stroke, cerebral venous sinus thrombosis (CVST), and prevention of deep vein thrombosis (DVT). Demographic, clinical, and neurological findings were recorded. Stability of anticoagulation was determined by percentage of time international normalized ratio (INR) values were in therapeutic range. Time in therapeutic range (TTR) >65% was defined as stable and <65% was defined unstable. VKORC 1 polymorphism was studied by polymerase chain reaction and correlated with daily dose of OAC and stability of INR.Results:A total of 157 patients with a median age of 40 years were included in the study. Ninety-two patients received OAC for secondary stroke prevention, 62 for CVST, and 3 for DVT. Out of 2976 INR reports, 1458 (49%) were in the therapeutic range, 997 (33.1%) were below the therapeutic range, and 521 (17.5%) were above the therapeutic level. Stable INR was obtained in 75 (47.77%) patients which was improved by drug modification in 3 and dietary adjustment in 12 patients. VKORC1 polymorphism revealed GG genotype in 127 (80.9%), GA genotype in 22 (14%), and AA genotype in 8 (5.1%) patients. Therapeutic range of INR was seen in 49%, below therapeutic range was seen in 31.5%, and above in 17.5%.Conclusion:VKORC1 polymorphism was related to mean daily dose of OAC but not to the stability of INR.

Bleeding predictors in patients following venous thromboembolism treated with vitamin K antagonists: Association with increased number of single nucleotide polymorphisms

IntroductionSingle nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE). Materials and methodsIn 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleeds within the preceding 24 months. We assessed eight SNP, including those in cytochrome P450 isoform 2C9 (CYP2C9) and isoform 4F2 (CYP4F2), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), apolipoprotein E (APOE) and multidrug resistance gene 1 (MDR1). ResultsWithin 48 months before enrolment, bleeding events occurred in 80 (25%) patients, including 14 (4%) major bleeds. Patients with bleeds had 16.2% lower median time in therapeutic range (TTR) and were more often carriers of CYP2C9*3 variant (26 [33%] vs. 19 [8%], p < 0.001) compared with the remainder. Bleeding occurred more frequently in patients with ≥4 SNP compared with the remainder (27 [34%] vs. 47 [19%], p = 0.009) with no intergroup differences of TTR. Number of SNP was one of the predictors of any bleeding. The regression model for major bleeding including factors such as CYP2C9*3 c. 1075 C, VKORC1 c. -1639 A and APOE c. 388 C showed good predictive ability (area under the curve - 0.79). ConclusionsIn VTE patients on the maintenance treatment with VKA, bleeding episodes are associated with CYP2C9 gene variations and increased number of SNP of genes involved in the action and metabolism of VKA.

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

ABSTRACTIntroduction: 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.

Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.

Fiix-prothrombin time (Fiix-PT) differs from traditional PT in being affected by reduced factor (F) II or FX only. In the randomized controlled Fiix-trial, patients on warfarin monitored with Fiix-PT (Fiix-warfarin patients) had fewer thromboembolisms (TE), similar major bleeding (MB) and more stable anticoagulation than patients monitored with PT (PT-warfarin patients). In the current Fiix-trial report we analyzed how reduced anticoagulation variability during Fiix-PT monitoring was reflected in patients with TE or bleeding. Data from 1143 randomized patients was used. We analyzed the groups for anticoagulation intensity (time within target range; TTR), international normalized ratio (INR) variability (variance growth rate B1; VGR) and dose adjustment frequency. We assessed how these parameters associated with clinically relevant vascular events (CRVE), ie TE or MB or clinically relevant non-MB. TTR was highest in Fiix-warfarin patients without CRVE (median 82%;IQR 72-91) and lowest in PT-warfarin patients with TE (62%;56-81). VGR was lowest in Fiix-warfarin patients without CRVE (median VGR B1 0.17; 95% CI 0.08-0.38) and with TE (0.20;0.07-0.26) and highest in PT-warfarin patients with TE (0.50;0.27-0.90) or MB (0.59;0.07-1.36). The mean annual dose adjustment frequency was lowest in Fiix-warfarin patients with TE (mean 5.4;95% CI 3.9-7.3) and without CRVE (mean 6.0; 5.8-6.2) and highest in PT-warfarin patients with TE (14.2;12.2-16.3). Frequent dose changes predicted MB in both study arms. Compared to patients monitored with PT, high anticoagulation stability in Fiix-warfarin patients coincided with their low TE rate. Those with bleeding had high variability irrespective of monitoring method. Thus, although further improvements are needed to reduce bleeding, stabilization of anticoagulation by Fiix-PT monitoring associates with reduced TE.

Genetic determinants of variability in warfarin response after the dose-titration phase.

Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans. One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR. The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.

Effect of medication timing on anticoagulation stability in users of warfarin (the INRange RCT): study protocol for a randomized controlled trial.

BackgroundWarfarin is an oral anticoagulant medication that disrupts the liver’s production of clotting factors. While this medication is highly effective for the prevention of thromboembolic events, it also has a narrow therapeutic range and a vulnerability to interactions with other drugs and vitamin K-containing foods. Warfarin is commonly ingested at dinnertime, the same time of day that dietary vitamin K consumption (found largely in green leafy vegetables) is most variable. While the long half-life of warfarin might make this irrelevant, the ultra short half-life of vitamin K and the possibility of a hepatic first-pass effect for warfarin make it worth evaluating whether morning ingestion of warfarin, when vitamin K levels are consistently low, leads to greater stability of its anticoagulant effect. An examination of the timing of administration on the effectiveness of warfarin has never before been conducted.Methods/designThis is a 7-month Prospective Randomized Open Blinded End-point (PROBE) study in which established evening warfarin users (primary care managed Canadian outpatients in the provinces of British Columbia and Alberta) will be randomized to either switch to morning ingestion of warfarin (the intervention) or to continue with evening use (the control). The primary outcome is the percent change in the proportion of time spent outside the therapeutic range of the international normalized ratio (INR) blood test. Secondary outcomes include change in proportion of time spent within the therapeutic INR range (TTR), percentage of patients with TTR >75 %, percentage of patients with TTR <60 %, and major warfarin-related cardiovascular events (including all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis/pulmonary embolism). We will also compare whether day-to-day variability in the consumption of high vitamin K-containing foods at baseline affects the baseline TTR in this cohort of evening warfarin users.DiscussionThis study addresses whether the timing of warfarin ingestion influences the stability of its anticoagulant effect. Should morning ingestion prove superior, the safety and effectiveness of this medication, and hence the prevention of stroke, pulmonary embolus, and major hemorrhage, could potentially be improved with no added cost or inconvenience to the patient.Trial registrationClinicalTrials.gov: NCT02376803. Registered on 25 February 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1516-9) contains supplementary material, which is available to authorized users.

Stability of High-Quality Warfarin Anticoagulation in a Community-Based Atrial Fibrillation Cohort: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.

BackgroundWarfarin reduces ischemic stroke risk in atrial fibrillation (AF) but increases bleeding risk. Novel anticoagulants challenge warfarin as stroke‐preventive therapy for AF. They are available at fixed doses but are more costly. Warfarin anticoagulation at a time in therapeutic range (TTR) ≥70% is similarly as effective and safe as novel anticoagulants. It is unclear whether AF patients with TTR ≥70% will remain stably anticoagulated and avoid the need to switch to a novel anticoagulant. We assessed stability of warfarin anticoagulation in AF patients with an initial TTR ≥70%.Methods and ResultsWithin the community‐based Anticoagulation and Risk Factors in AF (ATRIA) cohort followed from 1996 to 2003, we identified 2841 new warfarin users who continued warfarin over 9 months. We excluded months 1 to 3 to achieve a stable dose. For the 987 patients with TTR ≥70% in an initial 6‐month period (TTR 1; months 4–9), we described the distribution of TTR 2 (months 10–15) and assessed multivariable correlates of persistent TTR ≥70%. Of patients with TTR 1 ≥70%, 57% persisted with TTR 2 ≥70% and 16% deteriorated to TTR 2 <50%. Only initial TTR 1 ≥90% (adjusted odds ratio 1.47, 95% CI 1.07–2.01) independently predicted TTR 2 ≥70%. Heart failure was moderately associated with marked deterioration (TTR 2 <50%); adjusted odds ratio 1.45, 95% CI 1.00–2.10.ConclusionsNearly 60% of AF patients with high‐quality TTR1 on warfarin maintained TTR ≥70% over the next 6 months. A minority deteriorated to very poor TTR. Patient features did not strongly predict TTR in the second 6‐month period. Our analyses support watchful waiting for AF patients with initial high‐quality warfarin anticoagulation before considering alternative anticoagulants.

Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True?: A Systematic Review.

Educational advice is often given to patients starting treatment with vitamin K Antagonists (VKAs). A great emphasis is made on nutritional information. Common belief is that dietary vitamin K intake could counteract the anticoagulant effect by VKAs and for many years, patients have been discouraged to consume vitamin-K-rich foods, such as green leafy vegetables.The objective of this study is to summarize the current evidence supporting the putative interaction between dietary vitamin K intake and changes in INR with the VKAs.Data sources are MEDLINE via PubMed and Cochrane database.All clinical studies investigating the relationship between dietary vitamin K and measures of anticoagulation were included. We excluded all studies of supplementation of vitamin K alone.We performed a systematic review of the literature up to October 2015, searching for a combination of “food,” “diet,” “vitamin K,” “phylloquinone,” “warfarin,” “INR,” “coagulation,” and “anticoagulant.”Two dietary interventional trials and 9 observational studies were included. We found conflicting evidence on the effect of dietary intake of vitamin K on coagulation response. Some studies found a negative correlation between vitamin K intake and INR changes, while others suggested that a minimum amount of vitamin K is required to maintain an adequate anticoagulation. Median dietary intake of vitamin K1 ranged from 76 to 217 μg/day among studies, and an effect on coagulation may be detected only for high amount of vitamin intake (>150 μg/day).Most studies included patients with various indications for VKAs therapy, such as atrial fibrillation, prosthetic heart valves, and venous thromboembolism. Thus, INR target was dishomogeneous and no subanalyses for specific populations or different anticoagulants were conducted. Measures used to evaluate anticoagulation stability were variable.The available evidence does not support current advice to modify dietary habits when starting therapy with VKAs. Restriction of dietary vitamin K intake does not seem to be a valid strategy to improve anticoagulation quality with VKAs. It would be, perhaps, more relevant to maintain stable dietary habit, avoiding wide changes in the intake of vitamin K.

Abstract WP303: Stability of High-Quality Warfarin Anticoagulation in a Community-Based Atrial Fibrillation Cohort: The ATRIA Study

Introduction: Warfarin reduces stroke risk in atrial fibrillation (AF), but increases bleed risk. Frequent testing with dose adjustment is needed to maintain INR levels in the therapeutic range of 2.0-3.0. Novel anticoagulants (NOACs) now challenge warfarin as stroke-preventive therapy for AF. They are available at fixed doses but costlier. Warfarin anticoagulation at a time in therapeutic range (TTR) ≥70% is similarly effective and safe as NOACs. It is unclear whether AF patients with TTR ≥70% will remain stably anticoagulated and avoid the need to switch to a NOAC. We assessed stability of warfarin anticoagulation in AF patients with an initial TTR ≥70% primarily managed by anticoagulation clinics. Hypothesis: AF patients who achieve TTR ≥70% in the first 6 months of warfarin therapy will maintain high TTR subsequently. Methods: Within the community-based ATRIA cohort of AF patients, we identified 2521 new warfarin users who continued warfarin therapy over 15 months. We excluded months 1-3 to achieve stable dose. For patients with TTR1 (months 4-9) ≥70% (TTR by Rosendaal method), we describe the distribution of TTR2 (months 10-15) and assess multivariable (logistic regression) correlates of persistent TTR ≥70%. Results: Of 1074 patients with TTR1 ≥70%, 57% (95%CI: 53-61%) persisted with TTR2 ≥70% (Figure). Of multiple patient features, only initial TTR1 ≥90%, aOR [95% CI]: 1.43 [1.05,1.93]); and heart failure aOR: 0.78 [0.57, 1.06]) independently predicted TTR2 ≥70%. Conclusions: Nearly 60% of AF patients with high quality initial 6-month TTR on warfarin will maintain TTR ≥70% over the next 6 months. A minority deteriorate to very poor TTR. Patient features do not strongly predict deterioration. Our analyses support watchful waiting for AF patients with initial high quality warfarin anticoagulation before switching to a NOAC.

Gender Differences during Long-Term Warfarin Anticoagulation in Patients with Atrial Fibrillation Monitored with Fiix-Prothrombin Time or Prothrombin Time. the Fiix Trial

Background: During warfarin treatment rapid fluctuations occur in the traditional prothrombin time (PT) as a result of the short half-life of factor (F) VII which has little effect on the antithrombotic activity of warfarin, contrary to FII and FX. Such confounding INR fluctuations influence dosing and, hence also the variability of FII and FX. The new Fiix-PT measures only the activity of the longer half-life FII and FX leading to less variability of anticoagulation as shown in the Fiix-trial.Objectives: To assess if stability of warfarin anticoagulation monitored by PT and Fiix-PT was affected differently by gender.Methods: This study is a subgroup analysis of the prospective, randomized, double-blind Fiix-trial. A subgroup of 815 atrial fibrillation patients on long-term warfarin monitored with Fiix-PT (Fiix-warfarin patients) or PT (PT-warfarin patients) were assessed in an intention-to-monitor manner by comparing surrogate anticoagulation indicators such as dose and dose frequency, time in therapeutic range (TTR, Rosendaal method) and variance growth rate of the INR (VGR; an indicator of INR fluctuation size).Results: Baseline parameters between the 396 Fiix-warfarin and 419 PT-warfarin patients did not differ. The median observation time was 1.4 years. Fiix-warfarin patients had more tests within therapeutic range (66% vs 63%, p=0.0019) and fewer tests below range (19% vs 21%, p=0.0061) than PT-warfarin patients. The test-in-range improvement observed with Fiix-warfarin over that with PT-warfarin was mainly explained by an improvement observed in women, i.e. the fraction of monitoring tests within range was higher (64% vs 59%, p=0.0001) and the fraction below range was lower (20% vs 24%, p=0.0002) in women on Fiix-warfarin. Likewise, with Fiix-warfarin TTR was higher (81% compared with 79%) and this was mainly explained by higher TTR in women on Fiix-warfarin (80%) than in women on PT-warfarin (75%; p=0.0401). Little difference was observed in TTR in men. The INR varied less with Fiix-warfarin than with PT-warfarin (VGRB1 0.20 vs 0.24, p=0.0810). There was significantly more variation in VGR in women than in men. Thus, Fiix-warfarin men vs women had a VGRB1 of 0.18 vs 0.25, p=0.0372, and PT-warfarin men vs women had VGRB1 0.21 vs 0.30, p=0.0056. A trend for fewer annual dose changes with Fiix-warfarin than with PT-warfarin was observed (5.6 vs 6.2 annually, p=0.0822) and this was mainly explained by 20% fewer annual dose changes with Fiix-warfarin than with PT-warfarin in women (6.0 vs 7.4, p=0.0342). Also, there were fewer dose changes per monitoring test in Fiix warfarin women (0.27 vs 0.32, p=0.0292). Finally, women treated with Fiix-warfarin used a lower median daily warfarin dose than women treated with PT-warfarin (3.4 vs 4.2 mg, p=0.0029).Conclusions: Monitoring warfarin with the Fiix-PT improved the stability of warfarin anticoagulation and reduced the daily dose significantly in women. A non-significant but consistent smaller effect in the same direction was seen in men. DisclosuresGudmundsdottir:Fiix Diagnostics Ltd.: Equity Ownership, Patents & Royalties: Patent pending for Fiix prothrombin time. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: Patent pending status for Fiix prothrombin time.