Unstable Anticoagulation Research Articles

Stability of vitamin K antagonist anticoagulation after COVID‐19 diagnosis

BackgroundCoagulopathy has been reported in severely ill patients with coronavirus disease 2019 (COVID‐19). It is unclear whether outpatients with COVID‐19 who are treated with vitamin K antagonists (VKAs) have unstable anticoagulation. ObjectiveTo assess the stability of VKA therapy in patients with COVID‐19 through a case‐crossover study. MethodsBetween February and July 2020, we included patients who tested positive for COVID‐19 from two anticoagulant clinics in the Netherlands. We collected international normalized ratios (INRs) determined between 26 weeks before infection and 12 weeks after. Time in therapeutic range (TTR) and the variance growth rate (VGR) were calculated within patients. ResultsFifty‐one patients with COVID‐19 (mean age, 84 years) were included, of whom 15 (29%) were men. Mean TTR in the 26 weeks before COVID‐19 was 80% (95% confidence interval [CI], 75‐85) compared to 59% (95% CI, 51‐68) in the 6 weeks after infection. Mean TTR difference was −23% (95% CI, −32 to −14) with a time above therapeutic range of 38% (95% CI, 30‐47) in the 6 weeks after infection. The TTR rose again to 79% (95% CI, 69‐89) between 6 and 12 weeks after infection. Also, VGR increased, with a mean increase of 4.8 (95% CI, 2.1‐7.5) in the 6 weeks after infection. In the 26 weeks before infection, we registered 19 of 641 (3%) of INR ≥5.0 compared with 35 of 247 (14%) in the 6 weeks after (risk ratio, 4.4; 95% CI, 2.7‐7.3). ConclusionsCOVID‐19 is associated with a strong decrease in TTR and in therapeutic stability in patients taking VKAs. Additional monitoring in these patients is advised to maximize therapeutic stability.

Relative risk of thrombo-embolisms and major bleedings is high in left ventricular assist device patients with unstable anticoagulation control

Background and Aims: Left ventricular assist device (LVAD) patients are at increased risk of thrombo-embolisms and major bleedings, making anticoagulation therapy challenging. Unstable anticoagulant control expressed as high international normalized ratio (INR) variability, is associated with clinical events in atrial fibrillation patients. However, data on this association in LVAD patients are unavailable. We therefore aimed to study the association between anticoagulant control and clinical events in patients with an LVAD.

Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment.

Direct oral anticoagulants (DOACs) or non-vitamin K oral anticoagulants (NOACs) are increasingly used in the prevention of recurrent venous thromboembolism (VTE), including that associated with thrombophilia. The efficacy of DOACs in thrombophilic patients, especially those with severe trombophilia or triple positive antiphospholipid syndrome (APS) with arterial thromboembolic events, remains controversial. Most case reports and case series indicate that DOACs are an attractive therapeutic option in the vast majority of these patients at high risk of recurrent VTE with more concerns raised in high-risk APS patients and these deficient in protein S (PS). Adherence to DOACs is of paramount importance in these patients. In this review we presented available data on the management of patients with thrombophilia using rivaroxaban, dabigatran or apixaban at standard doses. Moreover, we also demonstrated the overall effects of DOACs on coagulation tests, particularly those determined during thrombophilia screening such as lupus anticoagulant, antithrombin, protein C, PS, activated protein C ratio. Despite the paucity of data from randomized studies, the current evidence supports the use of DOACs in thrombophilia, especially those who prefer such treatment or have unstable anticoagulation with vitamin K antagonists or unacceptable adverse events while using these drugs.

The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome

IntroductionAntiphospholipid syndrome (APS) is a common acquired thrombophilia associated with a high thrombotic risk, in which vitamin K antagonists (VKA) represent the mainstay of therapy. Case series involving up to 35 patients with APS suggested limited efficacy and safety of direct oral anticoagulants (DOACs). Material and methodsIn the prospective case series we followed 56 consecutive patients with APS (44 women and 12 men, aged from 22 to 64years), including 33 (60%) associated with systemic lupus erythematosus (SLE) and 16 (28.6%) with triple APS who were treated with DOACs due to their preferences or unstable anticoagulation with VKA. DOACs were started at least 3months since the thromboembolic event in patients with D-dimer below 500ng/ml. ResultsForty-nine (87.5%) patients were treated with rivaroxaban, 4 (7.3%) with dabigatran and 3 (5.4%) with apixaban. During follow-up of 2 to 43 (mean 22) months, 6 (10.7%, 5.8 per 100 patient-years) patients (4 women and 2 men, 4 with triple positive APS) experienced recurrent thrombosis, including deep vein thrombosis (n=4, including 2 episodes preceded by nonadherence), superficial vein thrombosis (n=1) and non-ST elevation myocardial infarction (n=1). The recurrence rate of VTE on DOACs was 5.8 per 100 patient-years. Two patients (3.6%) experienced severe bleeding. ConclusionsThis case-series suggests that DOACs are safe in patients with APS. These findings need to be confirmed in larger studies.

Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G>A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G>A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G>A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G>A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.

Effect of Vitamin K Intake on the Stability of Treatment with Vitamin K Antagonists: A Systematic Review of the Literature.

Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings.

Factors affecting the quality of anticoagulation with warfarin: experience of one cardiac centre.

IntroductionThe risk of complications in anticoagulation therapy can be reduced by maximising the percentage of time spent by the patient in the optimal therapeutic range (TTR). However, little is known about the predictors of anticoagulation control. The aim of this paper was to assess the quality of anticoagulant therapy in patients on warfarin and to identify the factors affecting its deterioration.Material and methodsWe studied 149 patients who required anticoagulant therapy with warfarin due to non-valvular atrial fibrillation and/or venous thromboembolism. Each patient underwent proper training regarding the implemented treatment and remained under constant medical care.ResultsThe mean age of the patients was 68.8 ± 12.6 years, and 59% were male. A total of 2460 international normalised ratio (INR) measurements were collected during the 18-month period. The mean TTR in the studied cohort was 76 ± 21%, and the median was 80%. The level at which high-quality anticoagulation was recorded for this study was based on TTR values above 80%. Seventy-five patients with TTR ≥ 80% were included in the stable anticoagulation group (TTR ≥ 80%); the remaining 74 patients constituted the unstable anticoagulation group (TTR < 80%). According to multivariate stepwise regression analysis, the independent variables increasing the risk of deterioration of anticoagulation quality were: arterial hypertension (OR 2.74 [CI 95%: 1.06-7.10]; p = 0.038), amiodarone therapy (OR 4.22 [CI 95%: 1.30-13.70]; p = 0.017), and obesity (OR 1.11 [CI 95%: 1.02-1.21]; p = 0.013).ConclusionsThe presence of obesity, hypertension, or amiodarone therapy decreases the quality of anticoagulation with warfarin. High quality of anticoagulation can be achieved through proper monitoring and education of patients.

Improving quality measurement for anticoagulation: adding international normalized ratio variability to percent time in therapeutic range.

Among patients receiving warfarin, percent time in therapeutic range (TTR) and international normalized ratio (INR) variability predict adverse events individually. Here, we examined what is added to the prediction of adverse events by using both measures together. We included 40 404 patients anticoagulated for atrial fibrillation, aged 65+, within the Veterans Health Administration. TTR and log-transformed INR variability were calculated for each patient. Our study outcomes were ischemic stroke and major bleeding, defined using International Classification of Diseases-9 codes. We estimated the hazard ratios (HRs) for the study outcomes using 3 nested Cox regression models, including (1) TTR or log INR variability separately; (2) TTR and log INR variability together; and (3) both predictors together plus an interaction term. We divided TTR into 3 categories (high, >70%; moderate, 50% to 70%; low, <50%) and log INR variability into 2 categories (stable and unstable). The reference groups high TTR and stable anticoagulation each denote good control. Higher log INR variability (ie, unstable control) predicted ischemic stroke (HR=1.45, P<0.001) and major bleeding (HR=1.57, P<0.001) independently, regardless of TTR levels. Our model with interaction terms showed that High log INR variability predicted a significantly higher risk for ischemic stroke and major bleeding compared with low log INR variability, at moderate TTR levels (HR= 1.27 and HR=1.29, respectively) and at high TTR levels (HR=1.55 and HR=1.56, respectively), but not at low TTR levels. Unstable anticoagulation predicts warfarin adverse effects independent of TTR. Moreover, knowledge about anticoagulation stability further stratifies the risk for adverse events at given levels of TTR.

The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate

The time in target International Normalized Ratio (INR) range (TIR) is used to assess the control and intensity of oral anticoagulation, but it does not measure variation in the INR. The value of assessing INR variability by use of the variance growth rate (VGR) as a predictor of events was investigated in patients treated with warfarin. Three different methods of VGR determination (A, B1, and B2) together with the TIR were studied. MethodA measures both INR variability and control, but methodsB1 and B2 measure variability only. The VGR and TIR were determined over three time periods: overall follow-up to an event, and 6months and 3months before an event. Six hundred and sixty-one control patients were matched to 158 cases (bleeding, thromboembolism, or death). With all VGR methods, the risk of an event was greater in unstable patients at 6months before an event than in stable patients. MethodA demonstrated the greatest risk 3months before an event in the unstable VGR group as compared with the stable group (odds ratio3.3, 95% confidence interval1.9-5.7, P<0.005). The risk of an event was 1.9 times greater in patients with a low TIR (<39%) than in those with a high TIR (>80%) in the 3-month period (P=0.02). Risk of bleeding was significantly greater in the 3-month period in patients with unstable VGR, with the greatest risk found with method B2 (P<0.01). Patients with unstable anticoagulation have a significantly increased risk of 'clinical events' at 3 and 6months before an event. The VGR can be incorporated into computer-dosage programs, and may offer additional safety when oral anticoagulation is monitored.

Effect of 200μG/day of vitamin k1 on the variability of anticoagulation control in patients on warfarin: A randomized controlled trial

Controversy exists whether low-dose vitamin K supplementation can improve anticoagulation control in patients with unstable anticoagulation under warfarin. In a single- centre randomized, double-blind, placebo-controlled study, we evaluated the effectiveness of 200 μg/day of vitamin K1 in patients with unstable control under warfarin. Effectiveness of Vitamin K1 supplementation was primarily assessed by the percentage (%) of Time-in-Therapeutic-Range (TTR) and secondarily by the standard deviation (SD) of the patient's INR values; the proportion of out-of-range INRs; and the number of dose changes on warfarin. Their change scores were obtained by subtracting the mean value in the 6 months pre-randomization from the mean value in the 6 months post-randomization. Multivariable linear-regressions identified factors associated with anticoagulation instability. Fifty out of 54 patients were analyzed (intervention: n=26; placebo: n=24). Most indications (87%) for anticoagulation were venous thromboembolism (VTE). The intervention was associated with a greater reduction in the change scores for the SD of INRs between the pre and post-randomization periods compared with placebo. The mean change score was -0.259±0.307 with the intervention and -0.046±0.345 with placebo (p=0.026). There was no effect on the change scores of the (%) TTR (p=0.98), the number of INRs out-of-range (p=0.58) and the number of dose changes (p=0.604). Factors independently associated with increased variability in the SD of INRs were increased alcoholic drinks/week (p=0.017), dosing errors (p=0.0009) and missed INR appointments (p=0.035). Vitamin K1 supplementation reduces the SD of INRs as an indicator of the variability in anticoagulation control in patients treated with warfarin for VTE.

Recombinant Thromboplastins vs Tissue-Extract Thromboplastins in Patients on Unstable Oral Anticoagulant Therapy

To the Editor: In a previous report in Clinical Chemistry , we described much higher international normalized ratios (INRs)1 with recombinant Neoplastin R (Roche Diagnostics) than with tissue-extract Neoplastin Plus (Roche Diagnostics) in patients initiating oral anticoagulant therapy (1). For patients on stable oral anticoagulation, we observed no significant differences in INRs between the thromboplastins. The increased INR values with Neoplastin R during unstable anticoagulation, such as in the initial phase of oral anticoagulation treatment, could be explained by fluctuations in coagulation factor VII (FVII) concentrations owing to the low half-life of FVII. Recombinant thromboplastin exhibits an increased sensitivity for FVII compared with tissue-derived thromboplastin (2, 3). The difference in sensitivity between Neoplastin R and Neoplastin Plus for FVII could implicate alterations in anticoagulation dosage and time period in obtaining stable anticoagulation. We investigated whether our findings could be extrapolated to other recombinant thromboplastins. We collected and citrate-treated blood samples from 20 patients in the initial phase of …

The c.-1639G&gt;A polymorphism of the VKORC1 gene in Serbian population: retrospective study of the variability in response to oral anticoagulant therapy

A single nucleotide polymorphism c.-1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral vitamin K antagonist (VKA). Our aim was to study the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in a group of patients under stable anticoagulation, and to estimate the variability in response to VKA. We conducted a retrospective cohort analysis of 200 stable anticoagulation patients followed from the initiation of VKA. Out of 43 low-dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high VKA dose; among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. Patients with GG genotype required 2.6 times higher dose than patients carriers of AA genotype (P < 0.0001). Carriers of AA genotype were more likely to be overanticoagulated during follow-up after initiation of VKA when compared with carriers of the GA and GG genotypes (P < 0.0001). Patients with GG genotype spent more time below therapeutic range compared with patients carriers of AA (P = 0.0328) and GA genotype (P < 0.0001). VKORC1 c.-1639G>A polymorphism significantly influenced VKA dose and represented a good predictor of individuals predisposed to unstable anticoagulation. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients, carriers of AA genotype, before the initiation of anticoagulation.

Switching from acenocoumarol to warfarin in patients with unstable anticoagulation and its effect on anticoagulation control

Unstable oral anticoagulation increases the risk of thrombotic events and bleedings. Acenocoumarol use has been reported to be associated with two-fold higher risk for instability of anticoagulation control compared to warfarin administration. The aim of the study was to evaluate the effect of introducing warfarin on anticoagulation control in patients with a variable response to acenocoumarol. Sixty-eight subjects treated with acenocoumarol for 5 months or more and displaying intraindividual variability of international normalized ratio (INR) results were switched to warfarin. Unstable anticoagulation was defined as a failure to achieve a target INR within the preceding 3 months, i.e. > or = 50% of 8 or more INR values below 2 or above 3.5. Patients with stable anticoagulation (<20% of out-of-range INRs), matched for age, gender, and anticoagulation indications, served as a reference group. Patients with unstable anticoagulation on acenocoumarol had higher body mass index (p<0.01) and serum C-reactive protein levels (p<0.01) compared to stable counterparts. The transition factor between acenocoumarol and warfarin was 1.8 (95% CI 1.69-1.96). The percentage time within the target INR range in patients with unstable anticoagulation was 40.2% at baseline and increased to 60.4% following 6 months on warfarin therapy (p<0.05). The number of subjects with <20% of out-of-range INRs among individuals switched from acenocoumarol to warfarin was 22 (32.4%) vs. 63 (92.6%) in patients on stable anticoagulation after 6 months of follow-up (p<0.001). Switching acenocoumarol to warfarin in patients with unstable anticoagulation can improve anticoagulation control.

The largest prospective warfarin-treated cohort supports genetic forecasting

AbstractGenetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 × 10−34) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 × 10−100). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

Will a once-weekly anticoagulant for the treatment and secondary prevention of thromboembolism improve adherence?

Oral anticoagulation, most commonly with warfarin once daily, has long been the main form of long-term treatment and secondary prevention of thromboembolism. The efficacy of warfarin has been established in clinical trials, but problems with unstable anticoagulation with international normalized ratios (INRs) outside the recommended range due to incorrect dosing, drug and food interactions, and with adherence and persistence have been reported in practice. Poor adherence and persistence are serious problems because they result in out-of-range INRs. Many new thromboembolic events, such as strokes, occur when INRs are out-of-range or after warfarin discontinuation. Among the new anticoagulants currently being investigated, some offer the possibility of more stable anticoagulation and weekly administration. Less frequent dosing schedules generally improve adherence. In many cases, such as bisphosphonate treatment for osteoporosis, and the long-term treatment of depressive disorders or multiple sclerosis, adherence to, and persistence with, weekly dosing is improved compared with daily dosing, and most patients prefer weekly dosing. The advent of novel anticoagulants such as idraparinux with its long half-life offers hope for improved adherence with anticoagulation, and ultimately improved outcomes.

The c.-1639g&gt;A polymorphism of the VKORC1 gene and his influence on the therapeutic response during oral anticoagulants use

A single nucleotide polymorphism c.-1639G > A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G > A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. Out of 43 low dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001). VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients--carriers of AA genotype, before anticoagulation therapy initiation.

Strongly Increased International Normalized Ratio with Recombinant Neoplastin R® Compared with Tissue Extract Neoplastin Plus® in Patients Initiating Oral Anticoagulant Therapy: Implications for Anticoagulation Dosage

High-accuracy determination of the international normalized ratio (INR)1 is of importance in controlling treatment of patients with oral anticoagulants. The INR is defined according to a calibration model adopted by the WHO (1) as the normalized prothrombin clotting time (PT/MNPT)ISI, where MNPT is mean normal prothrombin time of 20 healthy individuals. The factor ISI (international sensitivity index) compensates for the differing sensitivities of thromboplastin reagents used to measure prothrombin clotting time. Thromboplastin reagents can vary widely in their sensitivities to clotting factor deficits (induced by coumarin treatment), resulting in INR differences(2). Recombinant thromboplastins have been discussed as being more sensitive to variation in coagulation factor VII (FVII) than tissue extract thromboplastins(2)(3)(4). FVII has a relatively short plasma half-life of 6 h compared to the half-lives of factor X (45 h) and prothrombin (60 h). The increased sensitivity for FVII may be observed during unstable anticoagulation, such as in the initial phase of oral anticoagulant therapy, and may lead to differences in observed INRs that have implications for subsequent oral anticoagulant dosing advice. To …

Predictors of unstable anticoagulation in African Americans

We sought to identify contributors to unstable anticoagulation in African Americans. Sixty African Americans on warfarin were enrolled. Cytochrome P450 2C9 and vitamin K epoxide reductase genotypes and vitamin K intake were assessed, and clinical and dietary data during the 12 months prior to enrollment were collected. Data were compared between stable and unstable patients, classified based on the proportion of international normalized ratio (INR) values outside the therapeutic range. The median proportion of out-of-range INRs among study participants was 44%; 28 patients had a higher proportion of INRs out-of-range and were included in the unstable group, with the remaining constituting the stable group. The median (IQR) number of clinic visits/year was higher among unstable versus stable patients [18 (15-22) vs. 16 (13-19); P = 0.03]. Higher warfarin doses, lower adherence, vomiting or diarrhea, and use of antiinfective agents were more common among unstable patients. Genotype was not associated with anticoagulation stability. After regression analysis, only poor adherence and gastrointestinal illness remained predictive of unstable anticoagulation. In a control group of Caucasians of similar age and sex distribution, poor adherence, but not gastrointestinal illness, was associated with unstable anticoagulation. We conclude that poor warfarin adherence and gastrointestinal illness are major contributors to unstable anticoagulation in African Americans. Our data suggest that, similar to Caucasians, improving warfarin adherence rates may be an important mean to improve anticoagulation control in African Americans. In addition, close monitoring during acute illness may be particularly important in this population.

Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants.

Variability in the intensity of anticoagulant therapy is considered a risk factor for complications, but it is unclear how best to quantify variability. We evaluated the association of three methods to measure variability with complications of oral anticoagulant therapy. We conducted a nested case-control study within a cohort of patients with prosthetic heart valves. 210 patients with a first hemorrhagic or thrombotic event during follow-up were selected with two controls per case, matched on age and sex. We calculated the time spent at an International Normalized Ratio below, above, and between 2.5 and 4.0, and the variance growth rate according to three different methods (A, B1, B2); method A combines variability and time in range, and methods B1 and B2 purely look at variability. Odds ratios of the variance growth rates for thrombotic events for patients in the second and third tertiles varied between 2 and 3, with the highest odds ratio for complications for the method that purely looked at variability. For hemorrhagic complications, the highest odds ratios were found for method A, which also incorporated time in range, with odds ratios of 2.6 (95% CI: 1.3-5.1) and 3.1 (95% CI: 1.6-6.0) for the second and third tertiles as compared to the first. The combination of time spent out of range with the highest tertile of variability increased the risk 2.6-fold (95% CI: 1.6-4.2) as compared to subjects with stable anticoagulation within the target range. Unstable anticoagulation was associated with hemorrhagic and thrombotic complications. Method A was best associated with complications, but methods B1 and B2, in combination with time spent in range, were equally well associated. As we prefer to disentangle variability and intensity of anticoagulation, we propose to use methods B1 or B2 to reflect pure variability of oral anticoagulant therapy.

Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin

AbstractPatients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts. We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation. Seventy warfarin-treated patients with unstable anticoagulation control were randomly assigned in a double-blinded fashion to receive a daily amount of 150 µg oral vitamin K or placebo orally for 6 months. Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it. Vitamin K supplementation resulted in a significantly greater decrease in standard deviation of international normalized ratio (INR) compared with placebo (−0.24 ± 0.14 vs −0.11 ± 0.18; P < .001) and a significantly greater increase in percentage time within target INR range (28% ± 20% vs 15% ± 20%; P < .01). Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation; of these, 19 fulfilled our criteria for having stable control of anticoagulation. However, only 24 of 33 patients receiving placebo demonstrated some degree of improvement, with only 7 patients fulfilling the criteria for having stable control. Concomitant supplementation of vitamin K, perhaps through reducing the relative day-to-day variability in dietary vitamin K intake, can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin.