Percentage Of Time In Therapeutic Range Research Articles

Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice

AimThe anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range.MethodsWe conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR.ResultsA total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4.ConclusionWe confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period.

Supra-therapeutic Anticoagulation with Warfarin: A Cross-sectional Study.

To identify the extent and associated factors for patients with prolonged prothrombin time, international normalized ratio (PT-INR), and the dosage modifications were carried out with warfarin. Studies evaluating patients on warfarin with supratherapeutic anticoagulation are limited. It is vital to understand the management strategies for patients receiving warfarin who are bleeding and those with only supratherapeutic PT-INR. To evaluate the factors associated with supratherapeutic anticoagulation without bleeding with warfarin. A cross-sectional study was carried out on patients receiving long-term warfarin with at least one PT-INR value > 3.2. Percent time in therapeutic range (TTR) was calculated and National Institute for Health and Care Excellence (NICE) guidelines were adhered to defining anticoagulation control into good (> 65%) and poor (< 65%). One hundred and forty-four patients were recruited. Nearly half of the study population had PT-INR values between 3.2 and 3.9. On average, individuals had at least 4 times PT-INR values in the supratherapeutic range. Elderly patients were observed with a significant trend of supratherapeutic INR. Duration of therapy was significantly correlated with the risk of PT-INR > 4. Lower TTR was observed in patients with frequent PT-INR > 4 and those patients had significantly poor anticoagulation control. Duration of warfarin therapy and HAS-BLED scores were observed to be significant predictors of supratherapeutic INR. Large variations were observed in the modifications of warfarin dose carried out at various supratherapeutic INR values and consequently PTINR values. We observed that the majority of patients with supratherapeutic INR had their INR values between 3.2 and 3.9. Elderly patients, with higher HAS-BLED scores and prolonged duration of warfarin therapy, were observed with an increased risk of supratherapeutic anticoagulation. Careful dosage modifications are needed particularly in high-risk categories as mentioned above.

Abstract 12596: Comparison of the Efficacy and Safety of Direct Oral Anticoagulants With Vitamin K Antagonists in Patients With Thrombotic Antiphospholipid Syndrome: Systematic Review and Meta-analysis of Randomized Clinical Trials

Introduction: The efficacy and safety of direct oral anticoagulants (DOACs) as treatment alternatives for patients with thrombotic antiphospholipid syndrome (APS) remain controversial. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the efficacy and safety of DOACs with vitamin-K antagonists (VKAs) in patients with thrombotic APS. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through April 9, 2022. Main efficacy outcomes were a composite of arterial thrombotic events, and a composite of venous thromboembolic events (VTE). The main safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. A random effects model with inverse variance was used for the primary analysis. Risk of bias was assessed using the Cochrane Collaboration criteria. Results: Our search retrieved 253 studies. Four RCTs involving 474 patients were included (Figure). All four RCTs were open-label but had proper random sequence generation and adequate allocation concealment. The DOACs used were rivaroxaban (3 trials) and apixaban (1 trial). The mean percent time in therapeutic range in the warfarin arm among the four studies was 60%. Overall, use of DOACs compared with VKAs was associated with increased odds of composite of arterial thrombotic events (OR 5.64, 95% confidence interval [CI] 1.96-16.27, p =0.001, I 2 = 0%). The odds of subsequent VTE events (OR 1.19, 95% CI 0.31-4.53, p =0.80, I 2 = 0%), or major bleeding (OR 1.02, 95% CI 0.42-2.47, p =0.97, I 2 = 0%) were not significantly different between the two groups. Conclusions: Patients with thrombotic APS randomized to DOACs compared to VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.

Time in therapeutic range for virtual anticoagulation clinic versus in-person clinic during the COVID-19 pandemic: a crossover study.

COVID-19 infection affects the quality of the medical services globally. The pandemic required changes to medical services in several institutions. We established a virtual clinic for anticoagulation management during the pandemic using the Whatsapp application. Compare anticoagulation management quality in virtual versus in-person clinics. A retrospective crossover study SETTINGS: Specialized cardiac care center PATIENTS AND METHODS: The study included patients who presented to Prince Sultan Cardiac Center in Riyadh for anticoagulation management during the pandemic from March 2020 to January 2021. We compared time in therapeutic range (TTR) in the same patients during virtual and in-person clinics. All international normalized ratio (INR) measures during the virtual clinic visits and prior ten INR measures from the in-person clinic were recorded. Patients who had no prior follow-up in the in-person clinic were excluded. TTR calculated using the Rosendaal method. 192 patients RESULTS: The mean age was 58.6 (16.6) years and 116 (60.4%) were males. Patients were diagnosed with atrial fibrillation (n=101, 52.6%), mechanical mitral valve (n=88, 45.8%), mechanical aortic valve (n=79, 41%), left ventricular thrombus (n=5, 2.6%) and venous thromboembolism (n=8, 4.2%). Riyadh residents represented 56.7% of the study population (n=93). The median (IQR) percent TTR was 54.6 (27.3) in the in-person clinic versus 50.0 (33.3) (P=.07). Virtual clinic results were comparable to in-person clinics for anticoagulation management during the COVID-19 pandemic. Number of INR measures during the virtual clinic visits, retrospective nature and single-center experience. None.

Comparison of Bivalirudin Versus Unfractionated Heparin for Anticoagulation in Adult Patients on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) contributes to coagulopathy, necessitating systemic anticoagulation to prevent thrombosis. Traditionally, unfractionated heparin (UFH) has been the anticoagulant of choice, however, due to many inadequacies new evidence suggests benefit with the use of direct thrombin inhibitors. This retrospective cohort sought to evaluate the safety and efficacy of bivalirudin compared to UFH in ECMO patients. Primary endpoints included incidence of bleeding and thrombosis. Percent time in therapeutic range (TR), time to achieve TR and number of dose titrations required to maintain TR were calculated to assess efficacy of institutional protocols. Overall incidence of thrombosis was low, with one event in the bivalirudin group and no events in the UFH group. No difference was found in rates of bleeding between groups (6% vs . 10%, P = 0.44). Bivalirudin yielded higher percent time in TR (86% vs. 33%, P < 0.001), faster time to TR (2 vs . 18 hr, P < 0.001) and required fewer dose adjustments to maintain TR (2 vs . 11, P < 0.001) compared to UFH. These results suggest bivalirudin and UFH are associated with similar rates of bleeding and thrombosis in patients requiring ECMO support. Our results demonstrate the favorable pharmacokinetic profile of bivalirudin, and its ability to consistently maintain TR when compared to UFH.

Evaluation of Time in Therapeutic Range of Patients with Non-Valvular Atrial Fibrillation on Oral Anticoagulation with Vitamin K Antagonist in Delta Region

Background: Non-valvular atrial fibrillation (AF) is the most common cardiac arrhythmia with a prevalence as high as 1.5±2.0% in the general population. This arrhythmia remains one of the major causes of stroke, heart failure, sudden death, and cardiovascular morbidity in the world. The aim of study was to evaluation of the patients in delta region who have non-valvular AF and on oral anticoagulation with Vitamin K antagonist as regard the time they spend within therapeutic range.&#x0D; Patients and Methods: A total of 100 patients were included in this study for evaluation of the patients in delta region who have non-valvular AF and on oral anticoagulation with Vitamin K antagonist as regard the time they spend within therapeutic range.&#x0D; Results: Our study showed that only 35% achieved the recommended TTR (percent time in therapeutic range) above 60% from studied risk factors, none showed statistical significance.&#x0D; Conclusions: The quality of anticoagulant control was lower that reported in European countries with a significant proportion of patients had TTR below 60%.

A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional.

Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies. Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype. The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.

Time in Therapeutic Range for Bivalirudin Among Pediatric Ventricular Assist Device Recipients.

Given the adverse event rates involving bleeding and thrombosis among children on ventricular assist devices (VADs), anticoagulant management has become a focal point for quality improvement and innovation. There may be advantages to using direct thrombin inhibitors, such as bivalirudin, though this has not been fully explored. As the percent time in therapeutic range (%TTR) for anticoagulants is classically associated with improved clinical outcomes, we evaluated the %TTR for bivalirudin among pediatric VAD recipients. Using a modification of the Rosendaal method, %TTR was calculated using activated partial thromboplastin time measurements for 11 VAD recipients in the early postoperative period (postoperative days 0-14) and for the duration of VAD support. In the initial 2 weeks after VAD implant, mean %TTR was 68.7 (±13.0). During the entire support course, the mean %TTR improved to 79.6 (±11.0). There was an era effect with improving %TTR in the latter half of the study period. We report very good %TTR for bivalirudin both in the first 2 weeks post implant and this improved over the duration of support. Because %TTR reflects the degree of safety and efficacy in chronic anticoagulation, this relatively high %TTR among a diverse, often critically ill cohort suggests that bivalirudin may be a promising agent. Although this study was underpowered to comprehensively evaluate adverse events on bivalirudin, this represents an important next step for larger scale study.

Time in Therapeutic Range Using Bivalirudin for Pediatric Ventricular Assist Devices

Purpose The optimal antithrombosis regime for children on ventricular assist devices (VADs) is controversial and the neurologic event rate remains unacceptably high. Bivalirudin, a direct thrombin inhibitor (DTI), may confer advantages over unfractionated heparin but has not been well-studied in this population. The primary aim of this study was to describe the percent time in therapeutic range for activated partial thromboplastin time (aPTT) using bivalirudin in a cohort of children on VADs. Methods All children on VAD support and treated with bivalirudin at a tertiary care children's hospital from January 1, 2016 to September 31, 2018 were retrospectively studied. Demographics, lab, medication data, and PediMACS complications were collected for the first 2 weeks after VAD implantation. Basic statistical analyses were used to describe the cohort. Percent time in therapeutic range was calculated by dividing the time an aPTT was in therapeutic range by the total time the patient received bivalirudin during the study period. Results Among 11 VAD recipients (median age 2.75 years [IQR 0.6 - 6.2], median weight 12 kg [IQR 7.3 - 17.1]), the majority were supported with a Berlin EXCOR (9/11; 82%). 3 patients were on BiVAD support and 2 required dialysis. Goal ranges for aPTT were tailored to each patient. The mean percent time in therapeutic range was 68.7% (range 49.2-87.8%) for the entire cohort. Time in therapeutic range improved during the study period. Stroke occurred in 3/11 patients (28%), with major bleeding in 1/11. There were no mortalities. 7/11 (64%) received solid organ transplant, 1 underwent device explant, and 3 continued on VAD support. Conclusion These findings suggest bivalirudin is a reasonable alternative anticoagulant in this population. Time in therapeutic range at our center was better than published reports using DTIs in adult patients with heparin-induced thrombocytopenia. Time in range appears to have improved over the study period, suggesting an era effect as institutional experience was gained.

The importance of mean time in therapeutic range for complication rates in warfarin therapy of patients with atrial fibrillation: A systematic review and meta-regression analysis.

Background\\Anticoagulation is used for stroke prophylaxis in non-valvular atrial fibrillation, amongst other by use of the vitamin K antagonist, warfarin. Quality in warfarin therapy is often summarized by the time patients spend within the therapeutic range (percent time in therapeutic range, TTR). The correlation between TTR and the occurrence of complications during warfarin therapy has been established, but the influence of patient characteristics in that respect remains undetermined. The objective of the present papers was to examine the association between mean TTR and complication rates with adjustment for differences in relevant patient cohort characteristics.MethodsA systematic literature search was conducted in MEDLINE and Embase (2005–2015) to identify eligible studies reporting on use of warfarin therapy by patients with non-valvular atrial fibrillation and the occurrence of hemorrhage and thromboembolism. Both randomized controlled trials and observational cohort studies were included. The association between the reported mean TTR and major bleeding and stroke/systemic embolism was analyzed by random-effects meta-regression with and without adjustment for relevant clinical cohort characteristics. In the adjusted meta-regressions, the impact of mean TTR on the occurrence of hemorrhage was adjusted for the mean age and the proportion of populations with prior stroke or transient ischemic attack. In the adjusted analyses on thromboembolism, the proportion of females was, furthermore, included.ResultsOf 2169 papers, 35 papers met pre-specified inclusion criteria, holding relevant information on 31 patient cohorts. In univariable meta-regression, increasing mean TTR was significantly associated with a decreased rate of both major bleeding and stroke/systemic embolism. However, after adjustment mean TTR was no longer significantly associated with stroke/systemic embolism. The proportion of residual variance composed by between-study heterogeneity was substantial for all analyses.ConclusionsAlthough higher mean TTR in warfarin therapy was associated with lower complication rates in atrial fibrillation, the strength of the association was decreased when adjusting for differences in relevant clinical characteristics of the patient cohorts. This study suggests that mainly the safety of warfarin therapy increases with higher mean TTR, whereas effectiveness appears not to be substantially improved.Due to the limitations immanent in the meta-regression methods, the results of the present study should be interpreted with caution. Further research on the association between the quality of warfarin therapy and risk of complications is warranted with adjustment for clinically relevant characteristics.

Influence of Kidney Transplant Status on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage.

To assess whether warfarin dose requirement, anticoagulation control, and risk of hemorrhage differ in kidney transplant recipients (KTRs) compared with patients without kidney transplants (non-KTRs). Analysis of data from the Warfarin Pharmacogenetics Cohort, a prospective cohort of first-time warfarin users followed at two anticoagulation clinics. Two outpatient anticoagulation clinics at two large, academic, tertiary care hospitals. Adults aged 20years or older starting warfarin for anticoagulation with a therapeutic international normalized ratio (INR) goal of 2-3 who were KTRs (n=65) or non-KTRs (n=1630). Warfarin dose requirement, anticoagulation control, and risk of hemorrhage were assessed in each group. KTRs required an approximately 20% lower warfarin dose (4.7 vs 5.6mg/day, p=0.0005) compared with non-KTRs. Genetic variants had similar effects on dose in both groups. Mean percentage of time in therapeutic range (PTTR) was similar among KTRs and non-KTRs. Although the proportion of patients achieving good anticoagulation control (PTTR≥60%) was low in both groups, it was similar among KTRs and non-KTRs. KTRs had a higher risk of major hemorrhage (hazard ratio 2.1, p=0.0081), but this difference was not statistically significant after controlling for kidney function, clinical, and genetic factors. KTRs initiating warfarin require lower doses and closer monitoring to optimize anticoagulation therapy. Additional studies are needed to confirm these findings.

Thromboembolism and bleeding risk scores and predictors of cardiac death in a population with atrial fibrillation.

BackgroundAtrial fibrillation (AF) is a common arrhythmia, with risk of systemic embolism and death. It presents rheumatic etiology in up to 32% of developing countries, whose anticoagulation and evolution data are scarce.Objectivesto determine the predictors of cardiac death considering the clinical profile, thromboembolism and bleeding scores of patients with AF of a single center, with high prevalence of rheumatic heart disease.Methods302 patients with AF were studied, mean age 58.1 years; 161 women; 96 pts with rheumatic etiology. Patients underwent clinical and laboratory evaluation, measurement of risk scores and the mean follow-up of 12.8 months.Results174 were using warfarin. The averages of the HAS-BLED and ATRIA scores were 1.4 and 1.2, respectively. Percent time in therapeutic range of international normalized ratio was 45.8%. Thirty patients (9.9%) had cardiac death and 41 had some type of bleeding due to warfarin. By univariate analysis, there was statistical significance between cardiac death and permanent AF, blood pressure, systolic dysfunction, R2CHADS2, CCS, EHRA and HAS-BLED. There was no association with valvular AF. By multivariate analysis, systemic arterial and pulmonary artery pressures, classification CCS and systolic dysfunction showed statistical significance.ConclusionsThere was no association between cardiac death and valvular AF. Independent predictors of cardiac death were low measures of blood pressure, higher score CCS classification and the presence of systolic ventricular dysfunction.

A Comparison of Socioeconomic Factors in Patients Continuing Warfarin Versus Those Transitioning to Direct Oral Anticoagulants (DOACs) for Venous Thromboembolic Disease or Atrial Fibrillation

Introduction: The regulatory approval and growing clinical acceptance of the direct oral anticoagulants (DOACs: apixaban, dabigatran, edoxaban, and rivaroxaban) has challenged warfarin as the mainstay of anticoagulation for the management of venous thromboembolic disease (VTE: deep vein thrombosis and pulmonary embolism) and atrial fibrillation/flutter (Afib). As clinicians and patients choose from the expanded menu of oral anticoagulant options, it is unknown how socioeconomic variables like income, race, gender, health insurance, or marital status may influence which anticoagulant a patient utilizes.We sought to explore if patients who stayed on warfarin differed from those who changed to a DOAC, with regard to the aforementioned socioeconomic variables. Furthermore, we desired to assess how the clinical variable of INR management, as reflected by the percent of time in therapeutic range (TTR), compared between these two groups.Methods: The Michigan Anticoagulation Quality Improvement Initiative (MAQI2) is a multi-center collaborative registry of 6 active anticoagulation clinics across Michigan. Patients newly initiating warfarin for Afib or VTE between October 2009 and July 2016 were included. Enrollees who remained on warfarin in follow-up ("non-switchers") were compared to those that transitioned to a DOAC ("switchers") on the basis of demographics, TTR by linear interpolation, race, marital status, and insurance. Patients in each group were further analyzed in quartiles based on the median household income of their zip code of residence, derived from the 2014 U.S. Census Bureau's American Community Survey. Analyses were performed using Student's t-tests and Wilcoxon Rank-sum tests for continuous variables, and chi-square and Fisher's exact tests for categorical variables.Results: 8,480 patients met the inclusion criteria, 54.4% with Afib, 45.6% with VTE, and 1.1% with both; out of this group, 675 (8%) switched from warfarin to a DOAC. There were no significant differences between switchers and non-switchers for age (mean 68.1±13.6 and 67.4±15.7, p=0.23), gender (53.9% vs. 51.5% male, p=0.23), percent TTR on warfarin (55.1% vs. 56.9%, p=0.056), or percent with commercial health insurance (33.9% vs. 34.4%, p=0.78) or uninsured (0.3% vs. 0.9%, p=0.17).Patients were more likely to switch to DOAC therapy if they had Afib vs. VTE (10.9% vs. 4.5%, p<0.001). When comparing switchers to non-switchers, switchers were more often white race (88.8% vs. 81.5%, p<0.001), married/living with a partner (68.9% vs. 59.7%, p<0.001), and had Government Health Insurance (58.9% vs. 54.6%, p=0.032). As compared to non-switchers, switchers were less often African American (7% vs. 15.3%, p<0.001), and less often had insurance through a Health Maintenance Organization (HMO) (6.9% vs. 10.2%, p=0.008). Non-switchers more often resided in a zip code with a lower median household income compared to switchers (p<0.001).Conclusion: While DOACs are often considered in patients who have difficulty maintaining a therapeutic INR, TTR was not predictive of changing from warfarin to a DOAC in this population. However, we found that SES factors, such as race, insurance status and income are associated with a patient's likelihood for switching to DOAC therapy vs. remaining on warfarin therapy. Further investigation into the reason for, and clinical impact of, these observed disparities in the care of our patients is needed. [Display omitted] DisclosuresSood:Bayer: Research Funding. Kline-Rogers:Janssen: Consultancy; ACP: Consultancy; AC Forum: Membership on an entity's Board of Directors or advisory committees. Almany:Abbott: Research Funding; Kona: Consultancy; Trice Orthopedics: Consultancy; MiCardia: Consultancy; Biostar Ventures: Equity Ownership; Ablative Solutions: Equity Ownership; Boston Scientific: Research Funding. Kaatz:Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Boehringer Ingelheim: Consultancy; Boehringer Ingelheim: Honoraria; Janssen: Honoraria; Bristol Myer Squibb: Honoraria; Pfizer: Honoraria; CSL Behring: Honoraria. Froehlich:Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Fibromuscular Disease Society of America: Research Funding; Blue Cross/Blue Shield of Michigan: Research Funding; Novartis: Consultancy; Janssen: Consultancy; Merck: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees. Barnes:Portolal: Consultancy; Blue Cross Blue Shield of Michigan: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding.

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.

The impact of new-onset cancer among veterans who are receiving warfarin for atrial fibrillation and venous thromboembolism

BackgroundA new cancer diagnosis adds significant complexity and uncertainty to the management of pre-existing warfarin therapy. ObjectivesTo determine how new-onset cancer affects anticoagulation control and outcomes among patients who had been receiving warfarin for atrial fibrillation (AF) compared to patients who had been receiving warfarin for venous thromboembolism (VTE) prior to cancer diagnosis. Patients/methodsThis cohort study started with 122,875 veterans who had been receiving warfarin for at least six months from a VA Medical Center between 10/1/06 and 9/30/08. We identified patients with incident cancer during this interval, and excluded those with a prior cancer history. We analyzed percent time in therapeutic range (TTR) at 6 and 12-month intervals after cancer diagnosis compared to pre-cancer baseline, as well as crude rates of warfarin-relevant outcomes (stroke, major bleeding, mortality) between patients with AF and VTE. ResultsAmong patients with new-onset cancer, patients anticoagulated for AF outnumbered those anticoagulated for VTE more than 2.5-fold. There were no significant differences in TTR by indication for warfarin in months 0–6 or 7–12 following cancer diagnosis, but TTR decreased significantly compared to the pre-cancer baseline for both groups in months 0–6. As expected, cancer patients with VTE had significantly worse mortality at six months and one year compared to cancer patients with AF. ConclusionPatients receiving chronic warfarin therapy who are newly diagnosed with cancer experience a significant decrease in TTR in the first 6months after diagnosis, regardless of indication for anticoagulation. This effect appears to attenuate in months 7–12.

Percent Time in Range with Warfarin as a Performance Measure: How Long a Sampling Frame Is Needed?

Warfarin is received by millions of patients in the United States and elsewhere and will remain the most commonly used anticoagulant for the foreseeable future. Percent time in therapeutic range (TTR) with warfarin is increasingly used as a performance measure. However, stakeholders have expressed concern that TTR lags behind changes in performance. Work in a larger study focused on the impact of shortening the conventional measurement period for TTR. Some 124 sites within the Department of Veterans Affairs (VA) were examined during a seven-year period (fiscal years [FYs] 2008-2014 (April 1, 2007-September 30, 2014). The duration of time segments (2, 3, 4, 6 months) used to calculate TTR were varied, and these four durations were compared in terms of the number of patients retained per site, mean and median site TTR, and site performance rankings. Data were obtained on 295,237 unique patients who received anticoagulation. As the calculation window shortened, patients with better control (that is, higher TTR) were selectively excluded from the measurement because their laboratory values were more widely spaced. Site mean TTR was highest when the most patients were included (6 months: 950 patients; TTR 65.2%) and lowest when the fewest patients were included (2 months: 567 patients; TTR 60.0%). However, the 3-, 4-, and 6-month segments achieved similar results, each of which included more than 800 patients per site, with mean TTR across a narrow range (64.9%-65.2%). Site rankings were less highly correlated between the 2-month period and longer periods (r = 0.7- 0.8) but were otherwise 0.95 or higher, with a nearly perfect correlation (0.985) between the 4- and 6-month periods. When TTR is used to measure site-level performance, comparable results can be achieved using a 4- or a 6-month measurement period. On the basis of these results, the use of a 4-month period for future measurement efforts is recommended.

Improving Anticoagulation Measurement Novel Warfarin Composite Measure.

Percent time in therapeutic range (TTR) and international normalized ratio (INR) variability both measure warfarin control and are associated with outcomes independently. Here, we examine the advantages of a warfarin composite measure (WCM), which summarizes the 2 when measuring patient outcomes. We also examine how the measure chosen would affect anticoagulation clinic performance rankings. We constructed WCM using an equally weighted method, adding standardized TTR to standardized log-transformed INR variability using 103 897 warfarin-experienced patients from 100 anticoagulation clinics. We examined the association of WCM with ischemic stroke, major bleeding, and fatal bleeding, using a subset of patients with atrial fibrillation (n=40 404). We divided patients into quintiles based on their level of control for TTR, log INR variability, and WCM. We calculated the hazard ratios for ischemic stroke, major bleeding, and fatal bleeding stratified by these quintiles. WCM hazard ratios for stroke and fatal bleeding showed the largest difference between excellent control and poorest control quintile compared with TTR and log INR variability, but not for major bleeding. In addition, we compared site rankings obtained using each of our 3 performance measures. Kappa scores for identifying outlier and nonoutlier clinics between WCM and its components were moderate (κ=0.56 for TTR and κ=0.62 for log INR variability) but was weak between TTR and log INR variability (κ=0.13). WCM produces the largest range of risk for warfarin complications, widening the floor ceiling effects that limit the use of TTR and INR variability as separate measures. Anticoagulation clinics ranking changed considerably according to the anticoagulation measure that was selected.

Effective and Safe Management of Oral Anticoagulation Therapy in Patients Who Use the Internet-Accessed Telecontrol Tool SintromacWeb.

BackgroundDespite the existing evidence that highlights the benefits of oral anticoagulation therapy (OAT) self-testing and self-management by patients in comparison with conventional control, significant progress is still needed in the implementation of computer-based, Internet-assisted systems for OAT within health care centers. The telecontrol tool “SintromacWeb” is a previously validated system for OAT management at home, which is currently operative and accessed by patients through a hospital Web portal.ObjectiveThe intent of the study was to assess the effectiveness and safety of OAT management in patients using the SintromacWeb telecontrol system in reference to control in patients using the conventional system (management at the hematology department), in terms of time in therapeutic range (TTR) of International Normalized Ratio (INR).MethodsIn this observational prospective study, patients were identified by their physician and divided in two groups according to the OAT management system that they were already using (conventional control or telecontrol with SintromacWeb). For 6 months, patients were required to visit the hematology department every time their physician considered it necessary according to usual clinical practice. Sociodemographic and clinical variables for the study were collected at first visit (baseline) and at those visits closest to 2, 4, and 6 months after first visit.ResultsA total of 173 patients were evaluated, 87 with conventional control and 86 with telecontrol. Follow-up time was a median of 6.3 (range 5.2-8.1) months. The average time of OAT treatment prior to enrollment was 9.2 (SD 6.4) years. Patients in the telecontrol group tested their INR a median of 21 (range 4-22) days versus a median of 35 (range 14-45) days in patients in the conventional control group (P<.001). TTR in the telecontrol group was 107 (SD 37) days versus 94 (SD 37) days in the conventional control group (an increase of 12.6%; P=.02). In all visits, the percentage of TTR was higher in the telecontrol group (at the third visit: 59% vs 48%; P=.01). Higher TTR (positive coefficient) was associated with patients under OAT telecontrol (P=.03). Under-anticoagulation (INR<1.5) and over-anticoagulation (INR>5) were observed in 34 (19.7%, 34/173) and 38 (22.0%, 38/173) patients, respectively (no differences between treatment groups). Seven thrombotic and/or bleeding events were serious, 12 were non-serious, and most of them (5 and 10, respectively) occurred in the conventional control group.ConclusionsIn clinical practice, OAT management with the Internet-based tool SintromacWeb is effective and safe for those patients who are eligible for OAT telecontrol.

Association Between Usual Vitamin K Intake and Anticoagulation in Patients Under Warfarin Therapy.

This study aimed to explore the correlation between usual vitamin K intake and response to anticoagulant therapy among patients under warfarin therapy. We conducted a retrospective survey of patients (n = 50) on continuous warfarin therapy. Clinical information and laboratory parameters were sourced from medical records. Anticoagulant effect was evaluated by using the percent time in therapeutic range (TTR) and the coefficient of variation (CV) of International normalized ratio (INR). Dietary vitamin K intake was assessed using a semi-quantitative food frequency questionnaire that has been developed for the purpose of assessing dietary intake of vitamin K. A total of 50 patients aged between 21 and 87 years were included in the study. The mean vitamin K intake was 262.8 ± 165.2 µg/day. Study subjects were divided into tertiles according to their usual vitamin K intake. The proportion of men was significantly higher in second and third tertile than first tertile (p = 0.028). The mean percent TTR was 38.4 ± 28.4% and CV of INR was 31.8 ± 11.8%. Long-term warfarin therapy group (≥ 3 years) had a higher percentage of TTR as compared to the control group (< 3 years) (p = 0.046). No statistically significant correlation was found between usual vitamin K intake and percent TTR (p > 0.05). In conclusion, no significant association was observed between usual vitamin K intake and anticoagulant effects. Further studies are required to consider inter-individual variability of vitamin K intake. Development of assessment tools to measure inter-individual variability of vitamin K intake might be helpful.

When the rubber meets the road: adherence and persistence with non-vitamin K antagonist oral anticoagulants and old oral anticoagulants in the real world-a problem or a myth ?

For patients taking vitamin K antagonist (VKA) anticoagulants, poor adherence to the drug regimen is associated with a lower percent time in therapeutic range and also with an increased risk of thromboembolic complications. The non-vitamin K antagonist oral anticoagulants (NOACs) do not require routine laboratory monitoring and therefore the risk of nonadherence remaining undetected and without any corrective attempts must be recognized. Persistence with the NOACs and VKA was quite comparable in the phase III trials, whereas a postmarketing study demonstrated better persistence with dabigatran than with warfarin. Preliminary studies on adherence to the dabigatran regimen have shown poor adherence in 12 to 27%, and also for this drug such behavior seems associated with an unfavorable outcome. There is uncertainty about the best methods to evaluate adherence. Studies on the adherence are needed for all the NOACs, for different clinical settings and patient populations. A combination of strategies should probably be used to achieve the best possible adherence, including patient education and some form of automatic reminders.