Initiation Of Warfarin Therapy Research Articles

Impact of Antibacterials on the Quality of Anticoagulation Control in Patients Initiating Warfarin Therapy.

Warfarin interacts with antibacterials to prolong the prothrombin time international normalized ratio (PT-INR) and increase the risk of bleeding. Patients initiating warfarin therapy often undergo precise dosage adjustments; however, the clinical implications of these interactions with antibacterials remain unclear. This study aimed to clarify the effect of antibacterials on PT-INR during the warfarin induction phase. This was a retrospective, observational study. Patients who were newly treated with warfarin after cardiovascular surgery were included. The primary endpoint was the comparison of the maximum PT-INR and time in therapeutic range (TTR) after warfarin initiation between the antibacterial-treated (ABx) and non-treated (non-ABx) groups. The maximum PT-INR was significantly higher in the ABx group (which included β-lactams, glycopeptides, quinolones, tetracyclines, and aminoglycosides) than in the non-ABx group (median [interquartile range] 2.37 [2.03-2.71] vs. 2.08 [1.93-2.33]; P = 0.005); however, the TTR did not differ significantly (65% [44-76] vs. 71% [43-85]; P = 0.150). The odds ratio for maximum PT-INR >2.6 with antimicrobial therapy was 2.51 (95% confidence interval 1.21-5.21). Antibacterial therapy was a risk factor for a maximum PT-INR >2.6. However, there was no association with the TTR, which is a marker of good outcomes. This was due to the strict warfarin dosing regimen according to the algorithm, which immediately and appropriately adjusted for PT-INR overexpansion. Antibacterials have been suggested to increase PT-INR during the induction phase of warfarin. However, with strict dose adjustments, the clinical impact on the PT-INR and TTR is likely limited.

Veterans Affairs Medical Center Racial and Ethnic Composition and Initiation of Anticoagulation for Atrial Fibrillation

Racial and ethnic disparities exist in anticoagulation therapy for atrial fibrillation (AF). Whether medical center racial and ethnic composition is associated with these disparities is unclear. To determine whether medical center racial and ethnic composition is associated with overall anticoagulation and disparities in anticoagulation for AF. Retrospective cohort study of Black, White, and Hispanic patients with incident AF from 2018 to 2021 at 140 Veterans Health Administration medical centers (VAMCs). Data were analyzed from March to November 2023. VAMC racial and ethnic composition, defined as the proportion of patients from minoritized racial and ethnic groups treated at a VAMC, categorized into quartiles. VAMCs in quartile 1 (Q1) had the lowest percentage of patients from minoritized groups (ie, the reference group). The odds of initiating any anticoagulant, direct-acting oral anticoagulant (DOAC), or warfarin therapy within 90 days of an index AF diagnosis, adjusting for sociodemographics, medical comorbidities, and facility factors. The cohort comprised 89 791 patients with a mean (SD) age of 73.0 (10.1) years; 87 647 (97.6%) were male, 9063 (10.1%) were Black, 3355 (3.7%) were Hispanic, and 77 373 (86.2%) were White. Overall, 64 770 individuals (72.1%) initiated any anticoagulant, 60 362 (67.2%) initiated DOAC therapy, and 4408 (4.9%) initiated warfarin. Compared with White patients, Black and Hispanic patients had lower rates of any anticoagulant and DOAC therapy initiation but higher rates of warfarin initiation across all quartiles of VAMC racial and ethnic composition. Any anticoagulant therapy initiation was lower in Q4 than Q1 (69.8% vs 74.9%; adjusted odds ratio [aOR], 0.80; 95% CI, 0.69-0.92; P < .001). DOAC and warfarin initiation were also lower in Q4 than in Q1 (DOAC, 69.4% vs 65.3%; aOR, 0.85; 95% CI, 0.74-0.97; P < .001; warfarin, 5.4% vs 4.5%; aOR, 0.82; 95% CI, 0.67-1.00; P < .001). In adjusted models, patients in Q4 were significantly less likely to initiate any anticoagulant therapy than those in Q1 (aOR, 0.88; 95% CI, 0.78-0.99). Patients in Q3 (aOR, 0.75; 95% CI, 0.60-0.93) and Q4 (aOR, 0.69; 95% CI, 0.55-0.87) were significantly less likely to initiate warfarin therapy than those in Q1. There was no significant difference in the adjusted odds of initiating DOAC therapy across racial and ethnic composition quartiles. Although significant Black-White and Hispanic-White differences in initiation of any anticoagulant, DOAC, and warfarin therapy were observed, interactions between patient race and ethnicity and VAMC racial composition were not significant. In a national cohort of VA patients with AF, initiation of any anticoagulant and warfarin, but not DOAC therapy, was lower in VAMCs serving more minoritized patients.

Association between gene polymorphisms and initial warfarin therapy in patients after heart valve surgery.

Warfarin is widely used for the prevention and treatment of thrombotic events. This study aimed to examine the influence of gene polymorphisms on the early stage of warfarin therapy in patients following heart valve surgery. Nine single nucleotide polymorphisms were genotyped using microarray chips, categorizing patients into three groups: normal responders (Group I), sensitive responders (Group II), and highly sensitive responders (Group III). The primary clinical outcomes examined were time in therapeutic range (TTR) and international normalized ratio (INR) variability. To investigate potential influencing factors, a generalized linear regression model was employed. Among 734 patients, the prevalence of CYP2C9*3-1075A > C, CYP2C19*3-636G > A, and CYP2C19*17-806C > T variants were 11.2%, 9.9%, and 1.9% of patients, respectively. VKORC1-1639G > A or the linked -1173C > T variant was observed in 99.0% of the patients. Generalized linear model analysis revealed an impact of sensitivity grouping on INR variability. Compared to Group I, Group II showed higher TTR values (p = 0.023), while INR variability was poorer in Group II (p < 0.001) and Group III (p < 0.001). Individual gene analysis identified significant associations between CYP2C9*3-1075A > C (p < 0.001), VKORC1-1639G > A or the linked -1173 C > T (p = 0.009) and GGCX-3261G > A (p = 0.019) with INR variability. The genotypes of CYP2C9, VKORC1, and GGCX were found to have a significant impact on INR variability during the initial phase of warfarin therapy. However, no significant association was observed between TTR and gene polymorphisms. These findings suggest that focusing on INR variability is crucial in clinical practice, and preoperative detection of gene polymorphisms should be considered to assist in the initiation of warfarin therapy.

Direct oral anticoagulation versus warfarin in atrial fibrillation: a nationwide cohort study of effectiveness and safety among frail patients

Abstract Background Frail patients with atrial fibrillation carry a high risk of both stroke and treatment-related bleeding complications, but evidence for the safety and effectiveness of anticoagulation regimens in frail patients remain sparse. Objectives To determine the comparative effectiveness and safety of DOAC versus warfarin in frail patients with atrial fibrillation. Methods A nationwide registry-based cohort study applying a new-user design including all frail patients with atrial fibrillation who redeemed a prescription for DOAC or warfarin between January 2012 and December 2020. We applied inverse probability of treatment weighting (IPTW) to account for baseline confounding and applied a marginal structural modelling approach with weighted pooled regression to compute hazard ratios (HR) and risk differences for thromboembolic events and major bleeding comparing specific DOAC doses with warfarin. Results We identified 32048 anticoagulation naïve frail patients (median age 80 years, 53% female) with atrial fibrillation who started anticoagulation treatment: 6747 (21.1%) patients initiated warfarin therapy, 17076 (50.3%) initiated standard dose DOAC, and 9179 (28.6%) patients with indication for dose reduction initiated reduced dose DOAC. The median CHA2DS2-VASc score was 5. The comparative effectiveness analyses showed a similar risk for thromboembolism with weighted HRs of 0.95 (95% CI 0.80-1.13) for standard dose DOAC versus warfarin, and 0.97 (95% CI 0.77-1.23) for reduced dose DOAC versus warfarin (see Table). The thromboembolic event free survival difference at one year was -0.2% for DOAC regardless of dosing when compared with warfarin. The comparative safety analyses revealed significantly lower risk of major bleeding among patients initiating standard dose (weighted HR 0.69, 95% CI 0.59-0.87) or reduced dose DOAC (weighted HR 0.67, 95% 0.55-0.81) when compared with warfarin. The risk difference of bleeding at one year for DOAC users varied between -1.3% and -3.0%, with the greatest difference for patients with high frailty level initiating reduced dose DOAC. Conclusion We observed similar risk of thromboembolism and significantly lower risk of major bleeding associated with both standard and reduced DOAC treatment regimens compared with warfarin in frail patients with atrial fibrillation in routine clinical practice.

Veno-occlusive Priapism, An Undesirable Outcome of Warfarin Therapy: A Case Report

Background: Priapism is one of the urological emergencies requiring prompt medical or surgical intervention. The clinical diagnosis is made with adjunct cavernosal blood gas analysis and colour doppler ultrasound to determine the underlying aetiology; ischaemic or non-ischaemic, and the majority are veno-occlusive in origin (ischaemic). The occurrence of warfarin-induced priapism complicated with penile necrosis is a rare occurrence, and many cases are related to protein C deficiency. Case Presentation: We report a case of warfarin therapy initiation following a thromboembolic event as a sequela of Covid-19 infection, subsequently developed veno-occlusive priapism complicated with penile gangrene despite being in an overwarfarinized state. The penis was non-salvageable following the gangrenous event, even with prior cavernosal blood aspiration. Thrombophilia panel screening, which includes Protein C activity, was done, where the protein C activity was low, measuring 23%. Unfortunately, he succumbed to death due to severe cardiorespiratory complications before this blood result was ready. Discussion: Prompt diagnosis and treatment of priapism is needed to prevent loss of penile function. Priapism as a sequela of anticoagulant therapy should be suspected in a patient with recent anticoagulant initiation. Thus, immediate treatment can be administered to correct the underlying coagulation disorder. Conclusion: The development of veno-occlusive priapism and penile gangrene in a patient on warfarin therapy raises a concern about protein C deficiency.

Allelic Variants in the Warfarin-related Genes VKORC1 and CYP2C9 in a Western Saudi Population

Objectives To investigate the allele and genotype frequencies of the warfarin-related genes VKORC1 (-1639G&gt;A), CYP2C9*2, and CYP2C9*3 among healthy Saudis. Materials and Methods This cross-sectional study involved 125 unrelated healthy Saudis ages 18–60 years visiting the King Abdulaziz University Hospital (KAUH) in Jeddah, Western Saudi Arabia. The Oragene™ DNA saliva collection kits were used to collect and extract DNA from saliva samples. A polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect the mutant alleles. Results Over 51.4% of the Saudi participants carried one or more mutant alleles. The frequency of the VKORC1 (-1639G&gt;A) allele in Saudi was relatively high at 54.8%. The frequencies of the CYP2C9 allele were 19.6% and 54% for the CYP2C9*2 and CYP2C9*3 alleles, respectively, which are substantially more abundant than in other populations. Conclusion The observed high frequencies of VKORC1 (-1639G&gt;A) and CYP2C9*2 and CYP2C9*3 polymorphisms suggest that genetic testing should be considered before initiating warfarin therapy to predict the optimal initial dose of warfarin and minimize warfarin-related side effects.

Online KidClot education for patients and families initiating warfarin therapy: The eKITE study

Anticoagulation with Vitamin K antagonists (VKA) has always posed challenges in terms of monitoring requirements. These challenges were further exacerbated in the setting of the COVID-19 pandemic, with limited access to and/or avoidance of laboratory testing. The importance of utilizing point of care (POC) health technology for individualized patient management is salient. The foundation of effective home INR monitoring is establishing patient knowledge about their therapy and INR testing proficiency. The eKITE series was developed to support patients in establishing foundational knowledge required for VKA (warfarin) management and INR monitoring. The primary objectives were to evaluate eKITE, a patient-oriented innovative online education program for warfarin therapy, participant learning stress, and patient preference for online learning. This multi-center prospective study provided patients access to warfarin online education. Participants were required to complete written quizzes assessing warfarin knowledge of key concepts proficiency and identifying knowledge deficits. Patient preference, evaluating calm (lack of anxiety) while learning, and an INR on a home meter was completed. Participants performed INR tests at home and reported INRs by telephone. The analysis included 144 children and caregivers enrolled at five US and CDN sites. Most indications for anticoagulation were cardiac (congenital or acquired heart disease) with varied INR target ranges. Mean knowledge scores for warfarin and INR self-testing modules were 97%, with low anxiety with TTR of 84%. Patient preferred online learning. eKITE is an effective teaching modality for warfarin/home INR monitoring with safe INR testing and warfarin management that is appropriate for pediatrics and adults alike. PrologueThe whir in the hallways is deafening. Lights bright, alarms are ringing in a chorus of unsynchronized beeps and screeches. It has been more than a week since I have slept. Snuggled beside me is my precious child, whining and equally irritated with the asynchronous symphony, further compounded by anxiety, procedures, and pain. The sun has broken.The staff smiles are welcoming and incessant, as one after one, they approach hurried, urgent, assiduous, their need to coach me for our upcoming departure to the warmth of home. Each provides essential information that I will require to keep my child, my treasure, safe and healthy. Yet, my eyes are heavy, blurred, and my brain foggy, trapped in a dark heavy cloud. How am I to follow? Comprehend? and retain anything? As they instruct, my precious child yearns for loving arms, compassion and love, whining, crying in disquiet. Overwhelmed does not adequately describe my ineffable exhaustion. Amidst this, how am I to learn about warfarin? Such a challenging medication, with so much to know. Concentrate, I tell myself, focus; now is my only opportunity to learn. I must be alert. It seems to be nonsensical.

Time to Stable Therapeutic Range on Initiation of Warfarin as an Indicator of Control

ObjectivesWarfarin remains widely used with a time in therapeutic range (TiTR) above 65% recommended for best outcomes. Patients not achieving or maintaining this warfarin control may be better suited to alternate anticoagulants. Despite this, there is limited data defining a suitable trial time in patients initiating warfarin therapy, therefore the aim of this study was to determine the mean time to stable therapeutic range (TtSTR). Materials and MethodsRetrospective data was collected for patients with atrial fibrillation enrolled in a dedicated warfarin program at a private pathology practice within 7 days of warfarin initiation. TiTR at specified timepoints was calculated and median TtSTR determined as defined by TiTR ≥ 65% over three months. Comparisons were made of populations with TtSTR above or below the median. ResultsThe 566 patients included in the study had a mean TiTR of 64.9±16.5% at month three and median TtSTR of six months. Patients with TtSTR≤6 months achieved a mean TiTR of 68.9±12.8% at month two and maintained a TiTR over 75% from month 3 to 24. Patients with a TtSTR>6 months obtained a TiTR of 66.4±10.6% at month nine and continued to achieve lower TiTR throughout the 24 months study period. ConclusionsA majority of patients can achieve a stable TiTR above 65% within six months so review at six to nine months is likely to be a good indicator of warfarin control and to determine if patients should continue warfarin or switch to alternate anticoagulant therapy.

Comparing outcomes and costs among warfarin-sensitive patients versus warfarin-insensitive patients using The Right Drug, Right Dose, Right Time: Using genomic data to individualize treatment (RIGHT) 10K warfarin cohort.

Oral anticoagulant (OAC) therapy has been the main treatment approach for stroke prevention for decades. Warfarin is the most widely prescribed OAC in the United States, but is difficult to manage due to variability in dose requirements across individuals. Pharmacogenomics may mitigate risk concerns related to warfarin use by fostering the opportunity to facilitate individualized medicine approaches to warfarin treatment (e.g., genome-guided dosing). While various economic evaluations exist examining the cost-effectiveness of pharmacogenomics testing for warfarin, few observational studies exist to support these studies, with even fewer using genotype as the main exposure of interest. We examined a cohort of individuals initiating warfarin therapy between 2004 and 2017 and examined bleeding and cost outcomes for the year following initiation using Mayo Clinic’s billing and administrative data, as well the Mayo Clinic Rochester Cost Data Warehouse. Analyses included descriptive summaries, comparison of characteristics across exposure groups, reporting of crude outcomes, and multivariate analyses. We included N = 1,143 patients for analyses. Just over a third of our study population (34.9%) carried a warfarin-sensitive phenotype. Sensitive individuals differed in their baseline characteristics by being of older age and having a higher number of comorbid conditions; myocardial infarction, diabetes, and cancer in particular. The occurrence of bleeding events was not significantly different across exposure groups. No significant differences across exposure groups existed in either the likelihood of incurring all-cause healthcare costs or in the magnitude of those costs. Warfarin-sensitive individuals were no more likely to utilize cardiovascular-related healthcare services; however, they had lower total and inpatient cardiovascular-related costs compared to warfarin-insensitive patients. No significant differences existed in any other categories of costs. We found limited evidence that warfarin-sensitive individuals have different healthcare spending than warfarin-insensitive individuals. Additional real-world studies are needed to support the traditional economic evaluations currently existing in the literature.

Genotype-guided warfarin dosing may benefit patients with mechanical aortic valve replacements: randomized controlled study

This prospective, single-blind, randomized study was designed to evaluate the effect of genotype-based warfarin dosing compared with standard warfarin dosing in Korean patients with mechanical cardiac valves. Patients were assigned to either the genotype-based dosing group or the standard dosing group using stratified block randomization. The genotype-based dosing equation was adopted from a previous study which included VKORC1 rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, and age. Primary outcomes included the percentage of time in the therapeutic range (pTTR): (i) during the first week following initiation of warfarin therapy, (ii) during hospitalization and (iii) until the first outpatient visit. A total of 91 patients were included in the analysis, 42 treated with genotype-based warfarin dosing and 49 treated with standard warfarin dosing. The genotype frequency differences of the three SNPs included in this study (ie, VKORC1, CYP2C9, CYP4F2), between the genotype-based dosing and standard dosing groups were not different. The genotype-based dosing group trended toward higher pTTR when compared with the standard dosing group, although this difference was not statistically significant. In patients with aortic valve replacement, TTRTraditional and TTRRosendaal were significantly higher in the genotype-based dosing group when compared with the standard dosing group during the first week following treatment initiation [ie, 58.5% vs. 38.1% (p = 0.009) and 64.0% vs. 44.6% (p = 0.012), respectively]. Based on the results, the genotype-guided dosing did not offer a significant clinical advantage, but a possible benefit in patients with aortic valve replacement has been suggested.

Frailty and Co-Prescribing of Potentially Interacting Drugs in New Users of Warfarin.

BackgroundWarfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known.ObjectiveThe objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients.MethodsWe conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation.ResultsIn total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively.ConclusionsThe overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results.Electronic supplementary materialThe online version of this article (10.1007/s40266-020-00755-0) contains supplementary material, which is available to authorized users.

Latent Classes of Adherence to Oral Anticoagulation Therapy Among Patients With a New Diagnosis of Atrial Fibrillation

Less than half of US patients with a diagnosis of atrial fibrillation (AF) receive oral anticoagulation. To identify patients with similar patterns of adherence to regimens of warfarin and direct oral anticoagulants (DOACs) in the first year after AF diagnosis and to evaluate associations between patient characteristics and membership in latent classes of adherence. This retrospective cohort study used 2013 to 2016 Medicare claims data to identify 7491 patients with a new diagnosis of AF in 2014 to 2015 who initiated warfarin after AF diagnosis and 9478 patients with a new diagnosis of AF in 2014 to 2015 who initiated DOAC treatment after AF diagnosis, for a total of 16 969 Medicare beneficiaries. Participants were followed up for 12 months after AF diagnosis. Statistical analysis was performed from February 1 to November 30, 2018. Treatment with warfarin or DOAC after AF diagnosis. The main outcome was the proportion of days that patients received warfarin or DOAC, measured in 30-day intervals after AF diagnosis. Independent variables included patient demographic characteristics, socioeconomic status, region of residence, and clinical characteristics. Latent class mixed models were used to identify latent classes of warfarin and DOAC adherence, and polytomous logistic regression was used to assess the association between patient characteristics and membership in each latent class. Among the 7491 patients receiving warfarin (4348 women), the mean (SD) age was 76.0 (10.0) years; among the 9478 patients receiving DOAC (5496 women), the mean (SD) age was 77.0 (8.5) years. Four latent classes of patients were identified based on warfarin adherence: late initiators (980 [13%]), early initiators who discontinued therapy at months 1 to 3 (1297 [17%]) or at months 5 to 10 (735 [10%]), and continuously adherent patients (4479 [60%]). Four latent classes of patients were also identified based on DOAC adherence: patients who initiated DOAC in months 1 to 5 (1368 [14%]) or months 6 to 11 (800 [8%]), patients with suboptimal and decreasing adherence (2267 [24%]), and continuously adherent patients (5043 [53%]). Membership in latent classes of warfarin adherence was significantly associated with sex, eligibility for Medicaid and income subsidy, region of residence, CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) risk score, and HAS-BLED (hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratio, elderly, and drugs or alcohol) score. Membership in latent classes of DOAC adherence was significantly associated with race/ethnicity, region of residence, HAS-BLED score, and use of antiarrhythmic medications. This study found that, among patients who initiated anticoagulation therapy, 40% of those who initiated warfarin therapy and 47% of those who initiated DOAC treatment did not continuously adhere to therapy in the first year after AF diagnosis. Identifying longitudinal patterns of warfarin and DOAC adherence and the factors associated with them provides suggestions for the design of targeted strategies to mitigate suboptimal oral anticoagulation use.

Guidance for Transitioning Among Anticoagulants.

Guidance for Transitioning Among Anticoagulants.

Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy.

Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.

An Assessment of the Effectiveness of Warfarin Therapy Monitoring Systems on Thrombophilic Patients in Zimbabwe.

Introduction Thrombophilia describes conditions that predispose individuals to increased blood clotting and includes conditions such as deep vein thrombosis and pulmonary embolism. Thrombophilia is associated with high morbidity and mortality rates, and is commonly treated by warfarin anticoagulation. However, warfarin may cause both bleeding and clotting episodes if the therapy is not monitored and managed effectively. Objectives The main objective of this study was to assess the effectiveness of warfarin monitoring systems on thrombophilic patients at a major hospital in Zimbabwe. Material and Methods A clinical and laboratory prospective and retrospective study was performed on patients who had been on warfarin therapy for at least 1 year. Questionnaires were administered to participants on warfarin from outpatients clinics at Parirenyatwa Group of Hospitals. Their international normalized ratio (INR) results were also accessed from the laboratory information system and captured in the Epi info and Microsoft Excel for analysis. Results Fifty questionnaires were administered and 47 (94%) participants responded adequately. Twenty-nine (61.1%) participants on warfarin were females. The majority of them were elderly and in the 31 to 40 age groups. Eighteen (38.3%) participants missed their medication at some point, while 12 (25.5%) had warfarin overdose. Sixteen (34%) and 11 (23.4%) admitted to taking alcohol and smoking, respectively, while on warfarin. Thirty-five (74.5%) did not change their medication nor were advised on the right diet. Thirty-four (72.3%) had appointments set after every month. Some participants indicated that they had symptoms of both clotting and bleeding. There were statistically significant differences ( p < 0.0001) between INRs for 3 monthly intervals from the initiation of warfarin therapy. Conclusion Women and the elderly formed the majority of the patients on warfarin, indicating gender and advanced age susceptibility to thrombophilia, respectively. The effectiveness of the warfarin monitoring systems appeared to be hampered by lack of a coordinated system that adequately monitors anticoagulant therapy in the country.

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System.

Warfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists. To (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system. A retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes. A total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24 times per year), or frequently adjusted warfarin dose (≥ 11 times per year) consistently showed poor TTRs (mean TTR for the highest quartiles was 45.3%-48.3%). A higher TTR was associated with a lower risk of clinical outcomes regardless of frequency of INR monitoring, pharmacist interventions, or number of dose adjustments. Patients whose TTRs were < 65%, even with frequent pharmacist interventions, had similar stroke or systemic embolism event rates, as compared with patients with TTRs < 65% and less frequent interventions (1.88 vs. 1.54 stroke or systemic embolism rates per 100 person-years, respectively, P = 0.78). The lowest TTR quartile (< 46%) was associated with a 3 times higher risk of stroke or systemic embolism (hazard ratio [HR] = 3.19, 95% CI = 2.71-3.77) and a 2 times higher risk of major bleeding (HR = 2.10, 95% CI = 1.96-2.24) compared with the highest TTR quartile (≥ 73%). Despite close monitoring with timely warfarin dose adjustments, there were still a substantial number of challenging patients whose TTRs were suboptimal despite a higher number of pharmacist interventions. These patients eventually experienced more stroke or systemic embolism and bleeding events among NVAF patients managed by anticoagulation clinics. New individualized treatment or management strategies for patients who are not able to reach optimal therapeutic ranges are necessary to improve outcomes. This research and manuscript were funded by Bristol-Myers Squibb Company and Pfizer. Authors from Bristol-Myers Squibb Company and Pfizer participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An received a grant for research support from Bristol-Myers Squibb/Pfizer. Niu, Rashid, and Zheng received a grant from Bristol-Myers Squibb/Pfizer to their institutions for salary reimbursement. Vo, Singh, and Aranda are employed by Bristol-Myers Squibb; Bruno was employed by Bristol-Myers Squibb at the time of this study. Mendes and Dills are employed by Pfizer, and Mendes was a member of the Pfizer Cardiovascular and Metabolic Field Medical Team during the time of this study. Lang, Jazdzewski, and Le have no known conflicts of interest to report. Study concept and design were contributed primarily by An and Rashid, along with the other authors. Niu took the lead in data collection, along with Zheng, and data interpretation was performed by An, along with Mendes and Dills, with assistance from the other authors. The manuscript was written by An and revised by Mendes, Dills, Vo, Singh, Bruno, and Aranda, along with Lang, Le, and Jazdezewski. Part of this study's findings was presented at the CHEST 2015 Annual Meeting in Montreal, Canada, on October 28, 2015.

Association Between Patient-Reported Medication Adherence and Anticoagulation Control

BackgroundThe prevention of thromboembolism events remains challenging in cases of poor medication adherence. Unfortunately, clinical prediction of future adherence has been suboptimal. The objective of this study was to examine the correlation between 2 measures of real-time, self-reported adherence and anticoagulation control. MethodsThe IN-RANGE2 cohort recruited patients initiating warfarin therapy in 3 urban anticoagulation clinics. At each study visit, participants reported adherence using a 100-point visual analogue scale (VAS, marking percentage of pills taken since prior visit on a linear scale) and 7-day recall of pill-taking behavior. Anticoagulation control was measured by between-visit percent time in international normalized ratio range (BVTR), dichotomized at the cohort median. The longitudinal association between adherence and anticoagulation control was estimated using generalized estimating equations, controlling for clinical and demographic characteristics, prior BVTR, and warfarin dose changes. ResultsAmong 598 participants with 3204 (median 4) visits, the median BVTR was 36.8% (interquartile range 0%-73.9%). Participants reported ≤80% adherence in 182 visits (5.7%) and missed pills in the past 7 days in 377 visits (11.8%). Multivariable regression analysis found poorer anticoagulation control (BVTR <36.8%) in those with a VAS ≤80% (odds ratio 1.89; 95% confidence interval, 1.12-3.18; P = .02) and self-reported change in adherence since last visit (odds ratio 1.55; 95% confidence interval, 1.20-2.01; P = .001). ConclusionSelf-reported VAS medication adherence at a clinic visit and changes in reported adherence since the last visit are independently associated with BVTR. Clinicians may gain additional insight into patients' medication adherence by incorporating this information into patient management.

Abstract 259: Two Readily Obtainable Measures of Patient-reported Adherence and Their Association With Anticoagulation Control

Introduction: Despite the emergence of new effective anticoagulation therapies, the prevention of thromboembolic events remains challenging in cases of poor medication adherence. Unfortunately, clinical prediction of future adherence has been suboptimal and electronic adherence measures are impractical. The inability of clinicians to easily and accurately identify poorly adherent patients has been an obstacle to the delivery of quality care. We examined two measures of real-time, self-reported adherence among warfarin treated patients to determine if these could be used to explain level of anticoagulation control. Methods: The IN-RANGE2 Cohort recruited patients initiating warfarin therapy in 3 urban anticoagulation clinics. At each study visit, participants reported adherence using a 100-point Visual Analogue Scale (VAS, marking % of pills taken since prior visit on a linear scale) and 7-day recall of pill taking behavior before their current INR was revealed. Anticoagulation control was measured by between visit time in therapeutic INR range (BVTR), dichotomized at the cohort median. The longitudinal association between these adherence measurements and anticoagulation control was estimated using generalized estimating equations, controlling for clinical and demographic characteristics, prior BVTR, and warfarin dose changes. Results: A total of 598 participants with 3204 (median 4) visits were studied. The median BVTR was 36.8% (interquartile range 0-73.9%). Mean VAS score was 96.6% (standard deviation 5.8), with participants reporting less than or equal to 80% adherence in 182 (5.7%) visits; missed pills in the past 7 days were reported in 308 (11.8%) visits. Multivariate regression analysis found poorer anticoagulation control (BVTR&lt;36.8%) in those with a VAS score less than or equal to 80% (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.12-3.18, p=0.02) and self-report of a change in adherence since last visit using 7-day recall (OR 1.55, 95% CI 1.20-2.01, p=0.001). Conclusion: Self-reported VAS medication adherence at a clinic visit and changes in reported adherence since the last visit are independently associated with BVTR. Incorporating information from both the VAS and changes in 7-day pill recall into clinical practice could improve the quality of anticoagulation management, by helping clinicians identify poorly adherent patients who might benefit from specialized interventions. Because the association is independent of knowing the prior BVTR, these findings may be translatable to direct oral anticoagulant, medications that are not easily monitored with laboratory testing.

Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation

The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain. Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada. 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded. Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis. Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding. Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories:≥90, 60 to 89, 45 to 59, 30 to 44, and<30mL/min/1.73m2. Information for baseline characteristics (sociodemographics, comorbid conditions, and prescription drug use) was obtained. Across eGFR categories, warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories≥ 90, 60-89, 45-59, 30-44, and<30mL/min/1.73m2: 0.59 [0.35-1.01], 0.61 [0.54-0.70], 0.55 [0.47-0.65], 0.54 [0.44-0.67], and 0.64 [0.47-0.87] mL/min/1.73m2, respectively). Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89mL/min/1.73m2 (HR, 1.36; 95% CI, 1.13-1.64). Selection bias. Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk for the composite outcome across all strata of kidney function. The risk for major bleeding associated with warfarin use was increased only among those with eGFRs of 60 to 89mL/min/1.73m2.

Late-Onset Warfarin-Induced Skin Necrosis: A Standing Shadow

One of the clinical situations linked to the use of warfarin is the skin necrosis occurring in approximately 0.01 to 0.1% of all patients receiving warfarin. Typically, lesions develop during the first days after initiation of warfarin therapy (usually around the tenth day) and are often associated with the administration of a loading dose. The pathophysiological mechanisms for warfarin-induced skin necrosis, despite several theories, remain uncertain. For the diagnosis, along with a high degree of suspicion, a rapid recognition and management is required.