Therapeutic International Normalized Ratio Levels Research Articles

Comprehensive Management of Anticoagulants Induced Decompensated Severe Anemia in Postmitral Valve Replacement

Abstract Mechanical prosthetic valve needs consideration for anticoagulation. The objective of this case report was to know how maintenance of oral anticoagulant therapy is very important in patients, especially with mechanical heart valve replacement. It is the holistic management of mitral valve replacement (MVR) patients with high international normalized ratio (INR) (>100), which led bleeding into the peritoneal cavity and causes decompensated severe anemia. Although it is a rare presentation for a patient of MVR with high INR level but which is most commonly presented for cerebrovascular accident. Anemia is a thoughtful worldwide problem that disturbs the quality of life in persons of all ages. A 28-year-old Indian woman with follow-up case of post-MVR came to the hospital with complaints of breathing difficulty, altered sensorium, pulse rate of 150–170 bpm (beats/min) irregularly irregular, blood pressure (80/50 mmHg), palpitation, and abdominal pain. Blood test report revealed her hemoglobin (Hb) was 3.2 g%, suggestive of severe anemia, INR was >100 s. Hence, patient diagnosed as follow-up case of MVR (#27 mm mechanical bileaflet mitral valve prosthesis) with peritoneal bleeding, an oral anticoagulant with decompensated severe anemia managment should be done. Ended the progression of her hospitalization, she received four units of packed red blood cell transfusions; Vitamin K was given intravenous once daily for 2 days and no anticoagulant was given, so far, INR was high with serial monitoring of INR and Hb. Her symptoms of breathing difficulty, pain in abdomen, weakness and giddiness resolute by the finish of her hospital stay, and she recompensed to her oral anticoagulant therapy with improved Hb and hemodynamics. Disapprovingly high INR levels are classically related with bleeding disorders revealed on imperative indicators and hemodynamic variability. To our understanding, one of the lowermost noted Hb is because of bleeding due to very high INR, so monitoring of therapeutic INR level with anticoagulants is very-very important.

Optimal INR Level in Nonvalvular Atrial Fibrillation Patients in Thailand: A Multi-Site Study

Background: Warfarin is a common drug for thromboembolic prevention in patients with nonvalvular atrial fibrillation (NVAF). However, hemorrhagic complications are also a concern. The optimal international normalized ratio (INR) level is different in each ethnicity. Objective: To establish the INR range with lowest all adverse event, optimal INR, in Thai NVAF patients from large data, nationwide Warfarin Registry Network (WaRN). Materials and Methods: The present study was a retrospective cohort study. It analyzed the data of 31,704 Thai NVAF patient between January 1, 2010 and December 31, 2020. The numbers of thromboembolic and bleeding events were correlated to INR level at the time of event. The six groups of INR range were defined as less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and greater than 3.5. Results: The data from 797 warfarin clinics were analyzed with an observation period of 21,328.52 patient-years. The median duration of follow-up was 519 days (IQR 172, 1,183). Of the 31,407 patients, 277 patients experienced 319 thromboembolic events, and 3,398 patients experienced 4,860 bleeding events. The thromboembolic events were 4.92, 1.89, 0.86, 0.72, 0.39, 0.36 per 100 patient-years in INR range of less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and more than 3.5, respectively. The bleeding events were 12.69, 9.51, 8.41, 15.35, 36.38, 125.03 per 100 patient-years in INR range of less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and more than 3.5, respectively. The all-adverse events were 17.61, 11.40, 9.27, 16.07, 36.77, 125.39 per 100 patient-years in the INR range of less than 1.5, 1.5 to 1.9, 2.0 to 2.5, 2.6 to 3.0, 3.1 to 3.5, and more than 3.5, respectively. Conclusion: The incidence density of all-adverse events was lowest in INR range of 2.0 to 2.5. This range should be the optimal therapeutic INR level for Thai NVAF patient. However, the INR range can extend to 1.5 to 2.5 in clinical practice. Keywords: Optimal INR; Nonvalvular Atrial Fibrillation, Bleeding, Thromboembolism

New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3–5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

Managing Anticoagulant Patients Undergoing Dental Extraction by using Hemostatic Agent: Tranexamic Acid Mouthrinse.

Background:Patient who is on antiplatelet therapy had an impaired fibrin formation which leads to fibrinolysis which is the main reason behind postextraction bleeding.Objectives:The aim of the study is to manage anticoagulated patient who has to undergo dental extraction by using hemostatic agent and the objective is to rule out potential risk factor which may trigger bleeding.Methods:One hundred patients with anticoagulant and antiplatelet therapy and having International Normalized Ratio (INR) in-between 1.9 and 3.5 were selected. Postextraction instruction use 5 ml of 10% tranexamic acid mouthrinse four times a day for next 7 days was suggested. All demographic data, history of anticoagulant and antiplatelet therapy, details of bleeding, and treatment requirement were recorded to identify potential risk factor.Results:Of 100 subjects, 16 were reported postextraction bleeding on days 1 and 2 which was controlled by tranexamic acid pressure pack. Bleeding from extraction socket of 10 patients was stopped by gelatin foam. No life-threatening risk was observed. In patients with age group of 41–60 years whose INR value was ≥2.5, the number of teeth undergoing extraction, whose bleeding time was increased, and were on long duration of antiplatelet and anticoagulation therapy might increase the risk of bleeding.Conclusion:Use of tranexamic acid mouthrinse after extraction is an effective way to control bleeding on patients who are under antiplatelet therapy with at therapeutic INR level is a secure and allowable method of minimizing postextraction oozing.

Seven Years of Ventricular Assist Device Support on Dabigatran

Introduction Currently, left ventricular assist device (LVAD) support mandates anticoagulation with coumarin derivatives such as warfarin and acenocoumarol as well as antiplatelet therapy with low-dose aspirin, for the prevention of thromboembolic events. Bleeding remains a major concern in LVAD recipients and is mainly attributed to the acquired von Willebrand factor deficiency exhibited in such patients. In addition, proper anticoagulation with vitamin K antagonists depend on targeted levels of international normalized ratio (INR) which can be influenced by several factors such as diet and liver function. Case Report A 64-year-old male patient underwent LVAD implantation as destination therapy 13 years ago due to end-stage heart failure caused by ischemic cardiomyopathy. The device used was the HeartMate II ventricular assist device. As per recommended guidelines, the patient was started on anticoagulation treatment using acenocoumarol and low-dose aspirin. The patient reports difficulty reaching therapeutic INR levels, necessitating very frequent coagulation blood tests. After six years on LVAD support, the patient presented to the emergency department with major intramuscular bleeding leading to compartment syndrome after a bicycle accident, necessitating transfusion of more than 2 units of packed red blood cells. His INR levels was within therapeutic range at the incident. The LVAD team then decided to change acenocoumarol to dabigatran exetilate, at the standard dose of 150mg bid as used in the prevention of thromboembolic disease in atrial fibrillation patients. Since then, after seven years of ventricular assist device support with dabigatran exetilate used for anticoagulation, the patient is still alive and has not had any bleeding or thromboembolic events. Summary The use of dabigatran exetilate as a second-line therapy in patients who have exhibited at least one major bleeding event on vitamin K antagonists seems intriguing.

Retrospective investigation of anticoagulant complications in long term after mechanical heart valve replacement surgery in Turkey

Background: Patients with mechanical heart valve replacement surgery (MHVRS) should be followed up in terms of prosthetic valve-related and open heart surgery complications. This study aimed to determine the anticoagulant complications in long term in patients with MHVRS. Methods: This retrospective and descriptive study was conducted in a university hospital, İzmir, Turkey. The data were collected from July to December 2019. In total, 73 patients referring for regular check-ups to the hospital with intervals not exceeded more than 90 days, and those who had international normalized ratio (INR) measurements for January-April-July-October 2018 were included in this study. Results: The mean age of the patients was obtained at 58.98±12.89 years, and 53.4% (n=39) of the cases were male. Moreover, the mean follow-up period was estimated at 65.98±28.47 months. According to the results, complications developed in 60 patients (82.2%). The first hospitalized unit was the emergency department. The factors affecting the development of complications after MHVRS were evaluated, and a difference was found regarding gender (X2=6.18, P=0.013), comorbidities (X2=25.58, P=0.018), and monthly referral for regular check-ups to the hospital (X2=5.20, P=0.023). There was no relationship between the INR levels and the development of complications. Furthermore, the results of evaluating the factors affecting the number of hospitalizations after MHVRS revealed that monthly referral to hospital for check-ups (t=3.18, P=0.002) and history of previous valve surgery (Z=201.00, P=0.03) affected the number of hospitalizations. Conclusions: It was observed that patients frequently refer to the emergency department and struggled with various complications. Moreover, it was found that the patients had frequent bleeding and refer to the emergency service repeatedly. Accordingly, there is a need for interventional studies to reduce postoperative complications and provide the therapeutic INR level.

Comparison of Different Anticoagulation Regimens Regarding Maternal and Fetal Outcomes in Pregnant Patients With Mechanical Prosthetic Heart Valves (from the Multicenter ANATOLIA-PREG Registry)

Mechanical prosthetic heart valves (MPHVs) are highly thrombogenic, and a pregnancy-induced procoagulant status increases the risk of MPHV thrombosis. Despite numerous case reports, 2 major registries and meta-analyses/systematic reviews, optimal anticoagulation therapy during pregnancy remains controversial. The goal of this study was to evaluate different anticoagulation regimens in pregnant patients with MPHVs. The outcomes of anticoagulation regimens were assessed retrospectively in pregnant women (110 women; 155 pregnancies) with MPHVs. The study population was divided into 5 groups according to anticoagulation regimens used; high-dose warfarin (>5 mg/d) throughout pregnancy (group 1), low-dose warfarin (≤5 mg/d) throughout pregnancy (group 2), low molecular weight heparin (LMWH) throughout pregnancy (group 3), first trimester LMWH, 2nd and 3rd trimester warfarin (group 4), first 2 trimester LMWH, and 3rd trimester warfarin (group 5). Of 155 pregnancies, 55 (35%) resulted in fetal loss; whereas 41 (27%) cases with abortion (miscarriage and therapeutic) and 14 (9%) stillbirths occurred. The comparison of the groups showed that the whole abortion rates including therapeutic abortion were significantly higher in Group 1, and lower in groups 3 and 5 (p <0.001). However, miscarriage rates were similar between the groups. A total of 53 pregnancies (34%) suffered from prosthetic valves thrombosis (PVT) during pregnancy or in the postpartum period. Group 2 had significantly lower rates of PVT than the other groups (p <0.001). In conclusion, the current data suggests that there is no optimal therapy, and that all managements have advantages and disadvantages. Low-dose warfarin (≤5 mg/day) regimen with therapeutic international normalized ratio levels may provide effective maternal protection throughout pregnancy with acceptable fetal outcomes.

Warfarin-related nephropathy in a patient with renal pelvic cancer

An 83-year-old Japanese man had a history of chronic heart failure due to bradycardia-tachycardia syndrome. He was admitted to our hospital because of macrohematuria and acute kidney injury (AKI), which were detected by an urologist at an outpatient visit. He had a history of recurrent macrohematuria and transurethral resection of bladder tumors twice in the preceding 2 years. He had been on warfarin for 12 years, with a stable international normalized ratio (INR) that was usually less than 2.1. Urinalysis revealed numerous red blood cells (RBCs) and mild proteinuria without RBC casts. His serum creatinine level was elevated to 2.41 mg/dL from 0.96 mg/dL at 3 weeks before admission. INR was 1.44. Hydronephrosis was not observed. Ureteroscopy detected invasive urothelial carcinoma of the renal pelvis, and right laparoscopic nephroureterectomy was performed at 41 days after diagnosis of AKI. The background renal parenchyma displayed tubular obstruction by red blood cell casts and acute tubular injury, which were changes compatible with warfarin-related nephropathy (WRN). Warfarin was discontinued, and the serum creatinine level recovered to 1.66 mg/dL after 3 months. In the present patient with nephrosclerosis, WRN occurred at a therapeutic INR level after 12 years of uneventful warfarin therapy, and the coexisting urothelial malignancy was a unique feature.

A novel point for warfarin usage in ACCP Guidelines, 2012 and its importance for quality of anticoagulation. Commentary on the article by Dr. Ciurus et al. (Kardiochir Torakochir Pol 2015; 12 (4): 334-340).

We have read with great interest the article about the factors affecting the quality of anticoagulation with warfarin by Ciurus et al. [1]. The authors implicate the importance of predictors of controlling the anticoagulation. They aim to assess the quality of anticoagulant therapy in patients on warfarin and evaluate the factors affecting its deterioration. We thank the authors for their well-designed study. Regarding the current guidelines concerning anticoagulant therapy, we detected some contradictory and overlooked points that should be highlighted. We want to make some contributions to the report by Ciurus et al. [1] about the warfarin usage introduction update and education change according to current guidelines. Despite the presentation of new anticoagulants, vitamin K antagonists (VKA) still maintain their importance in clinical administration [2]. Unfortunately, this wide use of VKA is still associated with a wide spectrum of complications. Particular concerns have been raised regarding prevention of these complications. As one of them, the Ciurus et al. emphasized that maximizing the time in the optimum therapeutic range has great importance for avoiding adverse clinical outcomes [1]. To attain this goal, controlling the patient-specific factors such as adherence to the therapeutic plan, appropriate dosing, and reliable international normalized ratio (INR) control are very important. Among such patient-related factors, the feeding habit of the patients is a special issue. Many doctors and patients remember the wide VKA interaction food list containing dietary vitamin K. It has been a frequent practice to limit or alter dietary habits of the patients according to those food lists. But this clinical advice has been changed by the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines, 2012 [3]. It is suggested in the abovementioned document that limitations of diet deteriorate the therapeutic INR levels. Because most people have long-lasting dietary habits, which are very difficult to change, attempts to change any dietary habit may result in uncontrolled alterations of oral vitamin K intake, resulting in difficulties sustaining the therapeutic INR levels. The ACCP guidelines recommend that “A consistent intake of vitamin K-containing foods is advisable, but neither specific restrictions nor additions seem necessary in patients with stable anticoagulant control. Patients should be informed of possible changes in INR, in particular in response to the use of dietary supplements or herbs, or alcohol used chronically or ingested in large quantities.” The authors reported that, “The participants were informed about the diet limitations required in order to improve the effectiveness of the anticoagulant therapy.” Although this suggestion is valid for attaining a therapeutic level, it is very difficult to maintain this level in therapeutic doses. That is why we think the ACCP guidelines made a modification on warfarin use in 2012, which we cannot see in the previous guidelines from 2008 [4]. We also agree with the suggestion that the patient should be informed about the food and drug interactions but no suggestion should be made on limiting dietary intake, in order to maintain therapeutic INR levels.

Improving transitions of care for patients on warfarin: The safe transitions anticoagulation report.

Adverse drug events are common during the transition period after hospitalization, and anticoagulants are among the medication classes for which the incidence is highest. We aimed to develop a concise report to improve the timeliness of international normalized ratio (INR) testing and quality of warfarin management posthospitalization. We developed the Safe Transitions Anticoagulation Report (STAR), which contains essential information on anticoagulation and is embedded in the discharge summary, and implemented the report and associated workflow in a tertiary care hospital within an integrated healthcare system. We performed a retrospective administrative database review of 505 patients in the preintervention period and 292 patients in the intervention period who were discharged on warfarin and were established patients at an affiliated ambulatory practice. There was no change in the frequency of obtaining an INR value within 10 days of discharge (41.4% and 47.6%, respectively, P = 0.09), and no increase in attaining a therapeutic INR level within 10 days of discharge (17.0% and 21.2%, respectively, P = 0.14). Ambulatory clinicians reported that the STAR improved "workflow and efficiency" (58%) and "patient safety" (77%), and led to an altered warfarin dose for 34% of survey respondents. Our study found that a concise anticoagulation report embedded in the discharge summary was perceived by ambulatory physicians as improving patient safety, but had no impact on clinical outcomes, suggesting that this electronic medical record tool would need to be a component of a broader multifaceted intervention to be effective.

Epidemiology, anticoagulant treatment and risk of thromboembolism in patients with valvular atrial fibrillation: Results from Atrial Fibrillation in Turkey: Epidemiologic Registry (AFTER)

The aim of this study was to perform a multicenter, prospective investigation regarding the epidemiology, the current effectiveness of therapeutic anticoagulation, and the risk of thromboembolism in patients with valvular atrial fibrillation (AF) based on the records of the Atrial Fibrillation in Turkey: Epidemiologic Registry (AFTER) study. Patients were selected from a total of 2,242 consecutive admissions that presented with AF diagnosed via electrocardiogram. Those diagnosed with non-valvular AF were excluded from the AFTER study population, which left 497 patients with valvular AF for analysis. The etiology of valvular AF in patients was either attributed to rheumatic mitral valve stenosis (n = 217) or possessing a prosthetic heart valve (n = 280). Out of all the patients with valvular AF, 83.1% were taking warfarin for anticoagulation. Only 36.1% demonstrated a therapeutic international normalized ratio (INR), and among those patients it was found that 19.1% exhibited a labile INR. Multivariate analysis revealed that age was the only independent predictor of thromboembolic events in patients with valvular AF. Many valvular AF patients are not maintained at therapeutic INR levels, which poses a threat to patient health as they age and are at greater risk for thromboembolism.

Admission International Normalized Ratio Levels, Early Treatment Strategies, and Major Bleeding Risk Among Non–ST-Segment–Elevation Myocardial Infarction Patients on Home Warfarin Therapy

Background— Non–ST-segment–elevation myocardial infarction patients on home warfarin pose treatment concerns because of their potential increased risk of bleeding. Expert opinion from the American College of Cardiology/American Heart Association guidelines suggest holding anticoagulants and initiating antiplatelet therapy among therapeutically anticoagulated non–ST-segment–elevation myocardial infarction patients. Yet, little is known about contemporary treatment patterns and bleeding risks in this population. Methods and Results— We stratified 5787 non–ST-segment–elevation myocardial infarction patients on home warfarin therapy using data from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines by admission international normalized ratio (INR) levels: subtherapeutic (INR &lt;2), therapeutic (INR, 2–3), and supratherapeutic (INR &gt;3). Multivariable logistic generalized estimating equations models were constructed to examine the associations between admission INR level, early antithrombotic treatment and invasive therapy, and risk of in-hospital major bleeding. Among these patients, 46%, 35%, and 19% had subtherapeutic, therapeutic, and supratherapeutic admission INR levels, respectively. Risk of major bleeding was higher among patients with therapeutic (15%; adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.03–1.50) and supratherapeutic (22%; odds ratio, 1.60; 95% CI, 1.30–1.97) anticoagulation compared with the subtherapeutic group (12%). Among patients with admission INR ≥2, 45% were treated with early (within 24 hours) heparin, 35% with early clopidogrel, 14% with early glycoprotein IIb/IIIa inhibitor, and 36% with early invasive strategy. Early antithrombotic treatment was associated with increased bleeding risk (odds ratio, 1.40 [95% CI, 1.14–1.72] for heparin; 1.50 [95% CI, 1.22–1.84] for clopidogrel; and 1.82 [95% CI, 1.43–2.32] for glycoprotein IIb/IIIa inhibitor); however, an early invasive strategy was not (odds ratio, 1.09; 95% CI, 0.86–1.37). No significant interactions were observed between INR level and use of each early treatment in its association with bleeding. Conclusions— National patterns of early antithrombotic treatment for non–ST-segment–elevation myocardial infarction patients on home warfarin diverge from expert opinion provided by current practice guidelines. Early antithrombotic treatment was associated with increased bleeding risk regardless of admission INR level.

A retrospective assessment comparing pharmacist-managed anticoagulation clinic with physician management using international normalized ratio stability

To assess the rates of therapeutic international normalized ratio (INR) levels between pharmacist-managed clinics compared to traditional physician-management and to determine the variation in rates of therapeutic INR levels between pharmacist-managed clinic data compared to physician-management. Retrospective, randomized, chart review. Referral only, outpatient, pharmacist based anticoagulation clinic under a community based tertiary care health system. Sixty-four patients with at least 1year's worth of visits to the pharmacist managed clinic were reviewed for INR stability. The average percentage of visits within the defined therapeutic range, was 71.1% for the physician-managed group versus 81.1% for the pharmacist-managed group (P<0.0001). The estimated variance in average therapeutic INR rates was double for the physician-managed group (365.7) versus the pharmacist-managed group (185.2) (P=0.004). The pharmacist-managed anti-coagulation clinic had higher rates of INRs determined to be therapeutic and also exhibited significantly less variability in therapeutic INR rates relative to the physician-managed service.

Thirteen novel VKORC1 mutations associated with oral anticoagulant resistance: insights into improved patient diagnosis and treatment

Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is the molecular target of oral anticoagulants. Mutations in VKORC1 cause partial or total coumarin resistance. To identify new VKORC1 oral anticoagulant (OAC) resistance (OACR) mutations and compare the severity of patient phenotypes across different mutations and prescribed OAC drugs. Six hundred and twenty-six individuals exhibiting partial or complete coumarin resistance were analyzed by VKORC1 gene sequencing and CYP2C9 haplotyping. We identified 13 patients, each with a different, novel human VKORC1 heterozygous mutation associated with an OACR phenotype. These mutations result in amino acid substitutions: Ala26→Thr, His28→Gln, Asp36→Gly, Ser52→Trp, Ser56→Phe, Trp59→Leu, Trp59→Cys, Val66→Gly, Gly71→Ala, Asn77→Ser, Asn77→Tyr, Ile123→Asn, and Tyr139→His. Ten additional patients each had one of three previously reported VKORC1 mutations (Val29→Leu, Asp36→Tyr, and Val66→Met). Genotyping of frequent VKORC1 and CYP2C9 polymorphisms in these patients revealed a predominant association with combined non-VKORC1*2 and wild-type CYP2C9 haplotypes. Additionally, data for OAC dosage and the associated measured International Normalized Ratio (INR) demonstrate that OAC therapy is often discontinued by physicians, although stable therapeutic INR levels may be reached at higher OAC dosages. Bioinformatic analysis of VKORC1 homologous protein sequences indicated that most mutations cluster into protein sequence segments predicted to be localized in the lumenal loop or at the endoplasmic reticulum membrane-lumen interface. OACR mutations of VKORC1 predispose afflicted patients to high OAC dosage requirements, for which stable, therapeutic INRs can sometimes be attained.

Nephrology literature watch

Nephrology literature watch

Warfarin INR Patterns Following Total Hip Arthroplasty.

Abstract 1068Poster Board I-90 Introduction:Anticoagulant therapy is recommended for preventing venous thromboembolism (VTE) among patients undergoing total hip arthroplasty (THA). During warfarin therapy, monitoring of international normalized ratio (INR) is necessary to avoid underdosing (which can lead to VTE and associated events) or overdosing (which can lead to significant bleeding). The purpose of this project was to investigate the distribution of out-of-range INR results among warfarin-treated patients undergoing THA. Patients and Methods:A retrospective cohort analysis was conducted using the MedMining® database of electronic medical record. Data were obtained for patients with a THA procedure and a prescription for warfarin issued within 3 days of surgery from January 1, 2004 through January 31, 2009. We identified INR results following surgery during warfarin therapy for up to 90 days. INR results were categorized as in therapeutic range (2–3), below range (< 2), or above range (> 3). For each patient, we calculated the proportion of INR results in each category. Time to first in-range INR was calculated as days from warfarin start to first in-range level for those with at least 1 in-range level. Results:Of 1512 eligible patients, 58.4% were aged 65 years and above, 57.5% were female, and 98.5% were White/Caucasian. The most common reason for surgery was osteoarthritis (78.4%) and the mean length of hospital stay was 4.0 days (SD, 2.5 days). Most patients (77.6%) had 2 or more INR levels during warfarin exposure; 39.9% had 5 or more INR values. Among the 1173 patients with at least 2 INR levels available, patients had a mean of 15.7% of INR values within therapeutic range, 82.1% of INR levels below the therapeutic range and 2.2% of values above range. A total of 53.3% of patients with at least 2 INR levels had no INR fall within the therapeutic range. The median time to first in-range INR was 7 days (range 1-80 days). Conclusions:This population-based observational study found poor warfarin anticoagulation control in THA patients with only about half of patients having INRs within the therapeutic range. INR levels above the therapeutic range were rare, but many patients received insufficient doses of warfarin to achieve therapeutic INR levels. Among those who did achieve at least one in-range INR, the time to achieve this was long, exposing the patient to the risk of VTE during the highest post-op risk period (i.e., within the first 7 days after surgery). It is possible that surgeons are targeting sub therapeutic INR ranges or patients have poor adherence to warfarin therapy; the data do not permit an investigation of physicians' targets or whether patients took the medication as prescribed. These research findings may not be generalizable to the broader US population. A study of the consequences of INR values below the therapeutic range in the THA population is warranted. Disclosures:Kachroo:Ortho-McNeil Janssen Scientific Affairs, LLC: Research Funding; United BioSource Corp: Employment. Nordstrom:United BioSource Corp: Employment; Ortho-McNeil Janssen Scientific Affairs, LLC: Research Funding. Nutescu:Ortho-McNeil Janssen Scientific Affairs, LLC: Research Funding. Schein:Ortho-McNeil Janssen Scientific Affairs, LLC: Employment. Bookhart:Ortho-McNeil Janssen Scientific Affairs, LLC: Employment, Equity Ownership.

Warfarin INR Patterns Following Total Knee Arthroplasty.

Abstract 2100Poster Board II-77Introduction: Anticoagulant therapy is recommended for preventing venous thromboembolism (VTE) among patients undergoing total knee arthroplasty (TKA). During warfarin therapy, monitoring of international normalized ratio (INR) is necessary to avoid underdosing (which can lead to VTE and associated events) or overdosing (which can lead to significant bleeding). The purpose of this project was to investigate the distribution of out-of-range INR results among warfarin-treated patients undergoing TKA. Patients and Methods: A retrospective cohort analysis was conducted using the MedMining® database of electronic medical record data. Data were obtained for patients with a TKA procedure and a prescription for warfarin issued within 3 days of surgery from January 1, 2004 through January 31, 2009. We identified INR results during warfarin therapy following surgery for up to 90 days. INR results were categorized as in therapeutic range (2–3), below range (< 2), or above range (> 3). For each patient, we calculated the proportion of INR results in each category. Time to first in-range INR was calculated as days from warfarin start to first in-range level for those with at least 1 in-range level. Results: Of 1801 eligible patients, 63.3% were aged 65 years and above, 62.7% were female, and 98.3% were White/Caucasian. The most common reason for surgery was osteoarthritis (96.6%) and the mean length of hospital stay was 3.6 days (SD, 1.4 days). Most patients (82.7%) had 2 or more INR levels during warfarin exposure; 44.2% had 5 or more INR values. Among the 1173 patients with at least 2 INR levels available, patients had a mean of 15.3% of INR values within therapeutic range, 82.9% of INR levels below the therapeutic range and 1.8% of values above range. A total of 52.8% of patients with at least 2 INR levels had no INR fall within the therapeutic range. The median time to first in-range INR was 7 days (range 1-90 days). Conclusions: This population-based observational study found poor warfarin anticoagulation control in TKA patients with only about half of patients having INRs within the therapeutic range. INR levels above the therapeutic range were rare, but many patients received insufficient doses of warfarin to achieve therapeutic INR levels. Among those who did achieve at least one in-range INR, the time to achieve this was long, exposing the patient to the risk of VTE during the highest post-op risk period (i.e., within the first7 days after surgery). It is possible surgeons are targeting sub therapeutic INR ranges or patients have poor adherence to warfarin therapy; the data do not permit an investigation of physicians' targets or whether patients took the medication as prescribed. These research findings may not be generalizable to the broader US population.A study of the consequences of INR values below the therapeutic range in the TKA population is warranted. Disclosures:Kachroo:United BioSource Corp: Employment; Ortho-McNeil Janssen Scientific Affairs, LLC: Research Funding. Nordstrom:United BioSource Corp: Employment; Ortho-McNeil Janssen Scientific Affairs, LLC: Research Funding. Nutescu:Ortho-McNeil Janssen Scientific Affairs, LLC: Research Funding. Schein:Ortho-McNeil Janssen Scientific Affairs, LLC: Employment. Bookhart:Ortho-McNeil Janssen Scientific Affairs, LLC: Employment, Equity Ownership.

Epidemiology and outcomes in patients with atrial fibrillation in the United States

Nonrheumatic atrial fibrillation (AF) is a common cause of embolic stroke. Warfarin therapy can reduce stroke risk by two-thirds in patients with AF, but therapy may not always be used or always be used optimally. This study sought to document the patterns of anticoagulant use and the determinants and incidence of stroke, intracranial hemorrhage, and arterial thromboembolism in US patients with AF. Using health insurance claims and laboratory results, we examined events per unit of person-time and used Poisson regression to quantify the association of AF outcomes with the international normalized ratio (INR) and other covariates. In 116,969 patients age > or =40 years with an insurance claim for AF or atrial flutter between 1999 and 2005, warfarin was prescribed to 45%, and 48% had no claim for any anticoagulant or antiplatelet agent. Subtherapeutic INR levels (<2.0) raised the incidence of stroke (relative risk [RR]: 2.39, 95% confidence interval [CI]: 1.68 to 3.41) and arterial thromboembolism (RR: 5.68, 95% CI: 1.88 to 17.10) compared with therapeutic INR levels, whereas supratherapeutic INR levels (>3.0) doubled the incidence of intracranial hemorrhage (RR: 2.11, 95% CI: 1.16 to 3.84). Further covariate adjustment had little effect on these estimates. Warfarin remains underused within the outpatient setting. Nontherapeutic INR levels are associated with increased risk of stroke, bleeding, and thromboembolism compared with therapeutic INR levels.

Excessive prolongation of prothrombin time among patients treated with warfarin and admitted to the emergency room

Introduction Patients treated with warfarin are uncommonly admitted with excessive prolongation of international normalized ratio (INR) of prothrombin time (PT) to the emergency room (ER). Here we wanted to evaluate the reasons behind this prolongation, clinical and laboratory parameters, course and outcome of these patients. Patients and methods Consecutive patients admitted to the ER with prolonged PT-INR > 6 under warfarin treatment and who gave sufficient information regarding history of warfarin treatment, were followed prospectively. Patients or care-givers were asked about warfarin treatment, PT monitoring, current and new medications especially antibiotics and diet. Clinical and laboratory parameters, course and outcome were also documented. Age and gender matched patients with therapeutic INR level were used as a control group. Results 75 patients finished the study. The median INR level among the patients was 8.5 and a range of 6.1–59.5. The median duration of warfarin treatment was 12 months among the patients vs. 36 in the control group, p < 0.001 and family physician was the sole decider on warfarin dose in 71 patients vs. 49 in the control group, p < 0.100. 19 patients adhered to balanced diet vs. 34 in the control group, p = 0.01. Dose increment of warfarin was the most common definite cause of prolonged PT followed by adding new medication especially amiodarone and recently started warfarin. Significantly more patients had evidence of bleeding than the control group but no difference in mean hemoglobin level or number of patients transfused with packed cells. No difference in the number of patients hospitalized or duration of hospitalization, but 5 in-hospital fatalities in the patients' group vs. none in the control group. Conclusion Excessive PT prolongation is mainly due to warfarin dose increment, adding new medication especially amiodarone and recently started warfarin. It is significantly more associated with bleeding and higher in-hospital mortality.

Effect of methimazole on warfarin anticoagulation in a case of Graves' disease

The article describes a case of Graves' disease treated with methimazole and examines the influence of methimazole-induced alterations of thyroid hormone concentrations during warfarin therapy. A 22-year-old woman presented at our endocrinology outpatient clinic with palpitations, sweating, fatigue, tremors, and diarrhea. She had a pain in her right leg and had difficulty walking. Her thyroid profile was consistent with hyperthyroidism. The patient was treated with warfarin 5 mg once a day for deep vein thrombosis for 2 days. Since a therapeutic range of International Normalized Ratio levels could not be achieved, methimazole was stopped due to drug-drug interaction. Lithium was started instead. A euthyroid state was obtained in 2 weeks together with a therapeutic International Normalized Ratio level. Interactions between warfarin and drugs that alter thyroid hormone concentrations have been reported; however, the extent and significance of the interaction between methimazole and warfarin have been inadequately described. Concomitant therapy with warfarin and antithyroid drugs should be managed by frequent monitoring of both thyroid function and the International Normalized Ratio. Lithium is employed only to provide temporary control of thyrotoxicosis in patients who cannot take thionamide and iodide. The administration of lithium alone or in combination with other drugs is shown to be an effective method of controlling hyperthyroidism when conventional antithyroid drugs show adverse effects or become insufficient. When warfarins are used together with antithyroid medications, adequate anticoagulation may not be obtained due to drug-drug interactions. Lithium can be an alternative drug for antithyroid medication in patients on warfarin therapy.