Patients Receiving Warfarin Therapy Research Articles

Health Care Expenditures and Therapeutic Outcomes of a Pharmacist‐Managed Anticoagulation Service versus Usual Medical Care

To evaluate the differences in health care expenditures and therapeutic outcomes of patients receiving warfarin therapy management by a pharmacist-managed anticoagulation service compared with those receiving warfarin management by usual medical care. Retrospective, matched-cohort study. University of Pittsburgh Medical Center (UPMC) and UPMC Health Plan. Three hundred fifty adults who received warfarin therapy; 175 were managed by the pharmacist-managed anticoagulation service for at least 2 months between October 1, 2007, and September 30, 2008, (case patients) and 175 received usual care (matched comparison group). Medical claims data compared were direct anticoagulation cost and overall medical care costs, anticoagulation-related adverse events, hospitalizations and emergency department visits, frequency of international normalized ratio (INR) testing, and quantity of warfarin refills. Operational costs of the anticoagulation service were also calculated. The INR values and time within therapeutic range were assessed through anticoagulation service reports and laboratory results. The direct anticoagulation care cost was $35,465 versus $111,586 and the overall medical care cost was $754,191 versus $1,480,661 for the anticoagulation service group versus the usual care group. Accounting for operational and drug expenditure costs, the cost savings was $647,024 for the anticoagulation service group. The anticoagulation service group had significantly fewer anticoagulation-related adverse events (14 vs 41, p<0.0001), hospital admissions (3 vs 14, p<0.00001), and emergency department visits (58 vs 134, p<0.00001). The percentage of INR values in range and the percentage of time the INR values were in range were significantly higher in the anticoagulation service group (67.2% vs 54.6%, p<0.0001, and 73.7% vs 61.3%, p<0.0001, respectively). Compared with the usual care group, the anticoagulation service group had significantly more INR tests performed but demonstrated no significant difference in the quantity of drug refills. After accounting for operational costs, pharmacist-managed anticoagulation leads to reduced health care expenditure while improving therapeutic outcomes compared with usual medical care.

Effect of Acetaminophen on International Normalized Ratio in Patients Receiving Warfarin Therapy

Warfarin is known to have extensive interactions with many classes of drugs. The literature suggesting a relevant interaction between acetaminophen and warfarin is inconsistent. Considering the ubiquitous use of acetaminophen, a review of the effects on international normalized ratio (INR) in patients taking warfarin was necessary. Thus, we performed a search of the PubMed (1966-November 2010) and International Pharmaceutical Abstracts (1970-November 2010) databases to review the available literature addressing an acetaminophen-warfarin interaction and its possible mechanisms. A sample of case reports, in addition to all English-language studies were evaluated, and relevant references were examined for additional articles. Reports of nonwarfarin coumarin anticoagulants were excluded. Published documentation reporting an interaction between acetaminophen and warfarin is limited. Small prospective studies of various designs and case studies describe aberrant INR results in patients using acetaminophen while receiving warfarin. These INR elevations typically involved acetaminophen ingestion of at least 2 g/day for several consecutive days. In several small prospective studies, INR results were elevated to a statistically significant extent that would require a change in warfarin dosing and monitoring in clinical practice. The mechanism for this interaction remains to be elucidated yet is suggested to occur through alterations in hepatic metabolism. The use of moderate-to-high doses of acetaminophen while receiving warfarin results in supra-therapeutic INRs in some patients. The characteristics that may predispose a patient to this interaction are unclear, yet the widespread use of acetaminophen calls for enhanced clinician awareness and reinforcement of patient education about this interaction.

Thoracic aorta pseudoaneurysm with hemopericardium: unusual presentation of warfarin overdose

There have been few case reports which discuss a relationship between warfarin overdose and aortic pseudoaneurysm leakage. We report the case of a female receiving warfarin who presented with dsypnea. Her international normalized ratio was > 10. Chest radiograph revealed cardiomegaly, and chest computed tomography (CT) showed a bulging pouch-like lesion below the aortic arch greater than 6x6 cm in size and a fluid collection suggesting blood in the pericardium. Thoracic endovascular aneurysm repair (TEVAR) was successfully performed by a cardiovascular surgeon. Aortic pseudoaneurysm formation and leakage may be considered as a rare complication in patients receiving warfarin therapy. Further study regarding warfarin use and the incidence of pseudoaneurysm leakage is needed.

INR goal attainment and oral anticoagulation knowledge of patients enrolled in an anticoagulation clinic in a Veterans Affairs medical center.

In January 2009, the Joint Commission implemented a National Patient Safety Goal (NPSG) for ambulatory care, NPSG 3E, intended to reduce harm associated with the use of anticoagulation therapy. The 2011 NPSG 3E encompasses 8 elements of performance, including requirements that each organization (a) provide education regarding anticoagulation therapy to staff, patients, and families and (b) evaluate its safety practices and take appropriate action to improve its practices. The Alvin C. York (ACY) outpatient anticoagulation clinic provides education to new patients and their families at the initial clinic visit, with follow-up reinforcement of education as needed throughout their care. To (a) assess the knowledge level of patients receiving warfarin therapy in an anticoagulation clinic using the validated Anticoagulation Knowledge Assessment (AKA) questionnaire and (b) examine the relationship between patient anticoagulation knowledge and anticoagulation control as measured by the international normalized ratio (INR). All ACY Veterans Affairs (VA) anticoagulation clinic patients seen during their routine visit within an 8-week recruitment period from February 2010 to April 2010 were asked to complete the AKA questionnaire. Upon voluntary consent, the questionnaire was completed by the patient either during the clinic visit or returned later by mail. Demographic and clinical data were manually extracted from the computerized patient record system and included age, gender, indication for and duration of anticoagulation therapy, goal INR range, and the 10 INR values preceding the date of consent. A passing score was defined as at least 21 correct responses on the 29-item AKA questionnaire (72.4% correct). Statistical analyses included comparisons of demographic and clinical characteristics for patients with passing versus failing scores, assessed with Pearson chi-square and Fisher's exact test, and bivariate analyses of INR control with anticoagulation knowledge, assessed with Spearman's rho correlation. INR control was defined by 3 outcome measures: number of INRs within therapeutic range, time in therapeutic range (TTR) calculated using the Rosendaal method, and standard deviation (SD) of INR values. Anticoagulation knowledge was assessed with 2 measures: total AKA score and count of correct answers to a subset of 15 AKA items deemed by the investigators to be relevant to INR control. Of 447 patients enrolled in the anticoagulation clinic, 260 consented to participate in the survey, of whom 185 patients completed the AKA instrument (n=171 [92.4%] by mail) and were successfully matched to patient record system data. 178 (96.2%) respondents were male with a mean (SD) age of 68 (10.1) years. The majority of patients were undergoing anticoagulation treatment for atrial fibrillation (n=113, 61.1%) or deep venous/pulmonary thromboembolism (n=48, 25.9%). The majority of patients had been treated with warfarin for at least 1 year (n=162, 87.6%). Most patients had goal INR ranges of 2.0 to 3.0 (n=166, 89.7%). Of the 185 patients who completed the questionnaire, 137 (74.1%) achieved a passing score. The mean (SD) AKA questionnaire score was 78.1% (12.1%). There were 8 questions that were answered correctly by less than 70% of patients and identified as potential deficiencies in patient education. For the 167 patients who had been on warfarin therapy for at least 6 months and had 10 previous INR values, there was no significant Spearman's rho correlation between total number of correct questionnaire responses and INR control, defined as the count of the 10 previous INR values within goal range (rho =-0.022, P=0.776), TTR (rho=0.015, P=0.848), and SD (rho=0.047, P=0.550). There was also no significant relationship between number of correct INR-relevant responses and INR control by any of the 3 outcome measures (count in range rho=0.033, P=0.676; TTR rho=0.067, P=0.388; and SD rho=-0.029, P=0.708). Although 74.1% of patients on long-term warfarin therapy achieved a passing score of at least 21 correct answers on the 29-question AKA instrument, there was no significant relationship between patient warfarin knowledge and INR control. Areas for improvement in patient education have been identified and procedures for educational modification are currently in development.

Risk Factors Affecting Postoperative Hemorrhage After Tooth Extraction in Patients Receiving Oral Antithrombotic Therapy

We investigated risk factors affecting the onset of postoperative hemorrhage after tooth extraction in patients receiving oral antithrombotic therapy. A total of 443 tooth extractions were performed in 382 patients. All extractions were performed while continuing conventional antithrombotic therapy, and local hemostatic measures were performed. Among the 17 patients with postoperative hemorrhage, 9 received warfarin monotherapy, 6 received warfarin and antiplatelet combination therapy, and 2 received antiplatelet monotherapy. Postoperative hemorrhage occurred within 6 days in 16 patients (94.1%), with a median of 3 days. The international normalized ratio at the time of extraction was less than 3.0 for all 15 patients receiving warfarin therapy but was prolonged, at 3.0 or greater, in 7 of 12 patients in whom this value was measured at the time of postoperative hemorrhage. As for local hemostatic measures at the time of postoperative hemorrhage, thorough local hemostatic measures were required in 12 (80.0%) of the 15 patients receiving warfarin therapy. Conversely, in the 2 patients receiving antiplatelet therapy, hemostasis was achieved by use of compression alone. Concerning factors affecting postoperative hemorrhage, significant differences were seen in relation to surgical tooth extraction (P = .008) and acute inflammation findings (P = .007). In patients receiving antithrombotic therapy, surgical tooth extraction and acute inflammatory findings were associated with a significantly increased incidence of postoperative hemorrhage. In more than 90% of cases, postoperative hemorrhage occurred within 6 days of extraction. Thorough local hemostatic measures are therefore required in patients receiving warfarin therapy.

Management of Patients Receiving Warfarin during Invasive Procedures and the Adverse Effects of Warfarin

Aim: The aim of this study was to assess the frequency and characteristics of complications in patients on anticoagulant therapy who were to undergo invasive procedure.Methods and Results: We sent a questionnaire to 2758 doctors who were on the mailing list of the Japanese Society of Cardiac Pacing and Electrophysiology in August 2004. We received 614 questionnaires (response rate, 22.3%). Out of the 614 doctors, 19 (3.1%) reported that their patients had embolic events upon the interruption of warfarin therapy during dental extraction. In patients undergoing invasive procedures such as surgery, endoscopy, pacemaker implantation, and catheterization, 168 (27.4%) of the 614 doctors reported embolic events after the interruption of warfarin therapy. Further, 255 (41.5%) of the 614 doctors reported bleeding episodes when warfarin therapy was continued during the invasive procedures.Conclusion: Several complications of different types were reported to occur in patients receiving warfarin therapy who underwent elective invasive procedures, regardless of whether warfarin administration was interrupted or continued at the time of the invasive procedure. Therefore, it is necessary to make careful decisions about the management of patients on warfarin therapy who will be undergoing invasive procedures.

Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis

At the turn of the century, only 300 cases of warfarin-induced skin necrosis (WISN) had been reported. WISN is a rare but potentially fatal complication of warfarin therapy. There are no published reports of WISN occurring in patients with HIV-1 infection or tuberculosis (TB). We retrospectively reviewed cases of WISN presenting from April 2005 to July 2008 at a referral hospital in Cape Town, South Africa. Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%). All 6 cases occurred in HIV-1-infected women (median age 30 years, range 27 - 42) with microbiologically confirmed TB and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis 49 cells/microl, interquartile range 23 - 170). Of the 3 patients receiving combination antiretroviral therapy, 2 had TB-IRIS (immune reconstitution inflammatory syndrome). The median interval from initiation of antituberculosis treatment to venous thrombosis was 37 days (range 0 - 150). The median duration of parallel heparin and warfarin therapy was 2 days (range 1 - 6). WISN manifested 6 days (range 4 - 8) after initiation of warfarin therapy. The international normalised ratio (INR) at WISN onset was supra-therapeutic, median 6.2 (range 3.8 - 6.6). Sites of WISN included breasts, buttocks and thighs. Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 days after WISN onset. In 4 patients, the median interval from WISN onset to death was 43 days (range 25 - 45). One of the 2 patients who survived underwent bilateral mastectomies and extensive skin grafting at a specialist centre. This is one of the largest case series of WISN. We report a novel clinical entity: WISN in HIV-1 infected patients with TB and venous thrombosis. The occurrence of 6 WISN cases in a 40-month period may be attributed to (i) hypercoagulability, secondary to HIV-1 and TB: (ii) short concurrent heparin and warfarin therapy; and (iii) high loading doses of warfarin. Active prevention and appropriate management of WISN are likely to improve the dire morbidity and mortality of this unusual condition.

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application

Warfarin is a widely used oral anticoagulant with broad within- and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice. We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations. The mean maintenance dose of warfarin in 105 patients was 4.1 +/-1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3+/-0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r(2)=0.259, P<0.001) was higher than that with INR (r(2)=0.029, P=0.072). There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment.

Long-Term Oral Anticoagulation Therapy and the Risk of Hip Fracture in Patients with Previous Hemispheric Infarction and Nonrheumatic Atrial Fibrillation

Warfarin therapy has been demonstrated to reduce the risk of stroke in nonrheumatic atrial fibrillation (NRAF). We showed that long-term warfarin therapy reduces vitamin K and second metacarpal bone mineral density (BMD) in NRAF patients who had previous hemispheric infarction. To determine whether warfarin is associated with increased hip fracture risk, we compared the incidence of hip fracture between post-stroke patients receiving warfarin therapy and post-stroke patients without such therapy. Eighty-four post-stroke patients with NRAF who had been treated with warfarin and 93 post-stroke patients without warfarin were followed for 5 years and their incidence of hip fracture was compared. At baseline and 3 and 5 years later, sera were collected from both groups. Sera were assayed for undercarboxylated osteocalcin (ucOC), bone Gla protein and 25-hydroxyvitamin D (25-OHD). BMD was determined in second metacarpals. During 5 years, 8 hip fractures in the treated group and 9 hip fracture in the untreated group occurred (p = 0.92). After 5 years, serum ucOC concentrations were higher in treated patients (9.1 +/- 1.5 ng/ml) than in untreated patients (6.0 +/- 1.2 ng/ml). ucOC was significantly related to BMD in treated but not in untreated patients. Concentrations of 25-OHD were lower in both patient groups. Percent change of BMD from baseline was lower in treated patients than in untreated patients (p < 0.01). Long-term treatment with warfarin in stroke patients seems not to be associated with an increased risk of hip fracture.

Factors Associated With Long Hospital Length of Stay in Patients Receiving Warfarin After Cardiac Surgery

Patients receiving warfarin therapy after coronary artery bypass graft (CABG) or valve surgery have longer length of stay (LOS) than those not receiving warfarin therapy. Longer LOS increases patient costs, postdischarge recovery time, and rehabilitation. It is important to identify variables of longer postoperative LOS in this patient population so that the healthcare team can develop and facilitate interventions to minimize length of hospitalization. Using a hospital registry and medical record review of cases completed in 2004, data from cardiac surgery patients having CABG and/or valve procedures and given warfarin postoperatively were analyzed based on short (<7 days, CABG; 9 days, valve procedure) and long (> or =7 days, CABG; > or =9 days, valve procedure) postoperative LOS. By groups, significant associations were assessed using chi or Fisher exact test for categorical variables and Wilcoxon 2-sample test or Student t test for continuous variables. In 82 patients (33 CABG and 49 valve +/- CABG) who were given warfarin, most demographic, medical history, postoperative complications, and use of cardiac drugs did not predict longer LOS. Longer postoperative LOS was associated with being older (mean age, 73.5 vs 68.5 years), being not married, having postoperative respiratory insufficiency, and receiving more red blood cell transfusions, all P < .05; and having more healthcare consultations, longer critical care stay, and longer time between surgery date and start of warfarin; all P < .001. Variables associated with longer LOS were nonmodifiable by nursing services and were difficult to assess preoperatively. They primarily involved intraoperative or postoperative bleeding that led to red blood cell infusion and longer critical care stays that delayed warfarin initiation. However, older age and marital status are nursing targets because they may be associated with social isolation and other psychosocial issues. Transition of care programs can be developed to promote earlier discharge.

Thromboembolism in Patients With Atrial Fibrillation With and Without Left Atrial Thrombus Documented by Transesophageal Echocardiography

The incidence of cerebrovascular events (CVEs) was investigated in 95 consecutive patients with atrial fibrillation (AF) with left atrial thrombus (LAT) diagnosed by transesophageal echocardiography (TEE) and in 131 age- and sex-matched AF patients without LAT. Compared with patients without LAT, patients with LAT had a larger left atrial diameter (49 versus 44 mm, P < 0.0001), a lower left ventricular ejection fraction (40% versus 50%, P < 0.0001), a higher prevalence of spontaneous echocardiographic contrast (88% versus 25%, P < 0.001), a reduced left atrial appendage emptying velocity (0.25 versus 0.41 cm/s, P < 0.0001), and less use of antiarrhythmic drugs (61% versus 76%, P = 0.03). Before TEE, the prevalence of prior CVE was higher in LAT patients (20%) compared with patients without LAT (8%) (P = 0.01). Fifty-four of 95 LAT patients (57%) and 81 of 131 non-LAT patients (62%) were on warfarin before TEE. The incidence of prior CVE in LAT patients without warfarin (32%) was higher than that in non-LAT patients without warfarin (10%) (P = 0.02). The mortality rate in LAT patients with an international normalized ratio (INR) >or= 2.0 (42%) was higher than that in patients without LAT and an INR >or= 2.0 (11%) (P < 0.001). Fifty-one of 95 LAT patients (54%) underwent repeat TEE before cardioversion (48 patients received warfarin therapy). The thrombus resolved in 40 of 51 patients (78%) after the first TEE. There was no significant difference in INR between the patients with persistent and resolved LAT. AF patients with persistent LAT had a higher incidence of CVE (45%) than the patients with resolved LAT (5%) (P = 0.003). We suggest that patients with LAT be treated with warfarin to maintain an INR between 2.5 and 3.5 rather than between 2.0 and 3.0 because they are at a high risk for new thromboembolism.

Utility of an International Normalized Ratio Testing Device in a Hospital-Based Dental Practice

The authors aimed to evaluate the utility of an in-office international normalized ratio (INR) testing device in identifying patients with INR test values considered out of the normal range for dental procedures. This prospective cohort study involved use of an INR testing device to obtain INR test values in the dental office for patients thought to be at risk of experiencing bleeding complications after undergoing invasive dental procedures. The authors recorded demographic, social and medical history data, as well as clinical signs and symptoms of liver disease. The authors considered an INR out of range if it was greater than or equal to 1.4 for patients with potential liver disease and greater than 3.5 for patients receiving warfarin. The authors completed an in-office INR test for 66 patients receiving warfarin whose INR had not been tested within the preceding 48 hours and 34 patients suspected of having liver disease. Eleven (17 percent) patients receiving warfarin and seven (21 percent) patients suspected of having liver disease had INR values considered out of range. Dental treatment was deferred for eight of 11 patients in the warfarin group who had INR values in the range of 3.6 to 7.4, while three others had dental procedures without bleeding complications. Six of seven patients who had documented or suspected liver disease and an out-of-range INR (range 1.5-2.5) underwent their dental procedures without experiencing bleeding complications. Use of an in-office INR test indicated a high incidence of elevated INR values. The results of this study point to the importance of obtaining current INR values before performing invasive dental procedures for patients receiving warfarin therapy whose INR values have not been tested recently, and for patients thought to be at risk of developing or having liver disease.

Where does patient self-management of oral anticoagulation fit within the current models of service provision?

Therapeutic management of oral anticoagulation is not straightforward. The British Committee for Standards in Haematology produced updated evidence-based guidelines in 1998 for therapeutic management, which encourage clinicians to aim for a target International Normalized Ratio (INR), with specific targets and ranges stated for individual conditions [1]. However, there remain concerns over where and how warfarin monitoring should be undertaken [2,3]. Historically, oral anticoagulation has been underutilized as a thromboprophylactic agent for patients with atrial fibrillation, whilst without screening programs, it is possible that approximately 60% of patients with atrial fibrillation remain unidentified [3,4]. It is clear, therefore, that the number of patients receiving warfarin therapy will continue to rise above the currently estimated 1 million [5,6]. Traditionally, patients receiving oral anticoagulant therapy attended a hospital out-patient clinic where INR estimation was undertaken using either capillary or venous citrated blood samples, with the result being available either immediately or at a later stage. Whilst the clinic has traditionally been led by a consultant hematologist, alternative arrangements have utilized cardiologists, surgeons, specialist nurses [7], laboratory staff and pharmacists [8]. Based on UK data, patients should expect to be within their own therapeutic range at least 65% of the time. This is the standard to which any alternative models have to compare [6]. Where INR results are available with the patient present, dosing recommendations are made and the patient given a date for the next appointment (up to 12 weeks in a stable patient [1]). When there is a delay in the INR estimation, patients receive dosing and recall advice through the post via patient-held records, or

Dietary Vitamin K in Oral Anticoagulation Patients: Clinician Practices and Knowledge in Outpatient Settings

Background: Dietary vitamin K is a recognized variable associated with oral anticoagulant therapy. However, current practices of dietary education and instruction regarding vitamin K, as well as factors influencing related decision-making, are unknown. Research has examined healthcare providers' ability to identify a meal containing vitamin K, but the ability to classify portions of specific vegetables according to vitamin K content has not been evaluated. Objective: To characterize dietary evaluation and instructional methods provided to patients receiving warfarin therapy, assess factors influencing instructional methods, and evaluate clinician knowledge of vitamin K content for specific vegetable portions. Methods: A cross-sectional online survey of US healthcare providers involved with management of outpatient oral anticoagulation therapy was conducted. Results: One hundred twenty-two responses were received. Seventy-four percent of respondents collected initial dietary history from all patients and 52% asked all patients for dietary history at follow-up visits. Taking a verbal dietary history from all patients was significantly associated with larger clinic size and managing patients in person. Eighty-two percent of respondents reported providing dietary vitamin K education to all patients. Low patient literacy was a common factor influencing instruction to avoid foods high in vitamin K. Overall mean score reflecting the ability to classify vegetable portions by vitamin K content was 64.6 ± 10.9%. Conclusions: Acquisition of dietary history by anticoagulation providers is not always completed at initial and follow-up patient visits. Provision of patient education at initial visits is relatively high. Patient factors such as low literacy may influence a clinician's decision to provide a specific method of dietary instruction, including avoidance of foods high in vitamin K. Clinicians are least likely to correctly identify vegetable portions containing vitamin K in the range of 10–99 μg and should consider portion size when assessing dietary history.

Ethnic Differences in the VKORC1 Gene Polymorphism and an Association with Warfarin Dosage Requirements in Cardiovascular Surgery Patients

Vitamin K epoxide reductase (VKORC1) is the drug target for inhibition by coumarin-based anticoagulant drugs such as warfarin. Warfarin therapy has been reported as a leading cause of drug-related hospitalization and there is therefore an urgent need to develop tests for better warfarin prescription. We report here the distribution of the intron 1 -136 T>C (1173 T>C intron) polymorphism of VKORC1, previously reported to be associated with warfarin maintenance dose in Caucasians and Japanese, in several ethnic populations from Japan and Israel, and describe its significance for warfarin dosage in Japanese cardiovascular surgery patients. Subjects consisted of 132 Japanese individuals and 341 Israeli individuals from four Jewish ethnic groups (86 Ashkenazi Jews, 95 Yemenite Jews, 73 Moroccan Jews and 87 Libyan Jews). In addition, 31 Japanese patients receiving warfarin therapy after cardiovascular surgery, maintained with a target International Normalized Ratio, were studied. The genotyping for the 1173 T>C intron polymorphism of VKORC1 was determined using rapid real-time PCR. The allele frequency of the combined VKORC1 1173 CT and CC genotypes varied among the four Israeli ethnic groups and was, on average, much higher in the Israeli (0.728) than in the Japanese population (0.152). For the Japanese cardiovascular surgery patients, the maintenance dose of warfarin was significantly larger in the combined VKORC1 1173 TC and CC genotype group than in the 1173 TT genotype group (3.6 +/- 0.5 mg vs 2.8 +/- 0.7 mg, respectively; p = 0.02). The frequencies of the intron 1 VKORC1 1173 T>C SNP show significant differences between ethnic groups and are associated with warfarin dose requirements for achieving a recommended International Normalized Ratio range in Japanese cardiovascular surgery patients. This study supports the example of warfarin as an appropriate model for applying personalized medicine for anticoagulant drugs, and highlights the importance of ethnicity in pharmacogenetics.

Risk of Major Bleeding with Concomitant Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients Receiving Long‐Term Warfarin Therapy

To characterize the safety of concomitant aspirin, clopidogrel, and warfarin therapy after percutaneous coronary intervention (PCI), and to identify patient characteristics that increase the risk of hemorrhage. Retrospective, matched cohort study. Academic medical center and affiliated outpatient offices. The active group consisted of 97 patients who underwent PCI from January 1, 2000-September 30, 2005, and received warfarin, aspirin, and clopidogrel; the control group consisted of 97 patients who were individually matched to patients in the active group by procedure type, procedure year, age, and sex. Control patients received aspirin and clopidogrel. Clinical data were collected from inpatient records, outpatient physician office records, and telephone surveys administered to patients or caregivers. The primary end point was major bleeding. The median duration of follow-up after index procedure was 182 days (range 0-191 days) in the active group and 182 days (range 0-213 days) in the control group. Fifty-seven (59%) of the 97 patients in the active group received warfarin for atrial fibrillation. There were 14 major bleeds in the active group (including 1 death) and 3 major bleeds in the control group during the study period. Mean international normalized ratio at the time of bleeding was 3.4. Hazard ratio for major bleeding was 5.0 in patients receiving warfarin therapy (95% confidence interval 1.4-17.8, p=0.012). Aspirin dose, age, sex, body mass index, history of hypertension, diabetes mellitus, intraprocedural glycoprotein IIb-IIIa or anticoagulant type, and postprocedural anticoagulant use did not have a significant effect on the risk of major bleeding. Warfarin was an independent predictor of major bleeding after PCI in patients receiving dual antiplatelet therapy. Prospective data to further characterize the safety of concomitant warfarin and dual antiplatelet therapy after PCI are needed.

Development of a Contemporary Bleeding Risk Model for Elderly Warfarin Recipients

Develop and validate a contemporary bleeding risk model to guide the clinical use of warfarin in the elderly atrial fibrillation (AF) population. Chart-abstracted data from the National Registry of Atrial Fibrillation was combined with Medicare part A claims to identify major bleeding events requiring hospitalization. Using a split-sample technique, candidate variables that provided statistically stable relationships with major bleeding events were selected for model development. Three risk categories were created and validated. The new model was compared to existing bleeding risk models using c-statistics and Kaplan-Meier curves. Model development and validation was conducted on 26,345 AF patients who were > 65 years of age and had been discharged from the hospital while receiving warfarin therapy. The following eight variables were included in the final risk score model: age > or = 70 years; gender; remote bleeding; recent (ie, during index hospitalization) bleeding; alcohol/drug abuse; diabetes; anemia; and antiplatelet use. Bleeding rates were 0.9%, 2.0%, and 5.4%, respectively, for the groups with low, moderate, and high risk, compared to the bleeding rates for groups with moderate risk (1.5% and 1.0%) and high risk (1.8% and 2.5%) from other models. Using a nationally derived data set, we developed a model based on contemporary practice standards for determining major bleeding risk among AF patients receiving warfarin therapy. The larger sample size afforded the opportunity to incorporate additional risk factors. In addition, since the majority of our population was > 65 years of age, we had greater ability to stratify risk among the elderly.

Maintenance of Warfarin Anticoagulation for Patients Undergoing Vitreoretinal Surgery

To evaluate the risk of hemorrhagic complications associated with vitreoretinal surgery in patients whose warfarin sodium therapy was continued throughout the surgical period. A review of 1737 records of patients undergoing pars plana vitrectomy was conducted. Inclusion criteria included patients receiving warfarin therapy whose international normalized ratios (INRs) were elevated above normal values on the day of surgery. Intraoperative and postoperative hemorrhagic complications were documented. Fifty-four patients underwent 57 vitreoretinal surgical procedures with warfarin therapy and were divided into groups as follows: group S with INRs of 1.20 to 1.49, values considered subtherapeutic; group B with INRs of 1.50 to 1.99, values considered borderline therapeutic; group T with INRs of 2.00 to 2.49, values considered therapeutic; and group HT with INRs of 2.50 or greater, values considered highly therapeutic. No patients experienced anesthesia-related or intraoperative hemorrhagic complications. Two (7.7%) of 26 eyes in group S and 2 (16.7%) of 12 eyes in group HT experienced postoperative hemorrhages. All of the patients with vitreous hemorrhages had spontaneous clearing without additional treatment. Many patients may safely undergo vitreoretinal surgery while maintaining therapeutic levels of warfarin anticoagulation. We experienced no intraoperative hemorrhagic complications; the 4 postoperative complications resolved spontaneously without persistent visual sequelae or the need for supplemental surgery.

Utilization review of concomitant use of potentially interacting drugs in Thai patients using warfarin therapy

In Thailand, there has been no study determining the concomitant use of medications, known to potentially interact with warfarin, in patients receiving warfarin therapy. This paper examined the frequency of which specific interacting drugs were concomitantly used in warfarin users. We retrospectively examined the database of warfarin outpatient medical records from a regional 756-bed hospital located in the north of Thailand. All patients receiving warfarin from 10 June 1999 to 4 August 2004 were reviewed to identify all drugs possessing interaction potential with warfarin. The potential of significant interactions were divided into high, moderate and low, according to the extent of evidence documented in textbooks and literature. Among 1093 patients receiving warfarin therapy, 914 (84%) patients received at least one potentially interacting drug and half of them (457 patients) received at least one drug with high potential for interaction. The most frequently concomitant drug that increased INR was acetaminophen (63%, 316/457). Propylthiouracil was the most frequently concomitant drug that decreased INR response (4%, 19/457), while diclofenac was the most frequently concomitant drug that increased bleeding risk (16%, 73/457). About a half of patients receiving warfarin therapy was prescribed concomitant drug(s) that has a high potential of interactions with warfarin. These patients should be closely monitored and counselled to watch for signs and symptoms of bleeding and thrombosis to avoid adverse events associated with drug interactions.

Dietary Vitamin K Variability Affects International Normalized Ratio (INR) Coagulation Indices

Changes in daily vitamin K intake may contribute to marked variations in the International Normalized Ratio (INR) coagulation index in patients receiving oral warfarin anticoagulant therapy, with potentially serious adverse outcomes. Thus, patients receiving warfarin therapy are routinely counseled regarding this drug-nutrient interaction and are instructed to maintain consistent vitamin K intakes, though little quantitative information about this relationship is available. To determine the quantitative impact of variability in dietary vitamin K(1) (phylloquinone) intake, assessed by a validated patient self-monitoring instrument, on weekly INR in patients receiving warfarin anticoagulant therapy. A prospective dietary assessment study was conducted at the Massachusetts General Hospital in Boston. Sixty outpatients (37 males and 23 females) were selected with a mean age 60.3 +/- 16.8 years, who began oral warfarin anticoagulant therapy within 14 days prior to their first clinic visit to an outpatient anticoagulation therapy unit. Exclusion criteria included more than 2 drinks of alcohol per day, inability to speak English, and concurrent disease states affecting warfarin therapy such as liver disease and terminal illness. Over the five-week study period, participants recorded daily intakes in specified amounts of all food items appearing on a validated dietary self-assessment tool. Concomitant use of prescription and/or non-prescription medications was also obtained. Concurrent daily warfarin dose and adherence to the drug regimen, concomitant use of prescription and/or non-prescription medications known to interact with warfarin, and weekly INR were obtained. Week-to-week changes in vitamin K intake, warfarin dose, and INR were determined and cross-correlated. Forty-three patients (28 males and 15 females) completed the study and 17 dropped out. Pearson's correlation coefficient revealed the variability in INR and changes in vitamin K intake were inversely correlated (r = -0.600, p < 0.01). Multiple regression analysis (r = 0.848) indicated that a weekly change of 714 mug dietary vitamin K significantly altered weekly INR by 1 unit (p < 0.01) and a weekly change of 14.5 mg warfarin significantly altered weekly INR by 1 unit (p < 0.01) after adjustment for age, sex, weight, height, and concomitant use of medications known to interact with warfarin. Patients taking warfarin and consuming markedly changing amounts of vitamin K may have a variable weekly INR with potentially unstable anticoagulant outcomes.