Supratherapeutic International Normalized Ratio Research Articles

Warfarin: what are the clinical implications of an out-of-range-therapeutic international normalized ratio?

Warfarin is a commonly used oral anticoagulant, and has well-established clinical efficacy. However, it has a narrow therapeutic window, and a mode-of-action affected by inter-individual differences and environmental factors. The effectiveness and safety of warfarin are closely related to maintenance of the international normalized ratio (INR) within therapeutic range. A supra-therapeutic INR puts patients at risk of bleeding, whereas a sub-therapeutic INR may not protect against thromboembolic complications. Research suggests a lack of anticoagulation control during warfarin therapy in different settings. Careful monitoring of the INR is essential, especially in geriatric or cancer populations who are at an increased risk of major hemorrhage. Warfarin is an effective treatment but optimization of the risk-benefit ratio is crucial in order to maximize efficacy and safety. Here, we will assess the extent to which INRs are an issue in the management of warfarin therapy, and the effect INRs may have on clinical outcomes.

Retrospective Evaluation of a Method to Predict Fresh-Frozen Plasma Dosage in Anticoagulated Patients

In the United States, fresh-frozen plasma (FFP) is commonly used for urgent reversal of warfarin; however, dosage recommendations are difficult to find. If validated, a proposed method that uses a nonlinear relationship between international normalized ratio (INR) and clotting factor activity (CFa) would be useful. This study retrospectively evaluated a proposed equation with adult medical inpatients who received FFP for warfarin reversal. For each patient the equation was used to predict the dose of FFP required to achieve the observed change in INR, which was then compared to the actual dose. The equation was considered successful if the predicted dose was within +/-20% of the actual dose. Subgroup analyses included subjects who received concomitant vitamin K; subjects with supratherapeutic INRs (>3); and subjects with significantly elevated INRs (>5). Of the 209 patients screened, 91 met criteria for inclusion in the study. Use of the equation to calculate the predicted dose of FFP was successful in 11 patients (12.1%) with use of actual body weight for prediction and in 23 patients (25.3%) with use of ideal body weight (P = 0.02). The equation performed similarly in all subgroups analyzed. The mean predicted FFP dose was significantly greater than the actual dose in all patients when actual body weight was used (925.2 mL vs. 620.6 mL; P < 0.001). Least-squares regression modeling of repeat INR (converted to CFa) produced a model that accounted for 57% of the variance in repeat INR. The value predicted from the model was closer to the actual CFa than was the value predicted from the published equation in every comparison, but it was statistically different only when actual body weight was used. This study revealed that a published equation for calculation of FFP dose to reverse oral anticoagulation resulted in doses that were significantly higher than the actual dose. Use of ideal body weight improved accuracy but was still not successful for the majority of patients. Until trials are able to prospectively demonstrate the accuracy of a dose-prediction model for FFP, dosing will remain largely empiric.

Impact of preemptive warfarin dose reduction on anticoagulation after initiation of trimethoprim-sulfamethoxazole or levofloxacin

Antibiotics can potentiate warfarin anticoagulation. While preemptive warfarin dose reduction (DR) upon initiation of antibiotics has been advocated by experts, there are no published data regarding the efficacy of this strategy vs. the conventional strategy of not changing warfarin dose and carefully following international normalized ratio (INR) results. We compared the efficacy of preemptive 10-20% DR vs. no change in warfarin dosing in 40 chronically anticoagulated patients initiating trimethoprim-sulfamethoxazole (TMP-SMX) or levofloxacin. Eighteen patients received preemptive warfarin DR and 22 control patients underwent no change in warfarin dosing. There was no difference between the DR and control groups in the mean INR before beginning antibiotic therapy (2.53 +/- 0.12 vs. 2.52 +/- 0.11; P > 0.9). Mean interval between initiation of antibiotic and next INR was 5.1 +/- 0.4 vs. 4.7 +/- 0.5 days for DR vs. control patients, respectively (P > 0.5). For both TMP-SMX and levofloxacin, patients managed with a preemptive warfarin DR strategy did not exhibit a statistically significant change in the INR after initiating antibiotic therapy. In contrast, for each antibiotic, control group patients exhibited a significant increase in mean post-antibiotic INR compared to mean pre-antibiotic INR, though the effect was more pronounced in patients treated with TMP-SMX than with levofloxacin. Of DR group patients who were treated with TMP-SMX, none (0/8) developed a subtherapeutic INR, while 40% (4/10) of levofloxacin-treated patients developed a sub-therapeutic INR. Supra-therapeutic INR results led to transient interruption of warfarin dosing in 2 patients (11%) in the DR group vs. 12 patients (55%) in the control group (P = 0.007). Prophylactic warfarin DR of 10-20% is effective in maintaining therapeutic anticoagulation in patients initiating TMP-SMX. An expectant strategy consisting of no change in warfarin dosing with short-term INR follow-up appears reasonable in patients treated with levofloxacin.

Effect of Oral Corticosteroids on Chronic Warfarin Therapy

A potential drug interaction exists between oral corticosteroids and warfarin, but there is limited documentation. To evaluate the potential drug interaction between oral corticosteroids and long-term warfarin therapy. A retrospective review was conducted of 387 medical records for active patients within an anticoagulation clinic. Inclusion criteria were stable anticoagulation therapy, short-term oral corticosteroid therapy, international normalized ratio (INR) recorded within 30 days prior to corticosteroid initiation (pre-INR), and INR recorded during corticosteroid therapy or within 14 days of discontinuation (post-INR). Patients were excluded if they had been started on any antibiotic or other drug with a probable interaction with warfarin at the same time as corticosteroid initiation. Thirty-two patient encounters met the predetermined inclusion and exclusion criteria. The primary outcome assessed was the difference between pre- and post-INR values. Secondary endpoints included bleeding events, emergency department (ED) visits, hospitalizations, and warfarin dose modifications. The mean difference between pre- and post-INR values was 1.24 (95% CI 0.86 to 1.62). Ninety-seven percent of the 32 patient encounters resulted in a change in their post-INR value, and 62.5% of patients had supratherapeutic INR values at the post-corticosteroid assessment. The majority of patients assessed had an elevation of their INR following concomitant use of warfarin and corticosteroids. The INR change was observed at a mean +/- SD of 6.7 +/- 3.3 days following the first dose of corticosteroid. Overall, 16 patients (50%) required a modification of their anticoagulation therapy during or following corticosteroid therapy. Only one adverse event of minor epistaxis was reported, and no ED visits or hospitalizations occurred as a consequence of the drug combination. Use of oral corticosteroids in patients on long-term warfarin therapy may result in a clinically significant interaction, which requires close INR monitoring and possible warfarin dose reduction.

Search for Predictors of Nontherapeutic INR Results with Warfarin Therapy

The effectiveness and safety of warfarin require maintaining an international normalized ratio (INR) within the therapeutic range. To identify predictors of nontherapeutic INR results in patients receiving warfarin. A retrospective study was conducted using 350 ambulatory care patients from a broad geographic region, all receiving long-term warfarin therapy and followed in a tertiary-care cardiology clinic. Possible predictors of nontherapeutic INR results (gender, age, body weight, body mass index, height, race, tobacco use, alcohol use, warfarin dose, therapeutic indication, regimen intensity, INR monitoring frequency/category, interacting medications, adverse events) were assessed with logistic regression models. Subset analysis involved 146 patients concurrently monitored with capillary whole blood INR (CoaguChek). As measured on venous specimens, 52% (182/350) of the patients had subtherapeutic INR results and 13% (44/350) had supratherapeutic INR results despite frequent (< or =4 wk) monitoring in 75% of the patients. Due to the small sample size, supratherapeutic INR results could not be further analyzed. Of 19 predictors tested, only daily warfarin dose (p < 0.02) and regimen intensity (p < 0.03) were significant independent and additive predictors of subtherapeutic results. Patients on the high-intensity regimen (INR 2.5-3.5) and receiving warfarin < or =6 mg/day had >50% risk of having subtherapeutic INR results. Subtherapeutic CoaguChek results were independent predictors of subtherapeutic venipuncture INR results in the subset (p = 0.001). In the absence of readily identifiable predictors, only higher warfarin dosing and/or more frequent monitoring (possibly with point-of-care/home monitoring devices) may minimize the time that INRs are subtherapeutic, especially in patients receiving low-dose and/or high-intensity anticoagulation therapy.

Warfarin Initiation and the Potential Role of Genomic-Guided Dosing

Warfarin Initiation and the Potential Role of Genomic-Guided Dosing

The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.

Medication interactions account for a significant proportion of overanticoagulation in warfarin users. However, little is known about the incidence or degree of interaction with commonly used oral antibiotics. To investigate the incidence and degree of overanticoagulation associated with commonly used oral antibiotics. Retrospective cohort study of patients using warfarin who initiated an antibiotic (azithromycin, levofloxacin, or trimethoprim/sulfamethoxazole (TMP/SMX)) or terazosin for clinical indications between January 1998 and December 2002. The incidence of international normalized ratio (INR) elevation and the degree of change and bleeding events after institution of either medication type was recorded. Patients at a university-affiliated Veteran's Affairs Medical Center. The mean change in INR was -0.15 for terazosin, 0.51 for azithromycin, 0.85 for levofloxacin, and 1.76 for TMP/SMX. These mean INR changes in the antibiotic groups were all statistically different from the terazosin group. The incidence of supratherapeutic INR was 5% for terazosin, 31% for azithromycin, 33% for levofloxacin, and 69% for TMP/SMX. The incidence of absolute INR >4.0 was 0% for terazosin, 16% for azithromycin, 19% for levofloxacin, and 44% for TMP/SMX. Among acutely ill outpatients, oral antibiotics (azithromycin, levofloxacin, and TMP/SMX) increase the incidence and degree of overanticoagulation.

Cognitive Impairment as Determinant for Sub-Optimal Control of Oral Anticoagulation Treatment in Elderly Patients with Atrial Fibrillation

Atrial fibrillation is an indication for oral anticoagulation treatment. Maintaining the International Normalized Ratio (INR) within the therapeutic range minimises thromboembolic and bleeding complications. We have investigated whether cognitive capacity affects control of anticoagulation in elderly patients with atrial fibrillation. A retrospective study was conducted to investigate the association between cognitive impairment and control of anticoagulation. Patients > or =70 years of age with atrial fibrillation using acenocoumarol (nicoumalone) as anticoagulant were included. All patients were monitored by the Anticoagulation Clinic in the Midden-Brabant region in the Netherlands. The cognitive function of all patients was assessed using the Mini-Mental State Examination (MMSE) on the index date. INR values were obtained from the year preceding the index date. Patients with an MMSE score <23 were defined as cognitively impaired. The primary outcome of the study was the incidence of an INR value within the therapeutic range of 2.0-3.4 during < or =70% of treatment time in the year prior to the cognitive function assessment. The secondary endpoint was the number of patients with an INR <2.0 or > or =6.0 at least once during this year. Logistic regression analysis was used to evaluate the association between cognitive function and control of anticoagulation. A total of 152 patients were included in the study. An MMSE score <23 was associated with an inadequate INR control (odds ratio [OR] 2.77; 95% CI 1.13, 6.74). After correction for hospital admission and change of possibly interacting medication (both also associated with inadequate INR control), this association remained statistically significant. Significantly more patients with an MMSE score <23 had one or more INR values of six or higher (OR 3.06; 95% CI 1.14, 8.18). In elderly people with atrial fibrillation using oral anticoagulation, an MMSE score <23 is independently associated with an inadequate INR control, mainly because of an increased number of supratherapeutic INR values. This finding should be taken into account when making decisions about use of oral anticoagulants in the elderly.

The Risk of Hemorrhage and the Frequency of Vitamin K Use in Asymptomatic Patients with Warfarin-Associated Coagulopathy.

Background: Warfarin, although highly effective in preventing thromboembolism, can cause hemorrhage. For warfarin-treated patients, the risk of bleeding increases as the International Normalized Ratio (INR) rises, particularly if the INR exceeds 4. Although low-dose oral vitamin K reliably decreases supratherapeutic INR values, previous surveys indicate that many providers choose not to administer vitamin K to asymptomatic patients who present with excessive INR prolongation. In effort to help guide the management of asymptomatic outpatients with elevated INRs, we assessed the rate of hemorrhage as well as the frequency of vitamin K use in an observational study.Methods: A prospective cohort of patients taking warfarin was assembled from 101 sites with personnel designated as warfarin managers across the United States during the period August 2000 to December 2001; 98 sites were community-based physician office practices. Enrolled practices participated in mandatory on-site study training and all patients provided written informed consent. Patients with a first observed episode of INR ≥5.0 were identified. For the two-week period following the index INR, provider-generated outpatient progress notes that pertained to anticoagulation (and were part of the medical record) were individually reviewed by one of the investigators. Outcomes included: site-specific management of elevated INR (recorded vitamin K use versus simple withholding of warfarin), and number of patients sustaining a major hemorrhage within the 2 weeks following the index INR value. Major hemorrhage was defined as fatal, necessitating hospitalization with transfusion of at least 2 units of packed red blood cells, or occurring at a critical site (e.g., intracranial, retroperitoneal).Results: During the study period, 6,792 patients were enrolled providing 5,961 person-years of follow-up. Of these, 979 had a first observed episode of an INR of more than 5. Thirty-nine % of these patients were receiving warfarin for atrial fibrillation and 29% had a prosthetic heart valve. Mean age was 69 years (range 20–94) and 50% were women. Ninety-six % (n=937) of the INRs were between 5 and 9. Ninety-eight % (n=963) were managed exclusively as outpatients; management could not be assessed in 16 patients who were hospitalized for unrelated reasons.Patients with an INR >9 were more likely to receive vitamin K compared to those with an INR of 5.0 to 9.0 (62% versus 7%). The mean INR for those patients known to have received vitamin K was 9.9 versus 6.2 among those for whom no vitamin K use was recorded.Of the 979 patients, 99.7% (n=976) had 14-day follow-up information. Nine patients sustained a major hemorrhage within the 2-week period (0.9%), mean INR 9.4, none were fatal.Conclusions: Among asymptomatic patients with warfarin-induced coagulopathy, an intervention known to reduce the INR (low-dose oral vitamin K) is used infrequently, particularly for patients whose INR value is 9 or less. For asymptomatic warfarin-treated individuals who are managed in the outpatient setting and whose INR is less than 9, the short-term risk of major bleeding appears to be low. Prospective, controlled trials are needed to determine the risks and benefits of administering vitamin K to this population.

Warfarin Therapy for Atrial Fibrillation in the Elderly

OBJECTIVE:To evaluate a clinical practice model that addresses special needs for managing anticoagulation in a community-dwelling elderly population with atrial fibrillation and high risk of stroke.METHODS:Medical records of 18 patients (mean age 82 y) followed by the Geriatric Ambulatory Program over 2 years, with a target international normalized ratio (INR) of 2.0–3.0, were reviewed. Risk factors for stroke, number and results of INR tests, suspected reasons for suboptimal response, and adverse events were analyzed. Patients were defined as having cognitive impairment if they had a Folstein Mini-Mental State Exam score ≤26. Functional impairment was defined by ≥2 disabilities in activities of daily living.RESULTS:Eighty-three percent (15/18) had ≥2 additional stroke risk factors. Fifty-one percent (273/541) of INR responses were therapeutic. Female gender (p = 0.015) and cognitive (p = 0.019) and functional impairment (p = 0.001) were associated with supratherapeutic INR response. All patients with cognitive impairment and 85% of those with functional impairment received caregiver support for medication administration. There were 4 minor bleeding events and no thromboembolic events. The mean number of medications was 9.3 in those with bleeding versus 6.8 in those without bleeding (p = 0.052).CONCLUSIONS:Elderly patients with high stroke risk achieved therapeutic INR responses. However, those with significant cognitive or functional impairment require caregiver support and special consideration for anticoagulation management.

Warfarin therapy for atrial fibrillation in the elderly.

To evaluate a clinical practice model that addresses special needs for managing anticoagulation in a community-dwelling elderly population with atrial fibrillation and high risk of stroke. Medical records of 18 patients (mean age 82 y) followed by the Geriatric Ambulatory Program over 2 years, with a target international normalized ratio (INR) of 2.0-3.0, were reviewed. Risk factors for stroke, number and results of INR tests, suspected reasons for suboptimal response, and adverse events were analyzed. Patients were defined as having cognitive impairment if they had a Folstein Mini-Mental State Exam score < or = 26. Functional impairment was defined by > or = 2 disabilities in activities of daily living. Eighty-three percent (15/18) had > or = 2 additional stroke risk factors. Fifty-one percent (273/541) of INR responses were therapeutic. Female gender (p = 0.015) and cognitive (p = 0.019) and functional impairment (p = 0.001) were associated with supratherapeutic INR response. All patients with cognitive impairment and 85% of those with functional impairment received caregiver support for medication administration. There were 4 minor bleeding events and no thromboembolic events. The mean number of medications was 9.3 in those with bleeding versus 6.8 in those without bleeding (p = 0.052). Elderly patients with high stroke risk achieved therapeutic INR responses. However, those with significant cognitive or functional impairment require caregiver support and special consideration for anticoagulation management.

Venous Limb Gangrene during Warfarin Treatment of Cancer-Associated Deep Venous Thrombosis

The cause of cancer-associated venous limb gangrene is unknown but could paradoxically be due to warfarin. To determine the pathogenesis of venous gangrene in a patient with cancer. Case report. University hospital in Ontario, Canada. 66-year-old woman with metastatic lung cancer and deep venous thrombosis. Levels of vitamin K-dependent factors, additional coagulation factors, and thrombin-antithrombin complexes (marker of thrombin generation). During warfarin use, venous limb gangrene developed when the international normalized ratio (INR) reached 6.0 (therapeutic range, 2.0 to 3.0); at this time, the level of protein C (a vitamin K-dependent natural anticoagulant) was severely reduced, but thrombin-antithrombin complexes remained markedly elevated. The supratherapeutic INR was explained by the greatly reduced levels of factor VII, which correlated closely with protein C levels; therefore, the high INR was a surrogate marker for severely reduced protein C activity. Warfarin may contribute to the pathogenesis of cancer-associated venous limb gangrene by leading to severe depletion of protein C while at the same time failing to reduce thrombin generation.

A Review of Warfarin Dosing and Monitoring

The goal of anticoagulant therapy with warfarin is to administer the lowest effective dose of the drug to maintain the target international normalized ratio (INR). Warfarin, a vitamin K antagonist, is an oral anticoagulant indicated for the prevention and treatment of venous thrombosis and its extension and the prevention and treatment of the thromboembolic complications associated with atrial fibrillation. Warfarin has also been used to prevent recurrent transient ischemic attacks and to reduce the risk of recurrent myocardial infarction, but data supporting these indications are inconclusive at this time (1). Warfarin inhibits the synthesis of clotting factors II, VII, IX, and X, as well as the naturally occurring endogenous anticoagulant proteins C and S (2). The anticoagulant and antithrombotic activity of warfarin depends on the clearance of functional clotting factors from the systemic circulation once the drug is administered (2, 3). The earliest changes in INR are typically seen 24 to 36 hours after administration of the dose. The antithrombotic effect of warfarin is not present until approximately the fifth day of therapy, which is dependent on the clearance of prothrombin (1, 2). Initiation of warfarin therapy is challenging, since the pharmacodynamic response is delayed and difficult to predict. Because prothrombin has a half-life of around 50 hours, loading doses of warfarin are of limited value (4). In clinical practice, loading doses (e.g., 7.5 mg or more per day) of warfarin may increase the patient's risk of bleeding complications early in therapy by eliminating the production of functional factor VII (2, 5). Administration of loading doses may place a patient in a hypercoagulable state due to a severe depletion of protein C (2). The administration of a loading dose is a possible source of prolonged hospitalization secondary to dramatic rises in the INR value that may necessitate the administration of vitamin K (5). If a rapid anticoagulant effect is required, an initial dose of heparin or a low molecular-weight heparin should be used and overlapped with warfarin for approximately 4 to 5 days. Once the INR is therapeutic for at least 2 days, the supplemental anticoagulation treatment may be discontinued (1, 4, 5). The safety and efficacy of warfarin therapy are dependent on maintaining the INR within the target range for the indication (Table ​(Table11). When a patient is started on an oral anticoagulant, INR monitoring should be performed daily until the INR is within the therapeutic range for at least 2 consecutive days. Unexpected fluctuations in the INR in an otherwise stable patient could be due to a change in diet, poor compliance, undisclosed drug use, alcohol consumption, or self-medication (2). Lab error should also be considered for unexpected values. Table 1 Recommended therapeutic range for oral anticoagulant therapy* One of the major risks of warfarin therapy is bleeding, which correlates well with INR values. The Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy has published guidelines on the management of patients with high INR values with or without bleeding (Table ​(Table22). Table 2 Management of supratherapeutic INR values*

Initialization of warfarin dosages using computer modeling

Objective: Software incorporating warfarin pharmacokinetics and pharmacodynamics, as well as a Bayesian regression method, was evaluated for accuracy in predicting steady-state dosages of warfarin during initialization of anticoagulation therapy. Design: A cohort study was used to compare computer predictions with physician-determined doses during a retrospective chart review of 42 patients. Patients: Forty-two patient charts were selected for monitoring anticoagulation initialization therapy. Of the 42 patients reviewed, 22 were excluded on the following bases: uncontrolled congestive heart failure; ongoing treatment with medications that interfered with warfarin metabolism or displaced warfarin from protein binding sites; recent treatment with fresh frozen plasma or vitamin K; or any bleeding disorders, sepsis, malabsorption or significant changes in liver and/or renal function. Main Outcome Measures: Using physician-determined International Normalized Ratios (INRs) as target levels for the software, the number of INR feedbacks needed to stabilize blood drug levels during initialization were compared between physicians and computer forecasting. Population parameters and sequentially measured INRs were used for evaluation. Results: Current oral anticoagulation protocols require significantly more measured INRs than computer forecasting to achieve steady-state dosages (9.5 v 4.4, respectively, p < 0.01). Physicians showed a statistically significant pattern of underdosing patients (4.3 v 1.7 subtherapeutic INRs, respectively, p < 0.01). Computer predictions tended to overdose patients but did not significantly increase the number of supratherapeutic INRs. This study showed that five INR inputs consistently gave accurate steady-state dosage predictions, and in many ways computer modeling was more effective than clinician-determined steady-state dosing in warfarin initialization. Conclusions: Computer modeling provides a reliable means of predicting initialization dosages for warfarin anticoagulation therapy with five INR inputs and therefore has merit in the clinical setting if used with sound clinical judgment.