Subtherapeutic 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.

Potential Interaction Between Warfarin and High Dietary Protein Intake

A 55-year-old Caucasian man was receiving warfarin therapy after undergoing aortic valve replacement. His international normalized ratio (INR) was stabilized with warfarin 95 mg/week for 5 weeks. Commencement of a low-carbohydrate, high-protein diet resulted in a series of subtherapeutic INRs that led to a 16% increase in the dosage requirement to maintain therapeutic INRs. After the patient discontinued the diet, his INR increased, and several dosage reductions were required until his INR stabilized with his original dosage of 95 mg/week. Two additional case reports have described a possible interaction between warfarin and a high-protein diet. The potential for increased dietary protein intake to raise serum albumin levels and/or cytochrome P450 activity has been postulated as mechanisms for the resulting decrease in INRs. Given the available animal and human data that demonstrate alterations in drug metabolism in the presence of altered dietary protein intake, an increase in warfarin metabolism due to cytochrome P450 activation appears to be the most likely cause. In addition to the previously reported cases, this case indicates a potential interaction between warfarin and a high-protein diet. Because of the popularity of high-protein diets and because of the risks associated with inadequate or excessive warfarin anticoagulation, patients and health care providers should be aware of this interaction to ensure appropriate monitoring when warranted.

Periprocedural Anticoagulation for Atrial Fibrillation Ablation

Catheter ablation for atrial fibrillation (AF) can increase risk of left atrial (LA) thrombi and stroke. Optimal periprocedural anticoagulation has not been determined. We report the role of administering warfarin and aspirin without low molecular weight heparin in patients undergoing AF ablation. A total of 207 patients underwent ablation for AF. Transesophageal echocardiography (TEE) guided transseptal puncture and ruled out clot in the LA. After first puncture, the sheath was flushed with heparin (5,000 Units/mL). After second puncture, a bolus of 80 units/kg of heparin was given, followed by an infusion to maintain activated clotting time (ACT) around 300-350 seconds. Warfarin was stopped and aspirin was started (325 mg/day) 3 days preprocedure. Warfarin was restarted on the day of the procedure. Both medications were continued for 6 weeks postablation. Warfarin was continued for 6 months in patients with prior history of persistent or recurrent AF. Thirty-seven patients who showed smoke in the LA on TEE were given low molecular weight heparin postprocedure until international normalized ratio (INR) was therapeutic. Thirty-two patients had persistent and 175 had paroxysmal AF; 87 were cardioverted during ablation. Two patients had transient ischemic attack (TIA) on the sixth and eighth days, respectively, following ablation, with complete recovery. Both had subtherapeutic INRs. In patients without demonstrable clot or smoke in the LA, starting aspirin 3 days prior and warfarin immediately post-radiofrequency ablation, without low molecular weight heparin, with meticulous anticoagulation during the procedure, appears to be a safe mode of anticoagulation.

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.

Safety of Inferior Vena Cava Filter Retrieval in Anticoagulated Patients

To evaluate the safety of inferior vena cava (IVC) filter retrieval in therapeutically anticoagulated patients in comparison to prophylactically or not therapeutically anticoagulated patients with respect to retrieval-related hemorrhagic complications. This was a retrospective study of 115 consecutive attempted IVC filter retrievals in 110 patients. Filter retrievals were stratified as performed in patients who were therapeutically anticoagulated (group 1), prophylactically anticoagulated (group 2), or not therapeutically anticoagulated (group 3). The collected data included anticoagulant and antiplatelet medications (type, form and duration of administration, dosage) at the time of retrieval. Phone interviews and chart review was performed for the international normalized ratio (INR), activated partial thromboplastin time, platelet count, infusion of blood products, and retrieval-related hemorrhagic complications. Group 1 included 65 attempted filter retrievals in 61 therapeutically anticoagulated patients by measured INR or dosing when receiving low-molecular-weight heparin (LMWH). Four retrievals were not successful. In patients receiving oral anticoagulation, the median INR was 2.35 (range, 2 to 8). Group 2 comprised 23 successful filter retrievals in 22 patients receiving a prophylactic dose of LMWH. Group 3 included 27 attempted filter retrievals in 27 patients not receiving therapeutic anticoagulation. Six retrievals were not successful. Five patients were receiving oral anticoagulation with a subtherapeutic INR (median, 1.49; range, 1.16 to 1.69). No anticoagulation medication was administered in 22 patients. In none of the groups were hemorrhagic complications related to the retrieval procedures identified. These results suggest that retrieval of vena cava filters in anticoagulated patients is safe. Interruption or reversal of anticoagulation for the retrieval of vena cava filters is not indicated.

Risk of Impaired Coagulation in Warfarin Patients Ascending to Altitude (>2400 m)

Approximately 476,000 people on warfarin therapy visit a resort at altitude (>2400 m) annually in Colorado. Clinicians practicing at altitude have expressed concern that ascent to altitude adversely affects coagulation in patients taking warfarin in both high altitude residents and visitors. We sought to determine the effect of ascent to and descent from altitude on coagulation in warfarin patients, as assessed by the international normalized ratio (INR). A retrospective medical chart review was conducted on all warfarin patients treated between August 1998 and October 2003 at a cardiology clinic in which travel to and from altitude was documented in association with each INR measurement in high altitude residents. Of the 1139 INR measurements in 49 patients, 143 were associated with changes in altitude (in 32 of 49 patients). The odds of an INR measurement being below the prescribed range were 2.7 times (95% CI: 1.2-5.8) higher among warfarin patients with recent ascent to altitude, 2.1 times (95% CI: 1.4-3.2) higher among warfarin patients with atrial fibrillation, and 5.6 (95% CI: 2.3-13.7) times higher among warfarin patients with both atrial fibrillation and recent ascent to altitude. Increasing altitude is a risk factor for subtherapeutic INR in warfarin patients and this risk is doubled in atrial fibrillation patients.

A pilot study of home treatment of deep vein thrombosis with subcutaneous once-daily enoxaparin plus warfarin.

To evaluate patient satisfaction, effectiveness, and safety of at-home treatment of acute deep vein thrombosis (DVT) with subcutaneous enoxaparin dosed at 1.5 mg/kg once daily plus oral warfarin. Patients with acute DVT and no more than 1 previous episode of DVT received enoxaparin plus oral warfarin until their international normalized ratio (INR) was >2 on 2 consecutive days. Patients were recruited between November 2000 and June 2003, and a home-care nurse visited the patient daily to administer the enoxaparin and to perform a fingerstick INR test. Patients received warfarin at doses adjusted to maintain an INR in the range of 2 to 3. Efficacy and safety were assessed daily by a home-care nurse and then by telephone interview conducted by a pharmacist at 14, 30, and 90 days during follow-up. Patient satisfaction with treatment was assessed by a verbal questionnaire. There were 52 patients enrolled. The mean duration of enoxaparin home treatment was 4.5 days, and the mean INR on discontinuation of enoxaparin was 2.73. Most patients (84.6%) had INRs within the desired therapeutic range (INR value 2-3); no patient had a subtherapeutic INR. There were no symptoms of recurrent venous thromboembolism reported. Major bleeding occurred 7 days after discontinuation of enoxaparin in one patient with impending surgery for removal of a uterine tumor. There were 2 cases of minor bleeding. The patient satisfaction questionnaire revealed that patients considered home treatment to be acceptable. The average cost savings was $2,925 per patient compared with typical inpatient treatment with unfractionated heparin. The results of this pilot study suggest that home treatment with initial once-daily enoxaparin in conjunction with long-term oral warfarin is a safe and effective alternative to inpatient therapy with once-daily enoxaparin or unfractionated heparin for select patients with acute DVT. Cost savings are derived from the substitution of inpatient care with home care.

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.

Effect of Warfarin Anticoagulation on Below-Knee Polytetrafluoroethylene Graft Patency

When polytetrafluoroethylene (PTFE) must be used for below-knee bypass to achieve limb salvage, effective anticoagulation with warfarin may improve graft survival. We analyzed our practice of routinely using oral anticoagulation to improve graft patency rates for PTFE grafts to below-knee popliteal and crural vessels in limb salvage procedures. We reviewed our established vascular database from February 1999 through April 2003 to identify those patients who required below-knee and tibial artery bypass with PTFE for critical limb ischemia. All patients were initiated on warfarin anticoagulation postoperatively, with an international normalized ratio (INR) of 2.0-3.0 considered therapeutic. All patients were discharged in the therapeutic range. Life-table analysis and Kaplan-Meier estimates were used to compare primary patency rates with regard to INR and position of distal anastomosis. Cox proportional hazards analysis was performed to compare the patency rates for grafts with therapeutic versus subtherapeutic anticoagulation while correcting for variability in distal runoff. Between February 1999 and April 2003, 74 patients (mean age, 69.2 years; 58% men) had 77 below-knee PTFE bypasses. Indications for operation included rest pain (43), ischemic ulcer (27), and gangrene (7). Patients presenting with occluded grafts more often had a subtherapeutic INR. Patients with a subtherapeutic INR (< or = 1.9) had a median primary graft patency of 6.8 months and those with a therapeutic INR (> or = 2.0) had a median primary graft patency of 29.9 months (p = 0.0007). Analysis by Cox proportional hazards model demonstrated a significantly better graft patency rate in patients with a therapeutic INR regardless of outflow vessel. The patency rates of PTFE grafts to infrageniculate vessels may be improved by effective anticoagulation with warfarin. This improved patency rate may also result in improved limb salvage and further support the use of PTFE grafts for critical limb ischemia when autogenous vein is not available. Predictably, the best results are seen with an INR therapeutic range of 2.0 to 3.0.

Warfarin monitoring: Consider the three Ds

Warfarin is a narrow therapeutic index drug having a propensity for many drug–drug interactions which require scrupulous monitoring to ensure that the international normalized ratio (INR) is within therapeutic range. This range is usually between 2 and 3, as recommended by the expanded indications for oral anticoagulant therapy, particularly among older patients. However, older patients are especially prone to high and low INRs affected by many drug and disease parameters. The literature points to substantial interpatient and intrapatient variability with this drug, especially in frail older patients. Prescribers and pharmacists spend a lot of time ensuring that the patient is not at risk for bleeding because of increased INRs, or at risk of thrombosis because of subtherapeutic INRs. The three Ds that need to be considered every time for any changes to warfarin dosing because of fluctuations in INR entail:

Acute renal embolism. Forty-four cases of renal infarction in patients with atrial fibrillation.

Acute renal embolus is rarely reported in the medical literature; thus, accurate data regarding presentation, laboratory tests, diagnostic techniques, and treatment are lacking. To better define this condition, we examined the medical records of all patients admitted to Kaplan Medical Center and Sheba Medical Center in central Israel from 1984 to 2002 who had a diagnosis of renal infarction and atrial fibrillation. We noted demographic, clinical, and laboratory parameters; method of diagnosis; treatment received; and patient outcome. We identified 44 cases of renal embolus: 23 females and 21 males, with an average age of 69.5 +/- 12.6 years. Thirty (68%) patients had abdominal pain, and 6 (14%) had a previous embolic event. Nine patients were being treated with warfarin on admission, 6 (66%) of whom had an international normalized ratio (INR) < 1.8. Hematuria was present in 21/39 (54%), and 41 (93%) patients had a serum lactate dehydrogenase (LDH) level > 400 U/dL. The mean LDH was 1100 +/- 985 U/dL. Diagnostic techniques included renal isotope scan, which was abnormal in 36/37 cases (97%); contrast-enhanced computed tomography (CT) scan, which was diagnostic in 12/15 cases (80%); and ultrasound, which was positive in only 3/27 cases (11%). Angiography was positive in 10/10 cases (100%). Twenty-three (61%) of 38 patients had normal renal function on follow-up. The 30-day mortality was 11.4%. Renal embolus was diagnosed mainly in patients aged more than 60 years, some of whom had a previous embolic event. Most of those receiving anticoagulant therapy had a subtherapeutic INR. Abdominal pain was common, as well as hematuria and an elevated LDH. These patients are at risk of subsequent embolic events to other organs. The most sensitive diagnostic technique in this population is a renal isotope scan, but contrast-enhanced CT scan requires further assessment.

Effect of Soy Milk on Warfarin Efficacy

To describe the effect of soy milk on the international normalized ratio (INR) in a patient treated with warfarin. A 70-year-old white man who was stable on warfarin therapy developed subtherapeutic INR values after ingesting soy protein in the form of soy milk. The subtherapeutic INR values could not be explained by factors known to reduce the INR such as noncompliance, new medications, other alternative therapies, increased physical activity, changes in medication storage, or increased consumption of vitamin K. INR values returned to therapeutic concentrations within 2 weeks after discontinuation of the soy milk. Repeated coagulation test results during the next 2 months remained within the normal range. Impaired warfarin metabolism may be ascribed to various pharmacodynamic and pathologic factors. Subtherapeutic INR values may also be the result of concomitant administration of metabolic inducers resulting in drug-drug, drug-herb, or drug-food interactions. An objective causality assessment in this case revealed that INR decline in a warfarin-treated patient as a result of soy milk ingestion was in the range of possible to probable. Speculative mechanisms of soy milk-induced INR decline such as changes in warfarin absorption or metabolism resulting from alterations in the P-glycoprotein efflux system or organic anion-transporting polypeptides are discussed. The temporal relationship between the start of soy milk and subtherapeutic INR values in 1 patient suggests that soy milk may have possibly or probably caused a decline in INR. Soy protein food-drug interactions with warfarin may be more common than the literature suggests, and further studies are needed to determine the exact mechanism. Healthcare professionals should be alerted to the potential implications of this food-drug interaction.

Prevalence of intra-atrial thrombi in atrial fibrillation patients with subtherapeutic international normalized ratios while taking conventional anticoagulation

Anticoagulation with warfarin may fail to achieve the therapeutic target of the international normalized ratio (INR) in >30% of patients.1 This study examined the prevalence of intra-atrial thrombi in patients with atrial fibrillation (AF) who received warfarin for ≥3 weeks but had a subtherapeutic INR.

The management of coumarin-induced over-anticoagulation Annotation.

The management of coumarin-induced over-anticoagulation Annotation.

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.