Subtherapeutic International Normalized Ratio Research Articles

Initiation of glucose‐lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self‐controlled register study

ESSENTIALS: It is not known if initiation of glucose-lowering drugs alters the efficacy of vitamin K antagonists (VKA). We examined if glucose-lowering drugs affected international normalized ratio (INR) in VKA-treated patients. Upon initiating glucose-lowering drugs, 51% of patients had INR values below the therapeutic window. Monitoring of INR levels should be intensified upon initiation of glucose-lowering drugs. It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon. The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon. We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment. Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of -0.3 [95% CI: -0.1; -0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA. Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.

Survey of pharmacists' subtherapeutic INR management and anticoagulation bridging practices.

Despite extensive warfarin use, optimal management of subtherapeutic international normalized ratios (INRs) remains unclear. This study assessed the differences in bridging practices among pharmacists with varying levels of experience, residency training and prescribing privileges. An electronic survey was distributed to two ambulatory care pharmacist e-mail lists. Respondents indicated if they would utilize parenteral anticoagulation bridging in 16 clinical scenarios at three therapeutic time points. The scenarios included patients with atrial fibrillation (AFib) (CHADS2 score of 3-4), AFib (CHADS2 score of 5-6) and venous thromboembolism (VTE). The AFib time points were as follows: anticoagulation initiation, early phase (<1month) and maintenance phase (>1month). VTE time points included early phase (<1month), months 2-3 and maintenance phase (>3months). The survey was completed by 143 respondents. In only three of the scenarios did >50% of respondents indicate they would utilize parenteral anticoagulation bridging. No statistically significant differences in bridging practices were identified between pharmacists providing anticoagulation services in different clinic settings. However, there were significant differences in bridging practices between pharmacists with varying levels of experience, residency training and prescribing privileges in some, but not all of the scenarios. The standards of care for subtherapeutic INRs warrant further definition.

Determinants of oral anticoagulation control in new warfarin patients: analysis using data from Clinical Practice Research Datalink

The safety and effectiveness of warfarin therapy depends critically on the quality of anticoagulation control, often assessed using the percentage time in therapeutic International Normalised Ratio (INR) range (TTR). We aimed to identify patient characteristics related to anticoagulation control with warfarin, measured by TTR. We carried out a population-based study using the Clinical Practice Research Datalink, including two cohorts of patients starting warfarin after a first diagnosis of atrial fibrillation (AF) or venous thromboembolism (VTE) between 2000 and 2013. We used multivariate mixed regression and logistic regression models to predict the fully-adjusted effect of each predictor variable upon TTR. The study population comprised 29,717 incident AF and 19,113 incident VTE patients who initiated warfarin. In real world clinical practice a minority of patients achieve good anticoagulation control with warfarin (44% AF and 36% VTE patients had TTR≥70%). Poor anticoagulation control driven by subtherapeutic INRs was observed in younger patients (<45years) and in AF patients with increased number of hospitalisations. Poor anticoagulation control driven by sub and/or supratherapeutic INRs was seen in AF and VTE patients current smokers, in patients using medications for pain and in VTE patients with active cancer. In a real world clinical practice there is a high amount of unpredictable inter-individual TTR variability and in some patients good anticoagulation control is more challenging than in others. These findings may help to identify patients who will require closer monitoring or innovative strategies to optimise the outcomes of oral anticoagulant therapy.

Risk of recurrent venous thromboembolism among deep vein thrombosis and pulmonary embolism patients treated with warfarin

Objective:Guidelines for warfarin treatment of venous thromboembolism (VTE) recommend targeting an international normalized ratio (INR) level of 2–3. This study examines the association between INR levels and VTE recurrence among warfarin-treated patients.Methods:A retrospective cohort study in the MedMining electronic health record database included adults treated with warfarin for VTE in 2004–2011. INR levels during warfarin use were categorized as below therapeutic range (<2), in range (2–3), or above range (>3), with time in each category estimated using the Rosendaal method. Recurrent VTE was noted from 30 days after the initial VTE to end of follow-up, which ranged up to 8 years. The incidence of recurrent VTE was calculated, and association with time-varying INR levels estimated using Cox models.Results:Of 1753 qualifying patients, 867 had deep vein thrombosis, and 886 had pulmonary embolism. Mean age was 58 years, and 50.7% were female. Across all follow-up time, VTE recurrences were observed in 134 (7.6%) patients, at a rate of 3.2 (95% confidence interval [CI]: 0.7–9.1) events per 100 person-years. The risk of VTE recurrence was greater during time spent with INR <2 than with INR in the therapeutic range (hazard ratio [HR]: 3.37; 95% CI: 2.16–5.27). Low platelet counts also predicted greater risk of VTE recurrence (HR: 2.13; 95% CI: 1.24–3.67).Limitations:Exposure to warfarin and other anticoagulants was estimated based on prescription data and may be inaccurate. The study data include care within a single health system; thus, care received outside of the health system may be missing, and results may not be generalizable to the broader US population.Conclusions:Approximately 8% of patients experienced a recurrent VTE during follow-up. Subtherapeutic INR levels were associated with a more than three-fold increased risk of VTE recurrence.

Stroke/Thromboembolism and Intracranial Hemorrhage in a Real-world Atrial Fibrillation Population: The Complications of Atrial Fibrillation in the Bologna Area (CAFBO) Study

Ischemic events (IEs) and intracranial hemorrhages (ICHs) are feared complications of atrial fibrillation (AF) and of antithrombotic treatment in patients with these conditions. Patients with AF admitted to the EDs of the Bologna, Italy, area with acute IE or ICH were prospectively recorded over 6 months. A total of 178 patients (60 male patients; median age: 85 years) presented with acute IE. Antithrombotic therapy was as follows: (1) vitamin K antagonists (VKAs) in 31 patients (17.4%), with international normalized ratio (INR) at admission of < 2.0 in 16 patients, 2.0 to 3.0 in 13 patients, and > 3.0 in two patients; (2) aspirin (acetylsalicylic acid) (ASA) in 107 patients (60.1%); and (3) no treatment in 40 patients (22.5%), mainly because AF was not diagnosed. Twenty patients (eight male patients; median age: 82 years) presented with acute ICH: 13 (65%) received VKAs (INR, 2.0-3.0 in 11 patients and > 3.0 in two patients), while six (30%) received ASA. Most IEs (88%) and ICHs (95%) occurred in patients aged > 70 years. A modeling analysis of patients aged > 70 years was used to estimate annual incidence in subjects anticoagulated with VKAs in our Network of Anticoagulation Centers (NACs), or those expected to have AF but not included in NACs. The expected incidence of IE was 12.0%/y (95% CI, 10.7-13.3) in non-NACs and 0.57%/y (95% CI, 0.42-0.76) in NACs (absolute risk reduction [ARR], 11.4%/y; relative risk reduction [RRR], 95%; P < .0001). The incidence of ICH was 0.63%/y (95% CI, 0.34-1.04) and 0.30%/y (95% CI, 0.19-0.44), respectively (ARR, 0.33%/y; RRR, 52.4%/y; P = .04). IEs occurred mainly in elderly patients who received ASA or no treatment. One-half of patients with IEs receiving anticoagulant treatment had subtherapeutic INRs. Therapeutic approaches to elderly subjects with AF require an effective anticoagulant treatment strategy.

Rifampicin-warfarin interaction leading to macroscopic hematuria: a case report and review of the literature

BackgroundRifampicin remains one of the first-line drugs used in tuberculosis therapy. This drug´s potential to induce the hepatic cytochrome P450 oxidative enzyme system increases the risk of drug-drug interactions. Thus, although the presence of comorbidities typically necessitates the use of multiple drugs, the co-administration of rifampicin and warfarin may lead to adverse drug events. We report a bleeding episode after termination of the co-administration of rifampicin and warfarin and detail the challenges related to international normalized ratio (INR) monitoring.Case presentationA 59-year-old Brazilian woman chronically treated with warfarin for atrial fibrillation (therapeutic INR range: 2.0-3.0) was referred to a multidisciplinary anticoagulation clinic at a university hospital. She showed anticoagulation resistance at the beginning of rifampicin therapy, as demonstrated by repeated subtherapeutic INR values. Three months of sequential increases in the warfarin dosage were necessary to reach a therapeutic INR, and frequent visits to the anticoagulation clinic were needed to educate the patient about her pharmacotherapy and to perform the warfarin dosage adjustments. The warfarin dosage also had to be doubled at the beginning of rifampicin therapy. However, four weeks after rifampicin discontinuation, an excessively high INR was observed (7.22), with three-day macroscopic hematuria and the need for an immediate reduction in the warfarin dosage. A therapeutic and stable INR was eventually attained at 50% of the warfarin dosage used by the patient during tuberculosis therapy.ConclusionsThe present case exemplifies the influence of rifampicin therapy on warfarin dosage requirements and the increased risk of bleeding after rifampicin discontinuation. Additionally, this case highlights the need for warfarin weekly monitoring after stopping rifampicin until the maintenance dose of warfarin has decreased to the amount administered before rifampicin use. In particular, patients with cardiovascular diseases and active tuberculosis represent a group with a substantial risk of drug-drug interactions. Learning how to predict and monitor drug-drug interactions may help reduce the incidence of clinically significant adverse drug events.

Mild elevations of international normalized ratio at hospital Day 1 and risk of expansion in warfarin-associated subdural hematomas

A primary goal in the treatment of patients with warfarin-associated subdural hematoma (SDH) is reversal of coagulopathy with fresh-frozen plasma. Achieving the traditional target international normalized ratio (INR) of 1.3 is often difficult and may expose patients to risks of volume overload and of thromboembolic complications. This retrospective study evaluates the risk of mild elevations of INR from 1.31 to 1.69 at 24 hours after admission in patients presenting with warfarin-associated SDH. Sixty-nine patients with warfarin-associated SDH and 197 patients with non-warfarin-associated SDH treated at a single institution between January 2005 and January 2012 were retrospectively identified. Charts were reviewed for patient age, history of trauma, associated injuries, neurological status at presentation, size and chronicity of SDH, associated midline shift, INR at admission and at hospital Day 1 (HD1), concomitant aspirin or Plavix use, platelet count, and medical comorbidities. Patients were stratified according to use of warfarin and by INR at HD1 (INR 0.8-1.3, 1.31-1.69, 1.7-1.99, and ≥ 2). The groups were evaluated for differences the in rate of radiographic expansion of SDH and in the rate of clinically significant SDH expansion resulting in death, unplanned procedure, and/or readmission. There was no difference in the rate of radiographic versus clinically significant expansion of SDH between patients not on warfarin and those on warfarin (no warfarin: 22.3% vs 20.3%, p = 0.866; warfarin: 10.7% vs 11.6%, p = 0.825), but the rate of medical complications was significantly higher in the warfarin subgroup (13.3% for patients who did not receive warfarin vs 26.1% for those who did; p = 0.023). For warfarin-associated SDH, there was no difference in the rate of radiographic versus clinically significant expansion between patients reversed to HD1 INRs of 0.8-1.3 and 1.31-1.69 (HD1 INR 0.8-1.3: 22.5% vs 20%, p = 1; HD1 INR 1.31-1.69: 15% vs 10%, p = 0.71). Mild INR elevations of 1.31-1.69 in warfarin-associated SDH are not associated with a markedly increased risk of radiographic or clinically significant expansion of SDH. Larger prospective studies are needed to determine if subtherapeutic INR elevations at HD1 are associated with smaller increases in risk of SDH expansion.

Does Warfarin Use Impact Hospital Length of Stay? A Retrospective Study Looking at Patients Treated for Atrial Fibrillation

The authors received anecdotal practice information from clinicians indicating that when warfarin was initiated in the hospital setting, it may be associated with an increased length of stay (LOS): specifically to achieve a desired minimum international normalized ratio (INR) of 2.0 before discharge in a subset of patients where clinicians perceived follow-up after discharge was not deemed optimal. Given that oral thromboprophylactic anticoagulation with warfarin is the mainstay treatment for the prevention of stroke in atrial fibrillation (AF), the authors decided to look at hospitalized patients from this population to determine if a subset of these patients experienced an increased LOS. The study design entailed a retrospective chart review of consecutive patients admitted to a large, tertiary care, academic center. Patients were included if they were admitted with a primary, secondary, or most responsible diagnosis of paroxysmal or chronic AF. Medical records were audited over an 18-month period (February 1, 2009, to July 31, 2010) to determine the average LOS and to identify patients with a documented prolonged LOS secondary due to subtherapeutic INR at the time of potential discharge. Our final study cohort of 189 patients had an average LOS of 5.2 days (SD = 5.2). However, for eight (4.2%) of these patients discharge was delayed an additional 2.25 days (SD = 1.3) for reasons solely attributed to achieving a therapeutic INR.

Oral Anticoagulants – A Frequent Challenge for the Emergency Management of Acute Ischemic Stroke

Background: The emergency management of patients with acute ischemic stroke (IS) using oral anticoagulants (OAC) represents a great challenge. Effective anticoagulation predisposes to bleeding and represents a contraindication for systemic thrombolysis. However, patients on OAC can receive intravenous thrombolysis with recombinant tissue-type plasminogen activator if the international normalized ratio (INR) does not exceed 1.7, but data regarding the risk of hemorrhagic complications are highly controversial. Neurointerventional recanalization of intracranial artery occlusion represents an alternative option in OAC patients with acute IS. The proportion of OAC users among consecutive patients who suffer from acute IS or transient ichemic attacks (TIA) is unknown. Methods: A prospective observational study, consecutively enrolling all patients with IS or TIA admitted to our neurological emergency room (ER), was performed between August 2009 and February 2011. Basic demographic variables, present use of OAC, severity of stroke, cardiovascular risk factors, INR values and the symptom onset to presentation time were recorded. In IS patients on OAC presenting within 4.5 h after symptom onset, management was analyzed. In thrombolysed IS patients, bleeding events were documented. Outcome was assessed after 3 months. Results: During the study period, 12,237 patients were admitted to our neurological ER. IS or TIA were diagnosed in 2,074 (16.9%). Complete data were available for 1,914 of these subjects (92.3%); 53.8% were male (median age: 72 years). 69.7% suffered IS, 30.3% TIA. OAC were being used by 8.7% of all patients. OAC patients were older than non-OAC patients (78 vs. 72 years, p < 0.001). Subtherapeutic INR values (<2.0) were found in 67.3% of OAC patients with IS. 54.8% of all OAC IS patients presented at the ER within ≤4.5 h after the event (57/104). An INR ≤1.7 – compatible with systemic thrombolysis – was present in 33/57 patients (57.9%). Recanalization therapy was performed in 21/57 patients (36.8%). No difference in symptomatic or fatal intracerebral bleedings between thrombolysed patients with and without prior OAC use was observed (p = 0.720 and 0.135, respectively). Multivariable analysis of predictors of the 3-month outcome in IS patients revealed that prior medication with OAC was neither associated with an unfavorable clinical outcome after 3 months in the whole population of stroke patients (p = 0.235) nor in patients in whom recanalization approaches were used (n = 306; p = 0.271). Conclusions: Oral anticoagulation represents a frequent challenge for the emergency manangement of IS. A considerable proportion of anticoagulated IS patients appears to be eligible for thrombolysis. Establishing standardized treatment procedures in these patients is warranted.

Catheter ablation of atrial fibrillation: the need for studies to assess the efficacy and safety of novel anticoagulants

For selected patients with atrial fibrillation (AF), catheter ablation is an important treatment alternative and has about a 70 % success rate in carefully selected patients. Patients undergoing this procedure are at an increased risk of thromboembolic events during and following the ablation procedure. Bridging of anticoagulation, insertion of sheaths and catheters, left atrial endothelial damage, and atrial stunning may all lead to this increased thromboembolic risk. In order to minimize these thromboembolic events, anticoagulation, initiated as part of the procedure, increases bleeding complications including pericardial tamponade and vascular complications. Controlled data are not available to guide anticoagulation management of such patients during the peri-ablation period. Several years ago, we used to discontinue warfarin for several days before the procedure and the anticoagulation bridged with subcutaneous low molecular weight heparin (LMWH). The main limitation of this approach is that patients require LMWH after the procedure until the international normalized ratio (INR) becomes therapeutic. Excessive anticoagulation with LMWH and periods of subtherapeutic INR on warfarin post-procedure, have resulted in bleeding and thrombo-embolic complications [1]. More recently, in order to reduce these limitations, it has become more common to perform the ablation procedure without discontinuation of warfarin [2–4]. Several studies have demonstrated that uninterrupted warfarin is associated with fewer bleeding complications compared to LMWH bridging. With both approaches, unfractionated heparin is administered during the procedure and the dosing regimen is guided by a target activated clotting time (ACT) ranging from 225 to 450. Heparin infusion is discontinued once all catheters have been removed and the sheaths are removed once the ACT is less than 200 s. Post-procedure LMWH is usually not required since the patient is on a therapeutic level of anticoagulation with warfarin. Anticoagulation is then continued for 3–6 months or indefinitely depending on the patient’s risk factors. The problem with the above protocols is that there is no gold standard based on carefully collected prospective controlled data and the FDA has never approved LMWH bridging as an indication for this type of perioperative use. The commercial approval of dabigatran and rivaroxaban (and soon apixaban and edoxaban) has created a new anticoagulation challenge for AF patients undergoing catheter ablation procedures. Dabigatran has been commercially available for about 2 years and several reports have been published related to the safety and efficacy of using this drug during AF ablation procedures. Winkle et al. [5] demonstrated dabigatran to be safe and well tolerated when used after AF ablation (interrupted use prior to the ablation procedure) in a single-center study. The study included patients previously treated with warfarin, dabigatran, or aspirin. The post-procedure use of dabigatran was not associated with any major bleeding or thromboembolic events. However, three patients had to stop dabigatran due to dyspepsia, rash, and diarrhea. In this study, dabigatran was discontinued 36– 60 h prior to the procedure based on renal function and restarted 22 h after the procedure (post-procedure LMW heparin was given). The target ACT during the procedure was 225 s. A larger multicenter study by Lakkireddy et al. [6] reported that periprocedural dabigatran use significantly G. V. Naccarelli (*) :M. D. Gonzalez Electrophysiology Program, Heart and Vascular Institute, Penn State University College of Medicine, 500 University Drive, Room H1511, P. O. Box 850, MC H047, Hershey, PA 17033, USA e-mail: gnaccarelli@hmc.psu.edu

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

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

Thrombolytic therapy for ischaemic stroke in patients using warfarin: a systematic review and meta-analysis

BackgroundIt is uncertain whether thrombolytic therapy is safe in patients with acute ischaemic stroke who are treated with warfarin and have a subtherapeutic international normalised ratio (INR) at stroke onset.MethodsThe...

Incidence of thromboembolic complications in patients with atrial fibrillation or mechanical heart valves with a subtherapeutic international normalized ratio: A prospective multicenter cohort study

Subtherapeutic international normalized ratio (INR) is frequently encountered in clinical practice, and patients with high-risk atrial fibrillation (AF) and with mechanical heart valve (MHV) with inadequate anticoagulation may be exposed to an increased risk of thromboembolic events (TE). However, there are no prospective data evaluating this risk. Consecutive patients with a history of stable anticoagulation, but with a subtherapeutic INR, were prospectively included. Data on use and dose of low-molecular weight heparin (LMWH) bridging therapy were collected. The incidence of objectively confirmed TE and of major bleeding events within 90 days after the index INR was assessed. Five hundred and one patients with INR value 0.5-1 INR units below the lower limit of the patient-specific target INR were included in the study (280 with MHV and 221 with AF and CHADS2 score ≥3). LMWH was prescribed for 64 patients (12.8%). During follow-up, seven patients had a TE (1.40%; 95% confidence interval 0.68, 2.86%; 5.58 events for 100 patients year). All the events occurred within 14 days after the index INR. When we consider only patients who did not receive bridging therapy, the incidence of TE was 1.14% (5 of 437 patients; 95% confidence interval 0.49, 2.64%; 4.58 events for 100 patients year). There were no major bleeding events. The risk of TE in this population was not negligible. Given the frequent observation of subtherapeutic INR levels when monitoring vitamin K antagonists, this finding warrants additional investigation to improve the management of these patients.

A Randomized Controlled Trial of Empiric Warfarin Dose Reduction with the Initiation of Doxycycline Therapy

BackgroundWhen interacting medications, such as doxycycline, are initiated during warfarin therapy, one method to correct for non-therapeutic international normalized ratio (INR) is adjusting the warfarin dose, if necessary. Another approach is preemptive warfarin dose adjustment. This study's objective was to evaluate the utility of preemptive warfarin dose adjustment for preventing non-therapeutic INR following doxycycline-warfarin co-administration. MethodsPatients were randomized to either a 10% to 20% preemptive warfarin dose reduction (intervention) or reactive warfarin dose adjustment (control) within 72hours of warfarin-doxycycline co-administration. Subjects received a follow-up INR within 7days (index INR). Primary outcome was the occurrence of index INR≥1 point over the INR goal range upper limit. Secondary outcomes included INR control, purchases of prescription vitamin K, and warfarin-associated adverse events in the 30days after doxycycline initiation. ResultsTwenty and 17 patients comprised the intervention and control groups. The intervention group's warfarin dose was reduced by a median of 11%. More control patients (n=2) experienced an INR≥1 point over the INR goal range upper limit compared to intervention (n=0); however, the difference (12% vs. 0%) was not statistically significant (p=0.20). A higher percentage of intervention patients had subtherapeutic index INRs compared to control (35% vs. 6%, p<0.05). One patient from each group experienced warfarin-associated bleeding. No thromboembolic complications or vitamin K use were observed. ConclusionsFor warfarin patients initiating doxycycline therapy, preemptive warfarin dose reduction did not result in supratherapeutic INRs but increased the likelihood of subtherapeutic INRs compared to INR monitoring with reactive warfarin dose adjustment.

Striking a Balance Between the Risks and Benefits of Anticoagulation Bridge Therapy in Patients with Atrial Fibrillation: Clinical Updates and Remaining Controversies

Long-term anticoagulation with a vitamin K antagonist (VKA) or the new agent dabigatran is recommended to decrease stroke risk in patients with atrial fibrillation. When patients with atrial fibrillation undergo initiation or interruption of VKA therapy, or experience an isolated subtherapeutic international normalized ratio (INR), bridge therapy with a parenteral anticoagulant may be considered. To describe the literature for anticoagulation bridge therapy in patients with atrial fibrillation, we conducted a MEDLINE search (1966-February 2011) of the English-language literature to identify related studies. Ongoing clinical trials were identified through a search of the ClinicalTrials.gov registry. Major national and international guidelines were gathered and evaluated. Additional literature was obtained through review of relevant references of the identified articles. Bridging is not supported by guidelines or clinical trials for patients starting VKA therapy for atrial fibrillation. A subtherapeutic INR value during long-term VKA therapy may be associated with increased thromboembolic events, but the benefit of bridging has not been demonstrated. When VKA therapy is interrupted for procedures, retrospective and cohort data suggest that the decision to bridge should be based on a patient's thromboembolic and bleeding risks associated with the procedure. Typically, it is recommended to use bridge therapy in patients with atrial fibrillation at high risk for thromboembolism, but the benefit of bridging is less clear in patients at low risk. Not all procedures necessitate anticoagulation interruption. Recent trials suggest that VKAs can be continued when patients are undergoing cardiac device procedures and some types of radiofrequency ablation. Several clinical trials are ongoing that will provide more definitive guidance for perioperative anticoagulation management of patients with atrial fibrillation. Patients taking dabigatran are unlikely to require bridge therapy because of a predictable anticoagulant effect and rapid onset of action. However, evidence for optimal perioperative management of dabigatran is needed.

Prior Anticoagulant Therapy, Subtherapeutic International Normalized Ratio and Thrombolytic Therapy in Acute Ischemic Stroke

Prior Anticoagulant Therapy, Subtherapeutic International Normalized Ratio and Thrombolytic Therapy in Acute Ischemic Stroke

Relationship Between Subtherapeutic Warfarin Anticoagulation and the Development of Post Thrombotic Syndrome After a First Unprovoked Deep Vein Thrombosis: Results From the REVERSE Cohort Study

Abstract 712 Background & Objective:Risk factors for the post-thrombotic syndrome (PTS) remain poorly understood. In a prospective multinational multicenter cohort study of patients with a first episode of unprovoked deep venous thrombosis (DVT), we sought to evaluate whether subtherapeutic anticoagulation was associated with the development of PTS. Methods:The study population was derived from the REVERSE study, a prospective cohort study done to develop a clinical prediction rule to identify patients with unprovoked venous thromboembolism (VTE) at low risk of recurrent VTE. Patients with a first unprovoked VTE (index event) were treated with standard anticoagulant therapy with a target INR of 2–3 for a period of 5–7 months. Patients were then enrolled in the REVERSE study, anticoagulation was stopped, and patients were monitored for VTE recurrence.For the present study, patients with DVT as their index VTE event were assessed for PTS at enrollment into the REVERSE study, using the validated Villalta scale. PTS was defined by a score of > 4. Mild PTS was defined by a score of 5–9, moderate PTS by a score of 10–14 and severe PTS was defined by a score of ≥15 or presence of an ipsilateral leg ulcer. Using international normalized ratio (INR) data from the full period of warfarin anticoagulation, time in therapeutic range (TTR) was calculated by the Rosendaal method of linear interpolation. TTR data were analyzed to evaluate whether there was an association between sub-therapeutic INR values during various time windows since the index DVT and development of PTS. Based on published trials of warfarin anticoagulation for VTE, INR <2 for more than 20% of the time was considered to represent subtherapeutic anticoagulation. Univariate analysis was performed to determine the odds ratio (OR) for development of PTS if anticoagulation was considered subtherapeutic. Multivariate analysis was then performed to adjust for known confounding variables. Results:646 patients were enrolled into the REVERSE study, of whom 410 had DVT as their index event. Of these, 61 were excluded for insufficient INR or PTS data. Hence, the study population comprised 349 patients. The average age was 54.2 years, and 55.6% of the patients were male. Patients were on oral anticoagulation for a mean (SD) of 199 (17) days. Ninety-seven patients (27.8%) developed PTS; of these, 77 (74.7%) had mild PTS, 16 (15.5%) had moderate PTS and 4 (3.9%) had severe PTS.For the study population, the overall mean (SD) TTR during oral anticoagulation was 64.3% (19.4%) and the overall mean (SD) percentage time spent with an INR under 2 was 23.7% (18.7%). For the time window ‘first 3 months of anticoagulation’, patients who developed PTS had an INR of <2 for 30% of the time vs. 24% of the time in patients without PTS (p=0.023). For the time window ‘full period of anticoagulation’, patients who developed PTS had INR <2 for 27% of the time vs. 23% of the time in patients without PTS (p=0.08). Using our predefined cut-off for subtherapeutic anticoagulation (i.e. INR <2 for more than 20% of the time), patients with PTS were more likely to have received subtherapeutic anticoagulation than those without PTS during the first 3 months of anticoagulation (62.9% vs. 48.8%; p=0.02) and during the full period of anticoagulation (62.9% vs. 48.0%; p=0.01). The incidence of PTS in patients with an INR below 2 for >20% of the full time period was 33.5% compared to 21.6% in those with an INR below 2 for ≥20% of the time (p=0.02).In univariate analysis, the OR for development of PTS if the INR was <2 for more than 20% of the time during the first 3 months of anticoagulation was 1.78 (95% CI 1.10–2.87). In multivariate analysis adjusting for age, sex, body mass index, concurrent PE, previous secondary VTE and use of graduated compression stockings, the association between subtherapeutic anticoagulation and PTS remained robust (1.84 95% CI 1.13–3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14–3.00) [crude] and 1.88 (95% CI 1.15–3.07) [adjusted]. Conclusion:Subtherapeutic warfarin anticoagulation after a first unprovoked DVT may be a risk factor for the development of PTS. Careful attention to INR control may have value in preventing PTS. Further study of the risk of PTS associated with oral or parenteral anticoagulants that offer more predictable anticoagulation than warfarin may be of value. Disclosures:No relevant conflicts of interest to declare.

Bridging for an isolated subtherapeutic INR: an evaluation of clinical practice patterns, outcomes, and costs from an anticoagulation clinic

No formal recommendations support bridging patients taking warfarin for a subtherapeutic international normalized ratio (INR). This study aimed to: (1) characterize practices at one anticoagulation clinic, (2) evaluate adverse events, and (3) compare cost of bridging versus withholding bridging for subtherapeutic INR. A retrospective chart review of 320 patients having 546 isolated subtherapeutic INR episodes included patients with an INR below their therapeutic range, preceded by two INRs within or above range. Bridged episodes required more frequent follow-up visits to achieve therapeutic INR (2.5±1.0 vs. 2.2±0.6; P=0.097), but fewer days until the INR returned to therapeutic range (6.8±5.0 vs. 18.9±16.0; P<0.0001). The strongest predictor of bridging was the magnitude the INR fell below the therapeutic range, where those with a severely-low INR were 30-fold more likely to be bridged (P<0.0001), and moderately-low INR episodes were 6-fold more likely to be bridged compared with mildly-low INR (P<0.0001). Those at high thromboembolic risk were more likely to be bridged than at low-risk (OR 3.39 [1.50-7.68]; P=0.0034). Increasing age reduced the likelihood of being bridged (OR 0.97 [0.95-0.99]; P=0.0118). Adverse events were infrequent in both the bridged and non-bridged; thrombosis (2.0 vs. 0.7%), major bleeding (2.0 vs. 1.3%), minor bleeding (4.1 vs. 3.1%) and bruising (18.4 vs. 3.6%). Incremental cost difference of bridging was significantly greater for total cost ($967.13) and its components, direct medical ($951.32), transportation ($2.73) and productivity cost ($13.08). It is unclear if bridging for an isolated subtherapeutic INR reduces thrombosis risk, but it is associated with higher costs.

Evaluation of methods for achieving stable INR in healthy subjects during a multiple-dose warfarin study

No consistent method is available for finding stable warfarin maintenance doses and fast stabilization of international normalized ratio (INR) values among healthy subjects in experimental warfarin interaction studies. Using data from an earlier study that targeted a stable INR of 1.5-2.0 to test an interaction, we retrospectively evaluated potential dosing algorithms using all methods available to us to decrease the time needed for INR stabilization, which could be useful for future interaction studies in healthy subjects. Published pharmacogenetic and clinical dosing algorithms used to initiate pharmacotherapy with warfarin were applied, predicted doses and actual doses were compared by regression analysis, and concentration-time profiles of S-warfarin were simulated using SimCYP® software. No demographic variables were significantly associated with time to reach a stable, low-intensity INR in this population of relatively young, healthy subjects. Predicted and actual doses were positively correlated for the pharmacogenetic algorithm, but not for the clinical algorithm. INR levels and S-warfarin concentrations were associated with CYP2C9 and VKORC1 genotypes. Induction to a pharmacodynamic steady state for warfarin for future multiple-dose warfarin drug-interaction studies in healthy volunteers may be predicted using a pharmacogenetic-based dosing algorithm. Simulations revealed that the desired subtherapeutic INR level may be achieved by reducing the predicted dose by approximately 15%. Further study is needed to assess the applicability of this approach to decrease attrition rates and the time needed to reach INR stabilization.

Intensity of Anticoagulation with Warfarin and Risk of Adverse Events in Patients Presenting to the Emergency Department

The ability of patients receiving warfarin to maintain an international normalized ratio (INR) within the desired therapeutic range is important for both efficacy and risk of adverse events. It is unclear whether the desired INR is maintained in patients receiving warfarin who present to the emergency department (ED) and whether they have a higher rate of adverse events. To evaluate the intensity of anticoagulation with warfarin and the risk of bleeding and thromboembolic complications in patients in the ED. A prospective observational study was performed using a convenience sample of patients receiving warfarin and presenting to the ED over an 18-week period. Data were collected using a standardized form that included chief complaint, history of present illness, past medical history, medication history, and allergy status. Information from the physical examination, laboratory results, and other diagnostic tests obtained as part of routine assessment in the ED, was used as necessary. The primary outcome was the proportion of patients whose INR was within, above, or below the desired therapeutic range. Bleeding complications and thromboembolic events were recorded in an attempt to determine the relationship between the intensity of anticoagulation and adverse outcomes. Two hundred one patients were included, with a mean (SD) age of 74.0 (13.2) years; 53.7% were female. Primary indications for warfarin were atrial fibrillation (75.6%) and venous thromboembolic disease (14.9%). A therapeutic INR was observed in 88 patients (43.8%; 95% CI 37.1 to 50.7), while 45 patients (22.4%; 95% CI 17.2 to 28.7) and 68 patients (33.8%; 95% CI 27.6 to 40.6) had subtherapeutic and supratherapeutic INRs, respectively. Overall, there were 28 (18 major and 10 minor) bleeding complications (13.9%; 95% CI 9.8 to 19.4) and 4 thromboembolic events (2.0%; 95% CI 0.6 to 5.2). Among patients with a bleeding complication, 14 (50.0%) had a supratherapeutic INR, while 2 patients who experienced a thromboembolic event (50.0%) had a subtherapeutic INR. The majority of patients receiving warfarin on presentation to the ED had INRs outside the desired therapeutic range. By establishing the impact of warfarin-related adverse events in this population, focused interventions can be established in this setting to address factors that can be targeted to reduce these events.