Baseline International Normalized Ratio Research Articles

Lupus anticoagulant, warfarin, and alternative laboratory monitoring of anticoagulation

A 53 year old woman was evaluated for recurrent native and prosthetic mitral valve thromboembolism in the setting of antiphospholipid antibody syndrome. In 1989, at age 30 years, she suffered a thromboembolic stroke and was diagnosed with antiphospholipid antibody syndrome for which long-term warfarin therapy was prescribed. She was subsequently assigned a goal international normalized ratio (INR) of 2.5–3.5. In 2008, at age 49 years, she was diagnosed with mitral valve stenosis and underwent mitral valve replacement (29 mm Carbomedics prosthesis). Pathology was consistent with nonbacterial thrombotic endocarditis involving a fibrotic and focally calcified mitral valve. After valve replacement, the target INR range was increased to 3.0–4.0. Nine months later, she developed thrombosis of the prosthetic mitral valve and required redo valve replacement surgery (27 mm St. Jude Biocor). Postoperatively, she developed heparin induced thrombocytopenia (HIT) for which she received argatroban while transitioning to warfarin. Her target INR range was subsequently increased to 3.5–4.5. In 2012, she developed recurrent prosthetic mitral valve thrombosis despite being mostly therapeutic(INR 3.5–4.5) and at times supra-therapeutic with INR monitoring. Transesophageal echocardiogram confirmed an 8 mm thick layer of organized thrombus encasing each of the prosthetic mitral valve leaflets with severe valvular stenosis. Laboratory testing upon admission revealed a prothrombin time (PT) of 101.7s (INR 11.1). Simultaneously measured chromogenic factor X activity was 20 % (therapeutic range 20–35 %) and factor II activity was 14 % (normal reference range 75–145 %), confirming adequate anticoagulation at that time. A third mitral valve replacement procedure was pursued (27 mm Hancock II bioprosthesis) and she was yet again restarted on warfarin postoperatively. Initial special coagulation testing done at our institution in 1989 established the presence of a lupus anticoagulant (LAC). This diagnosis was subsequently confirmed on four occasions (1995–2012). Prior to 2004, the LAC assays were performed using the dilute Russel viper venom time (DRVVT) assay kit from American Diagnostica (Stamford, CT). After 2004, the DRVVT assay was performed using the kit from Precision Biologics (Dartmouth, NS, Canada) following the manufacturer’s instructions. She had a persistently high titer of anticardiolipin antibodies (IgG and IgM) as well. Her baseline prothrombin PT (11.3s) and INR (1.1), were normal and remained so until 2012, when measured during brief interruptions of warfarin anticoagulation (six occasions; 1995–2011). Prior to 2009, the PT assay was performed with Innovin (Siemens, New York, NY formerly Dade Behring, Deerfield, IL). Beginning in 2009, the PT was performed with Recombiplastin 2G (Instrumentation Laboratories, Bedford, MA). The temporal trends in INR and chromogenic factor X activity are shown in Fig. 1. Since INR differences are much larger at low factor activities than at high activities, we compared the log INR with the factor activities. Log INR did not correlate well with chromogenic factor X activity (Fig. 2a, r = 0.32) and factor II (Fig. 2b, S. S. Ketha (&) R. D. McBane W. E. Wysokinski Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Gonda 4-130 (VM), 200 First St. SW, Rochester, MN 55905, USA e-mail: Ketha.Siva@mayo.edu

Impact of International Normalized Ratio and Activated Clotting Time on Unfractionated Heparin Dosing During Ablation of Atrial Fibrillation

For ablation of atrial fibrillation, it is unclear how baseline international normalized ratio (INR) affects the dosing of unfractionated heparin (UFH). A retrospective review of 170 consecutive patients undergoing atrial fibrillation ablation with baseline activated clotting time (ACT) and INR values was performed. Patients were grouped according to INR <2.0 (G<2; n=129) and INR ≥2.0 (G≥2; n=41). Clinical variables, UFH doses, and ACT values were recorded. An equation was derived to calculate the first bolus of UFH required to achieve an ACT ≥300 seconds, and this was subsequently assessed in 168 patients. For the initial 170 patients, the baseline INR (2.47±0.31 versus 1.53±0.31) and ACT (185±26 versus 153±30 seconds) were significantly greater in G≥2 (P<0.001). The amount of UFH to achieve the first ACT ≥300 seconds was significantly higher for G<2 versus G≥2 (9701±2390 versus 8268±2366 U; P=0.0001). Baseline INR, ACT, and weight were predictors of the UFH dosage to achieve an ACT ≥300 seconds. An equation derived to achieve an ACT ≥300 seconds after a single bolus of UFH met this end point in 160 of 168 patients (95%). Baseline INR and ACT, in addition to weight, are the only predictors of UFH dosage needed to achieve an ACT ≥300 seconds. A derived equation predicted the UFH dosage to achieve an ACT ≥300 seconds.

INR reduction after prothrombin complex concentrate (Co-fact©) administration: comparison of INR outcomes in different patient categories at the emergency department

BackgroundCo-fact©, prothrombin complex concentrate, is used for restoring the international normalized ratio (INR) in patients on vitamin K antagonists (VKA) presenting with acute bleeding. In this prospective cohort study, we evaluated whether adequate INR values were reached in ED patients using the Sanquin (Federation of Dutch Thrombosis Services) treatment protocol.MethodsWe evaluated this protocol for two target INR groups: group 1, target INR ≤ 1.5 (for life-threatening bleeding/immediate intervention); group 2, target INR 1.6-2.1 (in cases of a minor urgent surgery or serious overdosing of anticoagulant). We specifically wanted to identify both under- and over-treated patients. Reversing VKA anticoagulation therapy to unnecessarily low INR values may involve thrombotic risks. Apart from this risk, the patient is also administered an excess amount of the drug. This means unnecessary costs and may present problems with restoring an anticoagulated state at a later time.ResultsIn our cohort, the Sanquin dosing protocol was followed for 45/60 patients. It appeared that out of the 41 patients in group 1 (target INR ≤ 1.5), 35 (85%) achieved the goal INR. This occurred more often than for the 19 patients in group 2 (target INR 1.6–2.1), where only 6 (32%) achieved the goal INR. Using the protocol resulted in a positive trend toward better INR reversal in group 1. In group 2, no relation between using the protocol and achieving the desired INR value was detected. Physicians ignoring the proposed dose of Co-fact© prescribed significantly less Co-fact© (even when correcting for patient weight). It appeared that patients in group 1 had a significantly lower baseline INR than patients in group 2. Group 2 patients, on the other hand, had a baseline INR > 7.5 in 53% of the cases.ConclusionIn our cohort, for most patients in INR group 2 treated with Co-fact©, the achieved INR value was outside the desired range of 1.6-2.1. The supra-therapeutic range of baseline INR in group 2 may have contributed to the different kind of bleeding witnessed in this patient group. Our results support the idea that treatment of patients on vitamin K antagonists with Co-fact© could benefit from a slightly different approach, taking into account the INR value to which the patient needs to be reversed.

Questionable reversal of anticoagulation in the therapeutic management of cerebral haemorrhage associated with vitamin K antagonists

Reversal of anticoagulation is recommended to correct the international normalised ratio (INR) for patients with intracranial haemorrhage (ICH) associated with vitamin K antagonists (VKA). However, the validity of such treatment is debated. We sought to identify, prospectively, the prognostic effect of VKA-ICH treatment in a cohort of patients (n=71; median age 78 years, range 20-89; 52% males). Data collated were: baseline characteristics, treatments, baseline and post-treatment INR, haematoma volume, and haematoma enlargement. Treatment effects and prognostic factor assessment were in relation to mortality and functional outcomes. On admission, the patients had a median score of 9 [p25; p75 of 5; 20] on the National Institute of Health Stroke Scale (NIHSS) and a mean INR of 2.7 (range: 0.9 - 10.8). Haematoma volume (34.6 cm³; SD: 24.9) correlated with NIHSS (r = 0.55; p<0.001) but not with INR. Anticoagulation reversal treatment was administered in 83% of patients. INR <1.5 was achieved in 60.7% of cases. Death or dependency at three months was 76%. Neither baseline INR, anticoagulation reversal nor haematoma enlargement were related to mortality or functional outcome. The only independent prognostic factor was clinical severity on admission. Baseline NIHSS predicted mortality (OR: 1.18; 95%CI: 1.09-1.27), independence (OR: 0.83; 95%CI: 0.74-0.94) and neurological recovery (NIHSS 0-1) (OR: 0.83; 95%CI: 0.73-0.95). The data indicate that VKA-ICH had a poor prognosis. Treatment and INR correction did not appear to affect outcomes.

Evaluation of recombinant activated protein C for severe sepsis at a tertiary academic medical center

PurposeEarly clinical trials of recombinant human activated protein C (rhAPC) for severe sepsis excluded patients at high risk of bleeding. Recent literature suggests bleeding rates are higher in clinical practice and may be associated with worsened outcomes. Our objective was to evaluate baseline demographics; incidence, and risk factors for major bleeding; and mortality of patients receiving rhAPC for severe sepsis at our institution.MethodsA retrospective study was performed for all patients receiving rhAPC for treatment of severe sepsis at a tertiary academic medical center from January 2002 to June 2009. Demographic information, clinical variables, intensive care unit, and hospital outcomes were recorded.ResultsOf the 156 patients that received rhAPC, 54 (34.6%) did not meet institutional criteria for safe use at baseline due to bleeding precaution or contraindication. Twenty-three (14.7%) patients experienced a major bleeding event. Multivariate analysis demonstrated baseline International Normalized Ratio ≥2.5 (odds ratio [OR] 3.68, 95% confidence interval [CI]: 1.28–10.56; P = 0.03) and platelet count ≤100 × 103/mm3 (OR 2.86, 95% CI: 1.07–7.67; P = 0.01) as significant predictors of a major bleed. Overall hospital mortality was 57.7%. Multivariate analysis demonstrated the presence of ≥3 organ dysfunctions (OR 2.46, 95% CI: 1.19–5.09; P < 0.05) and medical intensive care unit admission (OR 1.99, 95% CI: 1.00–3.98; P = 0.05) were independent variables associated with hospital mortality.ConclusionPatients receiving rhAPC at our institution had higher APACHE II scores, mortality, and major bleeding events than published postmarketing studies. Risk factors for major bleeding other than package-labeling contraindications and bleeding precautions were identified in our patient population.

24 Correction of INR and Coagulation Factor Levels in a Randomized Clinical Trial of Four-Factor Prothrombin Complex Concentrate (PCC-4) Versus Plasma for Urgent Vitamin K Antagonist Reversal

Study Objectives: Rapid anticoagulant reversal is essential for subjects on vitamin K antagonists (VKA) that present with acute, major bleeding. The International Normalized Ratio (INR), factor (F) levels (FII, FVII, FIX, and FX) and protein (P) C and PS were assessed pre- and post-administration of PCC-4 or plasma in subjects taking VKAs presenting with major bleeding. Methods: Subjects (aged ≥ 18 years) requiring urgent VKA reversal for acute, major bleeding were randomized (1:1) to receive PCC-4 (containing FII, FVII, FIX, FX, PC and PS; Beriplex P/N, CSL Behring) (N = 98) or plasma (N = 104) in this prospective, randomized phase IIIb trial. Dose was based on baseline INR and subject's weight. Consequently, PCC-4 (reconstituted to 25 IU of FIX/mL) was stratified by baseline INR (2 - <4; 4-6; > 6) into 3 different doses (as randomized): 25 (n = 47), 35 (n = 24), and 50 (n = 27) IU of FIX/kg, respectively. The corresponding plasma doses were: 10 (n = 53), 12 (n = 20) and 15 (n = 31) mL/kg. Per protocol, vitamin K was also administered by slow IV infusion. INR and factor levels (FII, FVII, FIX, FX, PC, PS) were measured pre-infusion (baseline) and up to 24 h after the start of the infusion. Results: No significant differences were detected between groups in the mean baseline INR (Table) . However, at 0.5 h after the start of the infusion, the mean INR in the PCC-4 group was significantly lower than the plasma group for each dose. The INR reversal was most pronounced in the baseline INR > 6 group; the mean INR in the PCC-4 group reduced from 10.6 to 1.5 within 0.5 h of the start of infusion versus INR 10.9 to 3.7 in the plasma group. The difference between groups was still evident at 1 h at all doses, although INR was similar by 24 h post-infusion. Median factor levels at baseline were <50% in both groups with no differences between PCC-4 and plasma groups at any dose (p > 0.05). Factor levels were higher than baseline at 0.5 h after the start of the infusion for both groups (p<0.05); for each PCC-4 dose at 0.5 h, factor levels were > 50% (except for FVII at INR 4-6 and > 6 [≥ 45%] and PS at INR 4-6 [> 48%]), whereas levels were <50% for all plasma doses (except for INR 2 - <4 for FIX [58%] and PC [53%]). Each factor level at 0.5 h was significantly higher after PCC-4 than plasma for each dose (p<0.05). Factor levels were also higher than baseline at 24 h for each dose in both groups (p<0.05).Tabled 1 Conclusion: Marked INR corrections and factor level increases were observed within 0.5 h of the start of PCC-4 infusion, irrespective of dose; these improvements were not observed until much later in the plasma group (> 3 h; data not shown). After 24 h, INRs and factor levels were similar between treatment groups. Therefore, whilst both products achieved INR reversal by 24 h, PCC-4 was more successful in the first hour.

Randomized trial of lottery-based incentives to improve warfarin adherence

Poor adherence to medications is a major cause of morbidity and inadequate drug effectiveness. Efforts to improve adherence have typically been either ineffective or too complex to implement in clinical practice. Lottery-based incentive interventions could be a scalable approach to improving adherence. This was a randomized, controlled clinical trial of a daily lottery-based incentive in patients on warfarin stratified by baseline international normalized ratio (INR). The trial randomized 100 patients to either a lottery-based incentive or no lottery intervention. Main outcome was out-of-range INRs. Over 6 months, the overall percentage of out-of-range INRs did not differ between the 2 arms (mean 23.0% in lottery arm and 25.9% in control arm, adjusted odds ratio [OR] 0.93, 95% CI 0.62-1.41). However, among the a priori subgroup with a baseline INR below therapeutic range, there was a significant reduction in out-of-range INR in the lottery arm versus the control arm (adjusted OR 0.39, 95% CI 0.25-0.62), whereas there was no such effect among those with therapeutic INRs at baseline (adjusted OR 1.26, 95% CI, 0.76-2.09, P value for interaction = .0016). Among those with low INR at baseline, there was a nonsignificant 49% reduction in the odds of nonadherence with the intervention (OR 0.51, 95% CI 0.23-1.14). Although a lottery-based intervention was not associated with a significant improvement in anticoagulation control among all study participants, it improved control among an a priori group of patients at higher risk for poor adherence.

Abstract 10: Intracranial Hemorrhage Risks among Warfarin Treated Acute Ischemic Stroke Patients Receiving Thrombolytic Therapy

Background While intravenous thrombolytic therapy (tPA) improves the outcomes of ischemic stroke, treatment of those receiving warfarin raises concerns regarding symptomatic intracranial hemorrhage (ICH). While guidelines suggest excluding patients with an international normalized ratio (INR) &gt;1.7, little is known about the use and safety of tPA in warfarin-treated patients in clinical practice. Methods Data from 23,437 ischemic stroke patients treated with tPA with an INR ≤1.7 in 1,203 Get With The Guidelines-Stroke hospitals between April 2009 and June 2011. Multivariable logistic regression analysis was performed to evaluate the association of preadmission warfarin use on ICH risk while adjusting for potential confounders. Results Overall 1,802 (7.7%) were taking warfarin prior to admission. Warfarin treated patients were older (median 77 vs. 71 years, p&lt;0.001) and had more comorbid illness and greater stroke severity (median National Institutes of Health Stroke Scale 14 vs. 11, p&lt;0.001). Crude rates of ICH were higher in those taking warfarin 5.7% vs. 4.7% (unadjusted OR 1.22, 95% CI 0.99-1.51). However, after risk adjustment, ICH risks were similar (adjusted OR 1.01, 95% CI 0.82-1.25). These findings were consistent across several sensitivity analyses (Table). There were no significant differences between warfarin and non-warfarin users for serious systemic hemorrhage (0.9% vs. 0.9%; adjusted OR 0.78; 95% CI 0.48-1.24), any tPA complications (10.6% vs. 8.4%; adjusted OR 1.09; 95% CI 0.93-1.29), and in-hospital mortality (11.4% vs. 7.9%; adjusted OR 0.94; 95% CI 0.79-1.13). Among those receiving warfarin, a trend toward higher crude ICH rates was observed among those with higher baseline INR levels (Cochran-Mantel-Haenszel trend test, p=0.03). After adjustment for risk factors, higher INR levels had a marginally significant association with ICH risk (adjusted OR 1.10, 95% CI 1.00-1.20, p=0.06 for each 0.1 units increase in INR). Conclusion This represents the largest clinical experience of the safety of thrombolysis in warfarin treated patients who meets clinical guideline eligibility criteria. Use of intravenous tPA among warfarin-treated stroke patients (INR ≤1.7) was not associated with increased ICH risk compared to non-warfarin treated patients in routine clinical practice. These data provide empirical support of current AHA/ASA guideline recommendations.

Risk factors for elevated INR values during warfarin therapy in hospitalized pediatric patients

There are currently no data describing the incidence of or risk factors for elevated International Normalized Ratio (INR) values in patients receiving warfarin at a tertiary care pediatric hospital. By minimizing risk factors for elevated INR values patient morbidity may be minimized. A 6-year retrospective chart review of inpatient admissions at our institution that received warfarin was performed. Factors for elevated INR values, such as patient demographics, disease state, and medication interactions were reviewed. Patients with an INR value ≥ 0.5 above the upper limit of the goal range were compared to patients without an elevated INR value. A logistic regression analysis was performed to identify independent variables for elevated INR values. A total of 298 patient admissions (184 patients) met study criteria, and the largest patient population was between 1 and 12 years old (36.9%). The most common indication for warfarin was mitral valve replacement (25.5%). An elevated INR occurred in 20.8% of admissions. Logistic regression analysis identified Asian race, an elevated baseline INR value, warfarin initiation after cardiac surgery, days of inpatient warfarin therapy, and drug interactions with ciprofloxacin and lansoprazole as independent variables for an elevated INR value (P < 0.05). Obesity was significant as an independent variable for a non-elevated INR value (P < 0.05). Elevated INR values occur often in patients receiving warfarin while admitted to a tertiary care pediatric facility and modifiable risk factors exist for elevated INR values.

Pharmacologic Reversal of Warfarin-Associated Coagulopathy in Geriatric Patients With Hip Fractures

Patients with acute hip fractures who are on maintenance warfarin for anticoagulation present a significant challenge and their management remains controversial. The purpose of this study was to assess thromboembolic and systemic complications associated with pharmacological reversal of warfarin-associated coagulopathy in a population of geriatric patients with hip fractures. This retrospective cohort study identified patients with operative hip fractures on oral warfarin therapy who had an international normalized ratio (INR) >1.50 on admission (N = 93) approximately over a 13-year span. The control group consisted of patients whose warfarin was held upon admission without further intervention preoperatively (n = 23). The treatment group consisted of patients who underwent pharmacologic reversal of elevated INR with vitamin K and/or fresh frozen plasma (FFP) in addition to holding warfarin (n = 70). Primary outcomes included thromboembolic and other complications as well as mortality within 3 months of presentation. Time to surgery was a secondary outcome. The 3-month mortality rate was 4% in the pharmacological intervention group and 17% in the watch-and-wait group; this difference trended toward statistical significance (P = .06). There were no significant differences in the likelihoods of other thromboembolic or nonthromboembolic complications between groups. While the difference in mean time to surgery was not significantly different overall between groups, this difference was significant in a subgroup of patients with higher baseline INRs (n = 46, INR >2.17), with a mean difference of 4.0 fewer days until surgery in the pharmacological intervention group (P < .01). Pharmacological reversal of warfarin-associated coagulopathy with a combination of vitamin K and FFP appears to be a safe way to optimize patients for operative fixation of hip fractures and is associated with a shorter delay to surgery in patients with more elevated INRs preoperatively. retrospective cohort study (level III).

Failure of Pharmacogenetic-based Dosing Algorithms to Identify Older Patients Requiring Low Daily Doses of Warfarin

Warfarin doses vary greatly among patients and warfarin administration is accompanied by risk of bleeding. Genes responsible for its metabolism (CYP2C9) and effect on clotting (VKORC1) have been identified. It has been suggested that genotyping for variants in these genes can improve warfarin dosing and decrease bleeding complications. We evaluated performance of pharmacogenetic-based warfarin dosing estimation algorithms in old and very old patients. Cross-sectional study of stable patients older than 65 years receiving warfarin with therapeutic International Normalized Ratio (INR) anticoagulation. Medical and laboratory data were reviewed and genotyping for CYP2C9 and VKORC1 performed. Warfarin dose estimates with and without genotype information were compared to clinically established therapeutic doses. Sixty-nine patients (32 men, 37 women; 41nursing home residents; 28 senior care community residents) aged 81.4 ± 8.3 (mean ± S.D) years; ethnicity: Caucasian in 53, Asian in 10, Hispanic in 4, and African American in 2, received 3.3 ± 1.7 mg/d (range 0.7-9) warfarin achieving target INRs of 2.5 ± 0.2. Pharmacogenetic-based dose estimates (in combination with age, weight, height, smoking history, ethnicity/race,history of liver disease, selected co-medications such as amiodarone and enzyme inducers, baseline INR, clinical indication, and target INR), explained 50% of variability (P < .0001) compared with 12% without genetic data (P= .003). However, doses were overestimated in 15 of 16 patients requiring less than 2 mg/d (2.6 ± 0.9 mg/d compared with observed 1.5 ± 0.3 mg/d, P= .0001). Renal disease was a potential variable contributing to low warfarin requirements. The role of pharmacogenetic testing in the management of warfarin administration in patients is undergoing evaluation. Currently available pharmacogenetic- based warfarin dose estimation algorithms reduce variability in estimates for groups of older patients but consistently overestimate doses for older patients requiring the lowest doses of warfarin. Pharmacogenetic data add to our understanding of variability in warfarin dosing requirements but do not accurately identify older patients requiring the lowest warfarin doses. Therefore, the most prudent approach to warfarin therapy in older patients should include low initial doses in the absence of genotype variants associated with very low warfarin sensitivity and careful monitoring of INR responses.

Comparison of the 5‐Fluorouracil‐Warfarin and Capecitabine‐Warfarin Drug Interactions

To compare the differences between the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions in patients receiving therapeutic doses of warfarin. Retrospective medical record review. Large academic Veterans Affairs health care system. Twenty-four patients who received concomitant therapeutic doses of warfarin and at least one dose of a fluoropyrimidine--5-fluorouracil or capecitabine--between January 2004 and May 2008. The primary outcome was mean change in international normalized ratio (INR) from baseline to end of 90-day study period. Only patients who were taking warfarin before starting either fluoropyrimidine-based chemotherapy were included in the primary analysis. Of the 24 eligible patients, 15 (9 receiving 5-fluorouracil, 6 receiving capecitabine) were taking warfarin before receiving either fluoropyrimidine. No significant differences were noted in the average weekly warfarin dose or baseline INR between the 5-fluorouracil and capecitabine groups. The mean change in INR for patients taking warfarin before fluoropyrimidine use was 4.62 in the 5-fluorouracil group compared with 5.11 in the capecitabine group (p=0.87). The capecitabine group had a similar proportion of patients achieving an INR above 9 while taking warfarin compared with the 5-fluorouracil group (17% vs 22%). In those patients who required a warfarin dosage reduction, the dose was reduced by 38% and 41% in the 5-fluorouracil and capecitabine groups, respectively. No significant differences in bleeding events were reported within 90 days of concurrent use of either fluoropyrimidine with warfarin. Our study suggests that in patients receiving concomitant warfarin and a fluoropyrimidine, no significant differences in INR elevation or bleeding events were noted with 5-fluorouracil compared with capecitabine.

Preemptive dose reduction of warfarin in patients initiating metronidazole

The goal of this study was to determine if preemptive dose reduction (PDR) of warfarin is effective in maintaining therapeutic anticoagulation in patients initiating metronidazole. This is a retrospective, single-center, cohort study in a pharmacist-managed anticoagulation clinic of a university affiliated Veteran's Affairs (VA) Medical Center. Subjects were anticoagulation patients initiating metronidazole between 1 January 2002 and 30 March 2009. At the time of metronidazole initiation, patients were managed with PDR of warfarin or no dose reduction. The primary outcome was the average change in International Normalized Ratio (INR) between patients that received PDR vs. those that did not. In total, 20 patients met inclusion criteria with seven patients receiving PDR at the time of initiation of metronidazole, whereas 13 did not. Patients managed with PDR and those that were not were similar in age (mean±SD 69.4±12.9 years vs. 72.1±9.9 years, p=0.61), mean baseline INR before metronidazole (2.58±0.49 vs. 2.57±0.66, p=0.98), and mean time to follow-up after initiation of metronidazole (5.6±2.9 days vs. 7.0±3.7 days, p=0.40), respectively. The primary outcome was statistically significant with a mean difference in INR of 1.28 (p=0.01) between patients manag-ed with PDR vs. those that were not. The mean preemptive warfarin dose reduction was 34.6%±13.4% which resulted in no significant increase in INR (p=0.61). Secondary outcomes including INR values >4.0 (0% vs. 46%, p=0.05), the average number of warfarin doses omitted (0.43±0.79 vs. 1.15±1.27, p=0.17), use of phytonadione or fresh frozen plasma, and rates of bleeding events were not significantly different be-tween groups. No thromboembolic events occurred during the 30 days following metronidazole therapy. In patients determined to be appropriate candidates for PDR, a 30%-35% reduction in mean daily warfarin dose was effective in maintaining therapeutic anticoagulation in patients started on concomitant metronidazole.

Pharmacy Students Provide Care Comparable to Pharmacists in an Outpatient Anticoagulation Setting

To evaluate whether student participation in ambulatory clinics influenced the percentage of therapeutic international normalized ratio (INR) results among patients on chronic warfarin therapy. Medical records in outpatient anticoagulation clinics managed by pharmacists under physician protocol were reviewed retrospectively in 2 university-affiliated clinics in Amarillo and Lubbock, TX. Pharmacy student activities included patient interviews, vital sign measurements, fingersticks, counseling, and documentation. Patient visits were conducted by a precepted pharmacy student or a pharmacist without a student, and the INR was measured at the subsequent patient visit. Records of 1,958 anticoagulation patient visits were reviewed; 865 patients were treated by pharmacists, and 1093 were treated by precepted students. The follow-up INR was therapeutic for 48.5% of third-year (P3) students' patients, 45.6% of fourth-year (P4) students' patients, 51.2% of residents' patients, and 44.7% of pharmacists's patients (p = 0.23). Eight variables were associated with the follow-up INR (baseline INR, warfarin noncompliance, held warfarin doses, a warfarin dosage adjustment, diet change, alcohol use, tobacco use, and any medication changes). Student participation in the patient-care process did not compromise patient care and no significant difference in patient outcomes was found between patients in an anticoagulation clinic cared for by precepted students and those cared for by pharmacists.

Effect of Therapeutic INR on Activated Clotting Times, Heparin Dosage, and Bleeding Risk During Ablation of Atrial Fibrillation

Ablation of atrial fibrillation (AF) with international normalized ratio (INR) ≥ 2.0 is safe and may reduce thromboembolic complications. Heparin is administered during the procedure, but the effect of elevated INR on heparin requirements and target activation clotting times (ACT) ≥ 350 seconds during ablation is unknown. To study the effect of INR on intraprocedural anticoagulation during ablation of AF. We retrospectively studied 427 consecutive patients over an 18-month period when we were transitioning to continuation of warfarin for AF ablation. Baseline INR, procedural ACT measurements, heparin doses and major complications were analyzed according to Group 1 with INR < 2.0 (n = 246) and Group 2 with INR ≥ 2.0 (n = 181). In Group 1, the mean INR was lower (1.3 ± 0.3 s vs 2.4 ± 0.3; P < 0.001), and the mean heparin dose was greater (106.82 ± 40.01 vs 77.03 ± 18.5 U/kg; P < 0.001). A single heparin bolus achieved ACT ≥ 350 seconds throughout the procedure in 51 patients (20.7%) in Group 1 compared to 108 patients (59.7%) in Group 2 (P < 0.01). Mean ACT values were higher in Group 2. Symptomatic pericardial effusions were similar (2.4% in Group 1 and 2.2% in Group 2). There were 3 thromboembolic cerebrovascular events in Group 1 and none in Group 2. Femoral hematomas occurred more frequently in Group 1 (8.1%) than in Group 2 (3.3%) (P = 0.007). AF ablation with INR ≥ 2.0 provides a consistent anticoagulant milieu during the procedure, with lower heparin requirements that are important to anticipate.

Effect of heart failure exacerbations on anticoagulation: A prospective, observational, pilot cohort study

Background: Some studies have suggested that heart failure (HF) is associated with excessive anticoagulation, but definitive data or data showing causation do not exist. Knowledge of risk factors for excessive anticoagulation is critical to manage warfarin therapy safely. Objective: This study characterized the relation between HF-associated hypervolemia and excessive anticoagulation in patients with HF taking chronic warfarin therapy. Methods: This was a prospective, observational pilot study conducted in a university-based HF clinic. Patients aged 18 to 85 years with HF and taking warfarin were enrolled and were observed for episodes of hypervolemia. Hypervolemia was determined based on multiple clinical factors, including patient-reported symptoms and physical examination. Anticoagulation was assessed longitudinally per standard of care by measurement of the international normalized ratio (INR). A x 2 analysis was used to determine whether hypervolemia was associated with an increased risk of excessive anticoagulation. Paired and unpaired t tests were used for ad hoc analyses. Results: Forty patients with 41 HF episodes who were taking warfarin were enrolled between December 2003 and July 2007. Mean (SD) age was 67.2 (11.1) years and mean weight was 218.5 (62.8) pounds; 29 patients (72.5%) were men and 34 (85.0%) were white. Most had systolic dysfunction (n = 26; 65.0%) and were taking warfarin for atrial fibrillation (n = 33; 82.5%); the mean weekly warfarin dose was 30.8 (17.5) mg. There were 41 evaluable hypervolemia episodes over a mean follow-up of 14.5 (9.0) months. The mean INR change during hypervolemia was −0.02 (0.82) INR unit ( P = NS vs baseline). No association was found between hypervolemia episodes and INR increases of >50% ( P = NS); the results remained nonsignificant for both diastolic and systolic HF when analyzed separately. There was no significant change from baseline INR between patients classified with mild, moderate, or severe hypervolemia or between patients classified according to New York Heart Association (NYHA) functional class (all, P = NS). Patients with NYHA class III had a lower weekly warfarin dose than those with NYHA class II (25.73 vs 31.75 mg; P < 0.01). Conclusion: Mild hypervolemia did not appear to be related to excessive anticoagulation in these patients with HF taking chronic warfarin therapy.

Interaction of vitamin K antagonists with heparin affect monitoring by activated clotting times

Unfractionated heparin is recommended during atrial fibrillation (AF) ablation to achieve activated clotting time (ACT) above 250-300 s to prevent clot. Many patients on therapeutic international normalised ratio (INR) undergo AF ablation procedures; however, it is unknown whether they require less heparin to achieve similar ACT levels. During AF ablation, the ACT was measured before and 10 min after administration of i.v. unfractionated heparin in patients with and without anticoagulation. The association of INR, heparin, pre-procedure ACT and body weight with ACT after heparin administration was tested using multivariable linear regression models. The subjects of this study were 149 patients undergoing AF ablation, among them 40 (27%) with subtherapeutic INR < 2, 79 (53%) with an INR between 2 and 3, and 30 (20%) patients with INR > 3. Baseline ACT was associated with INR (r = 0.33, p < 0.001). After a mean of 8,685 +/- 2,015 U (range, 5,000-15,000 IU) unfractionated heparin, univariate predictors of ACT were baseline INR (p < 0.001), heparin dose (p = 0.012) and baseline ACT (p = 0.027). In the multivariable model, baseline INR (part r = 0.64, p < 0.001) and heparin dose (part r = 0.33, p < 0.001) strongly predicted post-heparin ACT. Estimated from the regression model, the heparin dose reductions by approximately one third in those with an INR of 2-3 and by at least two thirds in those with an INR above 3 may be favourable. Over the following 3 months, no thromboembolism and acute bleeding were observed. The INR was the strongest predictor of post-heparin ACT, even more important than the heparin dose itself. The reduction of heparin dose by one third if INR is between 2-3 and by two thirds if INR is above 3 may be favourable.

Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with the oral anticoagulant warfarin and can cause a serious bleeding complication. In this study, we evaluated the risk factors for international normalized ratio (INR) increase, which is a surrogate marker of bleeding, after addition of an NSAID in a total of 98 patients who used warfarin. Patient age, sex, body mass index, maintenance warfarin dose, baseline INR, coadministered medications, underlying diseases, and liver and kidney functions were evaluated for possible risk factors with INR increase ≥15.0% as the primary end-point. Of the 98 patients, 39 (39.8%) showed an INR elevation of ≥15.0% after adding a NSAID to warfarin therapy. Multivariate analysis showed that high maintenance dose (>40 mg/week) of warfarin (P=0.001), the presence of coadministered medications (P=0.024), the use of meloxicam (P=0.025) and low baseline INR value (P=0.03) were the risk factors for INR increase in respect to NSAID-warfarin interaction. In conclusion, special caution is required when an NSAID is administered to warfarin users if patients are taking warfarin >40 mg/week and other medications interacting with warfarin.

Effects of requiring a baseline International Normalized Ratio for inpatients treated with warfarin

Ensuring the safety of anticoagulation continues to challenge the health care community and has led to the new Joint Commission national patient safety goals. [1][1]– [4][2] In response to this focus and to improve patient care, Sanford USD Medical Center initiated a new policy requiring baseline

Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists?

After a vitamin K antagonist (VKA) overdose, 1-2 mg of oral vitamin K can lower the International Normalized Ratio (INR) to the therapeutic range. To establish whether oral vitamin K can substitute for heparin bridging and decrease the INR to < or = 1.5 before elective surgery. Patients on long-term VKAs were randomized either to heparin bridging after the last VKA dose on day -5 before surgery (group H) or to VKA treatment until day -2, followed by 1 mg of oral vitamin K on the day before surgery (group K). Blood clotting variables were assessed on days -5/-2, 1 and 0, and postoperatively. If the target INR was not achieved 2 h before incision, surgery was deferred or performed after injection of prothrombin complex concentrate (PCC). In 30 of 94 included patients, baseline INR was outside the chosen range (18, INR < 2; 12, INR > 3.5), leaving 34 eligible patients in group H and 30 in group K. The groups were balanced in terms of body mass index, VKA treatment duration and indication, scheduled surgery, preoperative and postoperative hemoglobin, and blood loss. The INR was significantly higher in group K on days -1 and 0 than in group H. An INR < or = 1.5 was not achieved in 20 group K patients (66%). Surgery was postponed or performed after PCC injection in 12 of these 20 patients. Oral vitamin K (1 mg) cannot substitute for heparin bridging before surgery. In addition, one-third of patients on VKAs were exposed to a risk of bleeding (overdose) or thrombosis (underdose), thus highlighting the need for new oral anticoagulants.