International Normalized Ratio Range Research Articles

The clinical impact of different coagulometers on patient outcomes.

IntroductionLong-term anticoagulation therapy using vitamin K antagonists (VKA) is used in millions of patients worldwide to reduce the risk of thrombotic or thromboembolic events. Control and monitoring of VKA therapy is improved by the regular self-measurement of international normalized ratio (INR) using a home monitoring device. This retrospective analysis of a large cohort of patients in the Netherlands seeks to determine whether the choice of INR monitor could have a clinical impact on patient outcomes.MethodsThe National Thrombosis Service provides medical supervision, training and support to anticoagulant patients eligible for home-monitoring of INR in the Netherlands. Two INR monitors (CoaguChek XS and INRatio2) have been distributed at random to patients since June 2011, and patient self-testing data (INR measurements and other clinical parameters) have been recorded to measure and improve treatment outcomes. The data have been retrospectively analyzed to determine any effect of the choice of monitor. Univariate and multivariate statistical tests are used to assess any differences between groups in terms of efficacy and safety parameters.ResultsData from 4,326 patients were collated, and 156,507 INR values were included in the analysis. Over half the patients (54.3%) were being treated for atrial fibrillation, and 77.6% were prescribed acenocoumarol. There were few differences between the patient populations using the two different monitors. Anticoagulant control overall was good, with high percentage of time (87.9%) in the appropriate INR range and low incidence of excessively high or low INR values (0.085/month). Minor clinical events related to safety were low (0.78 per patient-year) and showed few differences between monitors. Mortality rates were similar [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.65–1.70].ConclusionSelf-testing data from a large cohort of patients in the Netherlands suggest that there is no clinically relevant effect of the choice of coagulation monitor (CoaguChek XS or INRatio2) on the time in therapeutic range (TTR), minor or fatal outcomes of long-term anticoagulation management.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-014-0124-x) contains supplementary material, which is available to authorized users.

Measures of vitamin K antagonist control reported in atrial fibrillation and venous thromboembolism studies: a systematic review

ObjectiveTo aid trialists, systematic reviewers and others, we evaluated the degree of standardisation of control measure reporting that has occurred in atrial fibrillation (AF) and venous thromboembolism (VTE) studies since...

Evaluation of a mobile electronic assistant to aid in fluindione prescription: The INRPlus cluster randomized trial

Regular monitoring of the international normalized ratio (INR) is crucial for dose adjustment of vitamin K antagonists (VKA) to maximize time in therapeutic range (TTR). We compared the use of a mobile electronic assistant INRPlus which proposes patient-specific fluindione doses, to standard fluindione management in a cluster randomized controlled study. Twenty clusters of six general practitioners were randomized to adjust fluindione doses in VKA-treated patients either using INRPlus or according to routine practice. TTR was measured over 6 months, along with time spent above or below the recommended INR range, frequency of measurements and related complications. Of the 595 included patients, 551 were assessable (259 INRPlus, 292 control) and had a mean of 1.6 INR measurements/month. TTR was not significantly different between the two groups, 72.7% [Q1: 58.1%; Q3: 90%] in INRPlus patients and 71.2% [Q1: 54.8%; Q3: 88.2%] in control patients (p=0.445). At least 60% time within reference ranges was reported in 73.4% of INRPlus patients and 67.1% of control patients (relative risk 1.09, 95%CI 0.98-1.22, p=0.115). No significant differences were reported between the two groups for time outside reference ranges, frequency of measurements or complications. Eighty-two percent (82%) of patients complying with INRPlus-proposed doses spent more than 60% of TTR versus 66.9% of non-compliant patients and 67.1% of reference patients. In this trial, the use of the INRPlus electronic assistant resulted in a non-significant improvement in TTR that may be due to a higher than expected TTR in the control group.

Abstract W P330: Antithrombotic Treatment Patterns Among Patients with Non-Valvular Atrial Fibrillation in a Managed Care Setting

Background: Antithrombotic therapy (warfarin or aspirin (ASA)) has been recommended to reduce the risk of stroke in patients with NVAF. The purpose of this study was to describe antithrombotic treatment patterns and baseline differences for managed care patients newly diagnosed with NVAF. Methods: Patients age ≥18 years and newly diagnosed with NVAF (index date) were identified between 01/01/2006_12/31/2011 within Kaiser Permanente Southern California databases and followed until 12/31/2012. Prescriptions, anticoagulation clinic information, and international normalized ratio (INR) monitoring were used to create 4 treatment groups: 1) continuous warfarin, 2) discontinuous warfarin (≥1 treatment gap >80 days), 3) ASA only, and 4) no antithrombotic therapy. Descriptive statistics were used to compare groups. Results: A total of 28,776 patients were identified with median follow up of 2.5 years. Among the 81% of patients (23,297) with ≥1 CHADS 2 risk factor for stroke at baseline: 27.4% were continuously treated with warfarin, 22.0% discontinued warfarin, 28.5% were on ASA only, and 22.1% received no therapy. Using the Rosendaal method, median time in INR range 2-3 for all warfarin-treated patients was 59%, which does not include patient-specific ranges. ASA users were older (mean±SD age: 77.6±10.8) compared to continuous warfarin users (73.7±9.6, p<0.001). Continuous warfarin users had higher rates of comorbidities: hypertension, diabetes, and stroke compared to the ASA group (stroke: 4.4% vs. 2.2% respectively, p<0.001), whereas the ASA and no therapy groups had higher rates of congestive heart failure, myocardial infarction, and bleeding (bleeding: 9.0% ASA, 9.8% no therapy, 6.5% continuous warfarin, p<0.001). CHADS 2 scores were slightly higher for ASA users compared to continuous warfarin or no therapy (2.04±0.92 ASA, 2.01±0.90 continuous warfarin, 1.93±0.93 no therapy, p<0.001). Conclusion: Patients with newly diagnosed NVAF have varied treatment patterns and baseline comorbidities including rates of stroke and bleed. Future studies should evaluate risks and benefits associated with these real world treatment patterns.

Warfarin treatment among Finnish patients with atrial fibrillation: retrospective registry study based on primary healthcare data

ObjectiveTo assess the frequency of warfarin use, the achieved international normalised ratio (INR) balance among warfarin users and the primary healthcare outpatient costs of patients with atrial fibrillation (AF).DesignRetrospective, non-interventional...

Knowledge, satisfaction, and concerns regarding warfarin therapy and their association with warfarin adherence and anticoagulation control

A better understanding of patients' knowledge, satisfaction and concerns can identify deficits and help develop targeted patient education. This study aimed to examine patients' knowledge, satisfaction and concerns regarding warfarin therapy and assess their association with warfarin adherence and international normalized ratio (INR) control. A cross-sectional survey was conducted in a convenience sample of patients taking warfarin in an anticoagulation clinic. The questionnaire consisted of questions on patients' knowledge, satisfaction and concerns regarding warfarin treatment. Patients' warfarin refill records and time within the therapeutic INR range were retrieved from hospital databases. One hundred and eighty-three patients participated in the survey. Patients had inadequate knowledge of warfarin-diet and warfarin-drug interactions. Over 40% of the respondents were not satisfied with the waiting time to see a pharmacist. The most common concerns of taking warfarin were worries about warfarin-drug interactions (36.1%), forgetting to take warfarin (26.2%) and worries about side effects (25.7%). Higher satisfaction was associated with better knowledge (r=0.24, p=0.001) and fewer concerns (rs=-0.23, p=0.002). Better knowledge and higher satisfaction were associated with higher warfarin adherence (rs=0.21 and 0.16; p=0.01 and 0.046, respectively). Better knowledge, higher satisfaction, fewer concerns, and better warfarin adherence were associated with good INR control (p=0.003, 0.02, 0.03 and 0.003, respectively). This study highlighted patients' concerns and deficits in knowledge regarding warfarin treatment, and also demonstrated their association with warfarin adherence and INR control.

Revalidation of CoaguChek XS plus system for INR monitoring in Taiwanese patients: effects of clinical and genetic factors.

In this study, we evaluated the performance of a point-of-care device, the CoaguChek XS Plus system, in the determination of prothrombin time and international normalized ratio (INR) based on ISO17593: 2007 criteria in Taiwanese patients. The underlying clinical and genetic factors were also investigated. Fifty patients receiving warfarin therapy were enrolled in this study. The accuracy of the CoaguChek XS Plus system was evaluated with linear regression analysis and bias plot by comparing with the data measured using Sysmex CA-1500. The clinical and genetic factors that may have caused a bias of ΃ 0.5 INR were evaluated with Fisher's exact test. From the 50 patients, 93 INR values were collected by each method. Linear regression analysis indicated a high correlation with r = 0.96, a slope of 1.05, and an intercept of - 0.14. Eight patients showed an INR bias ≥0.5 between the two methods. Only aspartate aminotransferase (AST) >34 U/L (3/8, 37.5% vs. 3/42, 7.1%; p = 0.044) and alanine aminotransferase (ALT) >36 U/L (3/8, 37.5% vs. 3/42, 7.1%; p = 0.044) were significantly different from each other. No differences were observed for hypoalbuminemia, elevated creatinine, anemia, and the polymorphisms of VKORC1 and CYP2C9. The CoaguChek XS Plus system presented results that were comparable with those obtained using laboratory CA-1500 method. Both methods fell within INR in the range of 2-4.5 defined by ISO17593:2007 and the clinically recognized therapeutic INR range of 2-3.5. Elevated AST and ALT levels might have interfered with the INR results.

Local Verification and Assignment of Mean Normal Prothrombin Time and International Sensitivity Index Values across Various Instruments: Recent Experience and Outcome from North America

Warfarin dosing relies on accurate measurements of international normalized ratio (INR), which is calculated from the prothrombin time (PT), International Sensitivity Index international sensitivity index (ISI) of the thromboplastin, and the geometric mean of normal PT (MNPT). However, ISI assignments of certain reagent/instrument combinations are frequently unavailable, especially when the reagent and instrument are not from the same manufacturer. The effort to be in compliance with widely endorsed Clinical and Laboratory Standards Institute (CLSI) guidelines by locally verifying or assigning an ISI to an unsupported reagent/instrument combination is further hindered by the lack of US Food and Drug Administration (FDA)-approved certified plasmas designated for a particular reagent/instrument combination. The objectives of the study include development of a process to verify/assign ISI and MNPT of a single thromboplastin reagent from one manufacturer across multiple instruments including several from another manufacturer and across several campuses of a single institution, the Mayo Clinic. In this study, RecombiPlasTin 2G (R2G), was evaluated on the ACL TOP 700 (IL), STA-R Evolution, STA Compact, and STA Satellite. Random normal donor samples (n = 25) were used to verify/assign MNPT. A subset of the normal donors (n = 8) and 13 warfarin pools (INR range: 1.3-3.9), created from stable warfarin patient plasma, were used for ISI verification/assignment. The manufacturer's assigned ISI was first verified on the ACL TOP 700 (reference method), then assigned on three unsupported instruments using orthogonal regression analysis. The MNPT and manufacturer assigned ISI (11.0, 0.95) were verified on the ACL TOP 700 and subsequently assigned on the STA-R Evolution (11.6, 1.04); STA Compact (11.5, 1.02); and STA Satellite (10.9, 0.99). Linear correlations of the INR results from all the four instruments demonstrated an r2 > 0.99. This process provides a reproducible approach to assigning ISIs on unsupported reagent/instrument combinations. Our data also confirm that ISIs of the same PT reagent differ significantly on different instruments, thus confirming the requirement for evaluations and validation of ISIs for different reagent/instrument combinations.

Evaluation of Differences in Percentage of International Normalized Ratios in Range Between Pharmacist-Led and Physician-Led Anticoagulation Management Services

Background: The safety and efficacy of warfarin depend on maintaining the international normalized ratio (INR) in an established range. Objective: The purpose was to determine whether a coordinated pharmacist-led approach improved percentage of INRs in therapeutic range in comparison to a physician-led anticoagulation management service (AMS). Methods: A retrospective chart review was conducted for patients at a multisite primary care organization. INR data for patients receiving warfarin management by a physician were collected from December 1, 2009 to May 31, 2010. These were compared to INR results from December 1, 2010 to May 31, 2011, during which patients received warfarin management from a pharmacist. The primary end points were percentage of INRs within a goal range of 2.0 to 3.0 and an expanded goal range of 1.8 to 3.2 for the physician-led group versus the pharmacist-led group. Results: The percentage of INR results within the goal range (2.0-3.0) was greater among patients in the pharmacist-led group (n = .130) than the physician-led group (n = 96; 57.5% vs 50.0%, respectively; P = .0004). The percentage of INR results <1.5 (7.3% vs 5.1%) and >3.5 (11.4% vs 7.1%) was also statistically significant in favor of the pharmacist-led AMS, with P values of .03 and .0004, respectively. Conclusion: A pharmacist-led AMS improved the percentage of INRs in range, with significantly less out-of-range results.

A Randomized Trial of Genotype-Guided Dosing of Warfarin

BackgroundThe level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.MethodsWe conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (−1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.ResultsA total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).ConclusionsPharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.)

Influence Of Concomitant NSAID Or ASA On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

BackgroundIn two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. However, some patients may already be taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA), which can have antihemostatic effects. ObjectivesWe performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without concomitant NSAIDs (half-life < 12 hours) or low-dose ASA. MethodsPatients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double-dummy; “oral only” treatment period) for 6 months. Concomitant use of ASA ≤ 100 mg/day or NSAIDs with a half-life ≤ 12 hours was permitted. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE, or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy, either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. ResultsOverall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without concomitant NSAIDs or low-dose ASA. Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects regardless of presence or absence of these concomitant medications. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral only treatment (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to concomitant NSAID or low-dose ASA use at baseline are shown in the Table. There was no significant treatment interaction by concomitant medication status for either MBE or MBE/CRBE. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by baseline NSAID or low-dose ASA use. ConclusionsThere was no apparent difference in recurrent VTE or VTE-related mortality across NSAID or low-dose ASA concomitant medication subgroups. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across subgroups. The results suggest that no increased bleeding risk exists when dabigatran is administered with NSAIDs with a half-life < 12 hours or low-dose ASA. Disclosures:Schulman:Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.Table: Incidence of recurrent VTE/VTE-related deaths, MBEs, and MBEs/CRBEs in the dabigatran and warfarin groups by use of concomitant NSAID or ASA at baselineConcomitant medication statusVTE or VTE-related death Patients, n/N (%)MBEs Patients, n/N (%)MBEs or CRBEs Patients, n/N (%)DEWarfarinDEWarfarinDEWarfarinNSAID No52/1973 (2.6)51/2015 (2.5)18/1922 (0.9)35/1982 (1.8)87/1922 (4.5)163/1982 (8.2)NSAID Yes16/580 (2.8)11/539 (2.0)6/534 (1.1)5/480 (1.0)22/534 (4.1)26/480 (5.4)ASA No60/2294 (2.6)57/2340 (2.4)21/2163 (1.0)33/2227 (1.5)95/2163 (4.4)167/2227 (7.5)ASA Yes8/259 (3.1)5/214 (2.3)3/293 (1.0)7/235 (3.0)14/293 (4.8)22/235 (9.4)DE, dabigatran etexilate.

Influence Of Active Cancer On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

▪ BackgroundIn two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. Cancer and its treatments are risk factors for VTE and bleeding. ObjectivesWe performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without active cancer at any time during the study. Active cancer was defined as: a diagnosis of cancer (other than basal-cell or squamous-cell carcinoma of the skin) within 5 years before enrolment; any treatment for cancer within 5 years before enrolment; or recurrent or metastatic cancer. MethodsPatients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. ResultsOverall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without active cancer at any time. Cox regression analysis showed that presence of cancer was associated with a statistically significant increase in the likelihood of VTE or VTE-related death. However, there was no significant interaction with treatment, indicating similar treatment effects regardless of the presence or absence of active cancer. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral treatment only (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, the MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to cancer status are shown in the Table. Patients with cancer had significantly higher rates of MBEs and MBEs/CRBEs than those without. There was no significant treatment interaction by cancer status for MBEs, whereas the treatment interaction for MBEs/CRBEs was significant (p = 0.0257) with a lower rate of bleeding with dabigatran versus warfarin in patients without compared to with cancer. Any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no significant treatment interaction with cancer status. ConclusionsThere was a significantly higher frequency of recurrent VTE or VTE-related mortality among patients who had cancer, but the efficacy of dabigatran versus warfarin was similar irrespective of cancer status. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across cancer subgroups. Disclosures:Schulman:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc.: Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée: Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory boards, Advisory boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

Influence Of Age On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis Of RE-Cover and RE-Cover II

BackgroundIn the RE-COVER and RE-COVER II trials, a fixed dose of dabigatran etexilate was as effective as warfarin for prevention of recurrent VTE and was associated with a lower risk of bleeding. It is not known whether this efficacy and difference in bleeding rates is maintained in older patients. ObjectivesOlder patients may be at greater risk of bleeding and/or VTE. Therefore, we performed a subgroup analysis on the pooled RE-COVER and RE-COVER II trial results to investigate the efficacy and safety of dabigatran versus warfarin for the treatment of acute VTE according to age. MethodsPatients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Outcomes were centrally adjudicated. The primary efficacy outcome was recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Major bleeding events (MBEs), the composite of MBEs or clinically relevant non-major bleeding events (CRBEs), and any bleeds were counted from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. ResultsOf 2553 patients randomized to dabigatran, 68 (2.7%) had recurrent VTE or VTE-related death compared with 62 (2.4%) of 2554 patients randomized to warfarin; hazard ratio (HR) 1.09 (95% CI 0.77, 1.54). The incidences of the primary efficacy outcome (dabigatran vs warfarin) by age group were 3.0% (53/1769) versus 2.4% (42/1748) for patients < 65, 2.3% (12/531) versus 2.5% (13/530) for patients 65–75, and 1.2% (3/253) versus 2.5% (7/276) for patients > 75 years; and in a second age-group comparison were 2.8% (67/2418) vs 2.3% (57/2429) for patients < 80 and 0.7% (1/135) versus 4.0% (5/125) for patients ≥ 80 years. Cox regression analysis showed no statistically significant interaction, indicating that there are similar treatment effects across age groups. MBEs were significantly less frequent with dabigatran than with warfarin overall (HR 0.60; 95% CI 0.36, 0.99). Incidences by age group are shown in the Table. MBE/CRBE incidence was also significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). The Table shows event rates for each age group. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall. There was no significant treatment-by-age interaction for MBEs or MBEs/CRBEs or any bleeds in either analysis. ConclusionsNo differences in recurrent VTE or efficacy were apparent across the age groups. Bleeding events increased with increasing age but numerically were similar or lower with dabigatran than with warfarin regardless of age. The results suggest there is no need for dose adjustment of dabigatran according to age for the treatment of VTE.Table:Incidence of MBEs and MBEs/CRBEs in the dabigatran and warfarin groups by ageAge, yearsMBEs Patients, n/N (%)MBEs or CRBEs Patients, n/N (%)DabigatranWarfarinDabigatranWarfarin< 6511/1722 (0.6)19/1685 (1.1)58/1722 (3.4)102/1685 (6.1)65–755/503 (1.0)11/515 (2.1)29/503 (5.8)54/515 (10.5)> 758/231 (3.5)10/262 (3.8)22/231 (9.5)33/262 (12.6)< 8020/2334 (0.9)37/2341 (1.6)98/2334 (4.2)173/2341 (7.4)≥ 804/122 (3.3)3/121 (2.5)11/122 (9.0)16/121 (13.2) Disclosures:Schulman:Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai Inc: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Kreuzer:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

Influence Of Renal Function On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

▪ BackgroundFor treatment of acute venous thromboembolism (VTE), dabigatran etexilate was as effective as warfarin with a lower risk of bleeding in two phase III trials, RE-COVER and RE-COVER II. As dabigatran is predominantly renally eliminated, its plasma concentration may be elevated in renally impaired patients, potentially increasing the bleeding risk. Warfarin is primarily metabolized hepatically. ObjectivesWe performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin according to renal function. MethodsPatients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. ResultsOverall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). Event rates for dabigatran vs warfarin in subgroups with CrCl ≥ 80, 50 to < 80 (mild renal dysfunction), and 30 to < 50 mL/minute (moderate renal dysfunction), respectively, were: 3.1% (58/1860) vs 2.6% (48/1838), 1.9% (10/539) vs 1.6% (9/561), and 0% (0/114) vs 4.1% (5/123). Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects across the CrCL groups. Overall, MBEs were significantly less frequent with dabigatran vs warfarin during the oral treatment only (double-dummy) period (HR 0.60; 95% CI 0.36, 0.99). Results for the respective renal function subgroups are shown in the Table. There was no significant treatment interaction by renal function. MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Renal function subgroup results are shown in the Table. There was no significant treatment interaction by renal function. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by renal function.TableIncidence of MBEs and MBEs/CRBEs in the dabigatran and warfarin groups by renal functionCreatinine clearance at screening, mL/minMBEsPatients, n/N (%)MBEs or CRBEsPatients, n/N (%)DabigatranWarfarinDabigatranWarfarin≥ 809/1811 (0.5)19/1783 (1.1)59/1811 (3.3)110/1783 (6.2)50 to < 809/504 (1.8)16/536 (3.0)36/504 (7.1)66/536 (12.3)30 to < 506/106 (5.7)5/114 (4.4)12/106 (11.3)12/114 (10.5) ConclusionsThere was no apparent difference in recurrent VTE or VTE-related mortality across renal function groups. Bleeding events increased with declining renal function but were similar or numerically lower with dabigatran than with warfarin. The results suggest no need for dose adjustment of dabigatran in patients with mild or moderate renal dysfunction. Disclosures:Schulman: Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Portola: Consultancy; Pfizer: Consultancy; Merck: Consultancy; Janssen: Consultancy; BMS: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc: Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria; BMS/Pfizer: Honoraria; Bayer Healthcare: Advisory boards, Advisory boards Other, Consultancy, Honoraria; Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

PCV135 - International Normalized Ratio (INR) Monitoring and Percent Time in Therapeutic INR Range (TTR) Have Impact on Patient’s Quality of Life? Application of Beta Regressions in a Prospective 3 Months Setting

PCV135 - International Normalized Ratio (INR) Monitoring and Percent Time in Therapeutic INR Range (TTR) Have Impact on Patient’s Quality of Life? Application of Beta Regressions in a Prospective 3 Months Setting

Suboptimal Time in Therapeutic Range (TTR) for International Normalized Ratio (INR) Measurements Observed in an Outpatient Cardiology Clinic: Impact of Gender, Ethnicity, Disease Etiology, Chadsvasc Score, Physicians and Clinic Site

Suboptimal Time in Therapeutic Range (TTR) for International Normalized Ratio (INR) Measurements Observed in an Outpatient Cardiology Clinic: Impact of Gender, Ethnicity, Disease Etiology, Chadsvasc Score, Physicians and Clinic Site

Postoperative bleeding risk for cutaneous surgery in the head and neck region with continued phenprocoumon therapy

In a total of 171 surgical procedures for lesions in the head and neck region in patients in whom phenprocoumon therapy was not stopped, 16 (9%) postoperative bleeding events were observed over a follow-up period of two weeks. Local measures were sufficient in all cases except one severe case where blood transfusion was needed and anticoagulant treatment was stopped for 7 days. The bleeding risk was significantly higher for the surgical procedures of the nose than those in other areas (21% versus 6%, P = 0.014), but was not influenced by the international normalized ratio (INR) of blood coagulation, size, site and type of the lesion, surgical procedure, and sex and age of the patients. The bleeding rate in patients not on any anticoagulation therapy was significantly lower (6/211 = 3%). Across both groups, just over 80% of the bleeding episodes were within the first two days (55% on the same day and 32% on the next day) of the surgery. No bleeding was recorded after 5 days. Our data suggest that cutaneous surgery in the head and neck region can be safely performed with continued phenprocoumon therapy in most cases in an INR range of 1.3–3.4, but rarely severe bleeding does occur and can be managed with a close-contact follow-up and with 24-h on call services during the first two days postoperatively.

Is home warfarin self-management effective? Results of the randomised Self-Management of Anticoagulation Research Trial

AimsThe Warfarin Self-Management Anticoagulation Research Trial (Warfarin SMART) was designed to determine whether patients self-managing warfarin (PSM) using the CoaguChek device and a dosing algorithm developed for the trial could keep the INR (International Normalised Ratio) test in target range at least as often as patients managed by usual care by the family doctor or hospital clinic. Methods and results310 patients were randomly assigned to PSM or usual care. The PSM group was trained to perform home INR testing and warfarin dosing using a validated ColourChart algorithm. The primary endpoint was the proportion of times over 12months that a monthly, blinded “outcome INR test”, measured in a central laboratory, was outside the patient's target therapeutic range.The rate of out-of-range outcome INRs was lower in PSM, and non-inferior to the usual care group (PSM: 36% vs. usual care: 41%, P<0.001 for non-inferiority; P=0.08 for superiority in closed-loop testing). The deviations from the patient's midpoint of target INR range (P=0.02) and number of extreme INRs (P=0.03) were significantly less in the PSM group than the usual-care group. There was no significant difference between groups in rates of bleeding or thrombotic adverse events. ConclusionPatient self-management performed at least as well as usual care in maintaining the INR within the target range, without any safety concerns. This treatment modality for the long-term use of warfarin has the potential to change current local and international practice.

Predictive accuracies of CHA2DS2-VASc and HAS-BLED, and anticoagulation quality in relation to thromboemblism and bleeding in patients with mechanical heart valves

Background: The variability of international normalized ratio (INR) is considered a risk factor in patients with mechanical heart valves (MHV) and INR target range still remains unestablished. CHA2DS2-VASc and HAS-BLED are risk stratification schemas designed for atrial fibrillation. Their ability to discriminate thromboembolism (TE) and bleeding for patients with MHV have never been investigated. Methods: We conducted a complete study of all patients with MHV followed in two centres. A total of 407 and 140 patients respectively were followed between 2008-2011. Data on INR, time in therapeutic range (TTR), variability, CHA2DS2-VASc and HAS-BLED were extracted. Results: The mean (±SD) age in centre 1 and 2 were 70 (14) and 61 (14) respectively. The target INR range for all MHV was 2-4 in centre 1 and 2-3 in centre 2 and mean INR was 2.9 (0.31) and 2.6 (0.19) respectively. The incidence of TE was 3.4 per 100 patient-years in centre 1 and 1.4 per 100 patient-years in centre 2, p=0.035, and for major bleeding 4.9 per 100 patient-years and 1.7 per 100 patient-years respectively, p=0.005. The HAS-BLED score correlated well with bleeding, with area under the curve of 0.63 (95% confidence interval [CI]: 0.57-0.70). CHA2DS2-VASc had 0.56 (95% CI: 0.48-0.64) for TE. Adding atrial fibrillation as a risk factor did not improve the c statistic. INR variability (SD), comparing the 3rd tertile with the first had (Odds ratio [OR]: 4.05; 95% [CI]: 2.09-7.84) for major bleeding and (OR: 2.01; 95% [CI]: 1.0-3.99) for TE. INR SD was higher with a higher mean INR and target range 2-4 (p<0.001) and independently predicted bleeding. Conclusion: HAS-BLED predicted bleeding with discriminatory ability similar to previous reports to atrial fibrillation whilst CHA2DS2-VASc predictive ability for TE was modest. Higher INR intensity is associated with higher variability, which correlates to primarily bleeding, but also TE. Some of the difference between the groups considering TE can be accounted for more significant risk factors in the centre 1 cohort. A more narrow INR target range could be recommended to reduce variability of anticoagulation.

The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate

The time in target International Normalized Ratio (INR) range (TIR) is used to assess the control and intensity of oral anticoagulation, but it does not measure variation in the INR. The value of assessing INR variability by use of the variance growth rate (VGR) as a predictor of events was investigated in patients treated with warfarin. Three different methods of VGR determination (A, B1, and B2) together with the TIR were studied. MethodA measures both INR variability and control, but methodsB1 and B2 measure variability only. The VGR and TIR were determined over three time periods: overall follow-up to an event, and 6months and 3months before an event. Six hundred and sixty-one control patients were matched to 158 cases (bleeding, thromboembolism, or death). With all VGR methods, the risk of an event was greater in unstable patients at 6months before an event than in stable patients. MethodA demonstrated the greatest risk 3months before an event in the unstable VGR group as compared with the stable group (odds ratio3.3, 95% confidence interval1.9-5.7, P<0.005). The risk of an event was 1.9 times greater in patients with a low TIR (<39%) than in those with a high TIR (>80%) in the 3-month period (P=0.02). Risk of bleeding was significantly greater in the 3-month period in patients with unstable VGR, with the greatest risk found with method B2 (P<0.01). Patients with unstable anticoagulation have a significantly increased risk of 'clinical events' at 3 and 6months before an event. The VGR can be incorporated into computer-dosage programs, and may offer additional safety when oral anticoagulation is monitored.