45/aph.1S187Annals of PharmacotherapyBaruch and Sherman 2013
Case Report
Inaccuracy of Point-of-Care International Normalized Ratio in Rivaroxaban-Treated Patients
Annals of Pharmacotherapy 47(9) 1210–1212 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013503129 aop.sagepub.com
Lawrence Baruch, MD1,2 and Olga Sherman, BS, PharmD3
Abstract Objective: To report 2 cases in which point-of-care international normalized ratios (POC-INRs) measured using a Hemochron Jr. Signature Elite device (International Technidyne Corporation) were inaccurate in rivaroxaban-treated patients. Case Summaries: Therapy in an 86-year-old man with atrial fibrillation was converted from warfarin to rivaroxaban 15 mg twice daily because of a deep venous thrombotic event despite an INR of 2.4, which was within the therapeutic range. One week later a POC-INR was inadvertently measured, which was 6.3. In light of the POC-INR being markedly elevated, a laboratory test for INR was performed, which gave a result of 2.74. Therapy in a 66-year-old man was converted from war-farin to rivaroxaban 15 mg twice daily because of unstable INRs and a pulmonary embolism despite a therapeutic INR. Seven days after rivaroxaban was started, the patient’s POC-INR was 9.2; simultaneously measured laboratory-determined INR was 2.0. For both patients, coagulation tests performed on follow-up visits revealed continued discordance between the POC and laboratory assays. Discussion: Rivaroxaban is an oral factor Xa inhibitor with a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. When patients’ therapy is switched from rivaroxaban to warfarin, it is recommended that the drugs be given concurrently until the INR is 2.0 or higher, to ensure adequate anticoagulation during this well-recognized vulnerable period for stroke. POC testing is a common method of INR assessment in clinical practice. During ROCKET-AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), POC-INRs were measured exclusively with the INRatio device (Hemosense), and values above 4 were seen very rarely (0.25%), which indicates that the values determined in our patients were highly unusual. Conclusions: Our 2 patients receiving rivaroxaban had POC-INRs elevated beyond what was expected; these measurements were discordant from INRs simultaneously measured via the laboratory. A prospective evaluation assessing the accuracy of other commonly used POC-INR devices in patients receiving rivaroxaban would determine whether our findings extend to other devices. Until that time, laboratory measurement of INR or POC-INR using an INRatio device is recommended when patients’ therapy is transitioned from rivaroxaban to warfarin. Keywords rivaroxaban, point-of-care INR, INR, anticoagulation, factor Xa inhibitor, deep vein thrombosis
Rivaroxaban is an oral direct factor Xa inhibitor approved for use in the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism.1,2 Rivaroxaban has a predictable pharmacokinetic profile, allowing for a fixeddose regimen to be administered without the need for routine coagulation monitoring.1,2 The international normalized ratio (INR) is elevated by rivaroxaban (mean value 1.4 at 12-15 hours after the last rivaroxaban dose),3 but does not provide a valid measure of its anticoagulant activity.1-3 In clinical practice, when patients’ therapy is switched from rivaroxaban to warfarin, this period has been identified during clinical development as high risk for stroke.1,2,4 During this vulnerable transition
period, it is recommended that rivaroxaban be given concurrently until the INR is 2.0 or higher1,2 to ensure adequate
1
Medical Program, James J Peters VA Medical Center, Bronx, NY Department of Cardiology, Mt. Sinai School of Medicine, New York, NY 3 Pharmacy Program, James J Peters VA Medical Center 2
Corresponding Author: Lawrence Baruch, MD, Director of Echocardiography, Medical Program, James J Peters VA Medical Center, Bronx, NY; Assistant Professor of Medicine, Department of Cardiology, Mt. Sinai School of Medicine, New York, NY. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV OF MONTANA on April 5, 2015
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Baruch and Sherman Table 1. Point-of-Care and Corresponding Laboratory-Determined INRs. Pt.
Time
Rivaroxaban Dose
Timing of INR Measurement After Last Dose
POC-INR
Laboratory INR
1 2
Week 1 Week 2 Week 4 Week 7 Week 8 Day 1 Day 15
15 mg bid 20 mg/day 20 mg/day 20 mg/day 15 mg/day 15 mg bid 20 mg/day
2 hours 14 hours 14 hours 14 hours 14 hours 2 hours 3 hours
6.3 2.3 4.5 4.8 3.4 9.2 7.9
2.74 1.4 1.83 2.18 1.8 2.0 1.78
INR = international normalized ratio; POC = point-of-care.
anticoagulation.4 Point-of-care (POC) testing is a common method of INR assessment in clinical practice. We report on 2 patients receiving rivaroxaban who had multiple POC-INRs that were elevated well beyond what was expected. These INRs were calculated using a Hemochron Jr. Signature Elite device (International Technidyne Corporation).
Case Reports Case 1 An 86-year-old male with atrial fibrillation, a history of deep vein thrombosis (DVT), and placement of a Greenfield filter more than 20 years ago presented with recurrent right superficial femoral and popliteal DVT. His INR 2 days prior to the DVT diagnosis was 2.4. He was referred to our anticoagulation clinic for rivaroxaban as he experienced a venous thrombotic event despite having an INR in the therapeutic range while on warfarin. His warfarin was discontinued the night before his regularly scheduled clinic visit. His POC-INR the morning of the clinic visit was 2.9 and rivaroxaban 15 mg twice daily was initiated. One week later, at a regularly scheduled clinic visit, a POC-INR inadvertently measured 2 hours after the patient had taken rivaroxaban was 6.3. In light of the markedly elevated POC-INR, the INR was measured via laboratory testing (also 2 hours after the patient had taken rivaroxaban), which gave a result of 2.74. Coagulation tests performed on follow-up visits revealed continued discordance between POC and laboratory assays (Table 1).
Case 2 A 66-year-old man with a history of DVT was followed in our anticoagulation clinic. His therapy was converted from warfarin to rivaroxaban because his INRs were unstable and he experienced a pulmonary embolism while receiving warfarin. On the day after therapy was switched from warfarin to rivaroxaban 15 mg twice daily, he was
admitted with gastrointestinal bleeding. Consequently, all anticoagulants were stopped for 5 days. On the day of discharge, his laboratory-determined INR was 0.91. On the night after discharge, the patient took his prescribed 15-mg evening dose of rivaroxaban with dinner. The following morning, at 6 AM, he took his prescribed 15-mg morning dose of rivaroxaban. At a scheduled anticoagulation clinic visit that morning, the POC-INR was 9.2; the INR measured simultaneously via laboratory testing was 2.0. Coagulation tests performed on a follow-up visit revealed continued discordance between the POC and laboratory assays (Table 1).
Discussion These 2 cases highlight the potential inaccuracy of POC devices in assessing the INR in patients receiving rivaroxaban. Both patients had unexpected unusually high POCINRs (>6), values that occurred at a rate of only 1 in 400 assessments in ROCKET-AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).3 Moreover, 6 of the 7 POC-INRs were greater than 3, a finding seen in only 0.7% of assessments in ROCKET-AF. Patient 2 had unusually high POC-INRs of 7.9 and 9.2, which were inconsistent with values seen in ROCKET-AF.3 This was in contrast to the corresponding laboratory-determined INRs, which were consistent with the values in ROCKET-AF.3 The inaccuracy of the POC device was not an isolated occurrence, as it was noted on 7 different occasions (each time both tests were performed) over a period of weeks. Falsely elevated INRs may affect patient care, as they lead to inappropriate downward adjustments of therapy and inadequate anticoagulation. This will be most common and of greatest clinical significance when transitioning patients’ therapy from rivaroxaban to warfarin, as those patients commonly undergo assessment of INR with a POC device to assess the adequacy of anticoagulation with warfarin. This transition period has been identified in ROCKET-AF
Downloaded from aop.sagepub.com at UNIV OF MONTANA on April 5, 2015
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Annals of Pharmacotherapy 47(9)
as a high-risk period for stroke, even in the absence of falsely elevated INRs,1,2,4 and has led to a boxed warning in the US prescribing information.1 European Medicines Agency documents state that when rivaroxaban is discontinued “the INR may be reliably done 24 hours after the last dose.”2 Our findings would call into question this recommendation when the INR is measured with the Hemochron Jr. POC device. None of the clinical conditions associated with high concentrations of rivaroxaban secondary to altered metabolism (eg, renal insufficiency or the use of P-glycoprotein inhibitors) were present in either of these patients.1 Neither patient had antiphospholipid antibodies, a lupus anticoagulant, or a hematocrit less than 20% or greater than 55%, conditions known to affect the accuracy of the Hemochron device.5 The samples were collected by a medical assistant with certification and extensive experience in performing POC-INR testing, ensuring a high quality of blood specimens, which could also affect the accuracy of the POC-INR. We recognize the limitations to our findings, most notably, the small sample size of 7 INRs derived from 2 patients. The laboratory-measured INRs were all performed with a single device, ACL Advance (Instrumentation Laboratory Company), with RecombiPlasTin 2G used to initiate clotting. The international sensitivity index (ISI) of our POC device, 1.0, is slightly higher than the ISI for our laboratory method, 0.98, which may result in slight differences in the INR. These limitations are largely offset by the fact that our findings were repeated on multiple occasions, the values were dramatically inconsistent with those seen in ROCKET-AF, and the laboratory-measured INRs were consistent with those in ROCKET-AF. Our findings are not inconsequential, as they could affect patient management, especially during the period of transition from rivaroxaban to warfarin, which places patients at high risk for stroke. Our findings do not extend to the INR device used universally in ROCKET-AF, the INRatio (Hemosense). Moreover, the effect of rivaroxaban on other commercially available POC-INR devices is unknown. Based on our findings, until the accuracy of other POCINR devices in rivaroxaban-treated patients is known, we advocate laboratory INR testing or the use of the POC INRatio device in situations in which rivaroxaban could
affect the INR. Our findings are particularly important when switching patients’ therapy from rivaroxaban to warfarin, where a falsely elevated INR would result in a decrease in the dose of warfarin, inadequate anticoagulation, and increased risk of stroke. A prospective evaluation assessing the accuracy of commonly used POC-INR devices, other than the INRatio, in patients receiving rivaroxaban would determine whether our findings extend to other devices. Clinicians should be aware that routine monitoring of coagulation is not indicated in patients receiving rivaroxaban and that the INR does not provide any representation of rivaroxaban’s anticoagulant effect. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Prescribing information. Xarelto (rivaroxaban). www.xarel tohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100 (accessed 2013 Jan 22). 2. Product information (EPAR). Xarelto (rivaroxaban). www .ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000944/WC500057108.pdf (accessed 2013 Jan 22). 3. Janssen Pharmaceuticals. FDA draft briefing document. www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/drugs/CardiovascularandRenalDrugs AdvisoryCommittee/ucm270796.pdf (accessed 2013 Jan 22). 4. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol 2013;61:651-8. 5. Package insert. Hemochron Jr. Whole Blood Microcoagulation Systems. www.itcmed.com/getattachment/41799766-2bdc49df-9f34-554fcc6938f7/ITC-HEMOCHRON-CuvettePackage-Inserts-PT-Assay-DE-.aspx (accessed 2011 Mar 30).
Downloaded from aop.sagepub.com at UNIV OF MONTANA on April 5, 2015
Case Report
Inaccuracy of Point-of-Care International Normalized Ratio in Rivaroxaban-Treated Patients
Annals of Pharmacotherapy 47(9) 1210–1212 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013503129 aop.sagepub.com
Lawrence Baruch, MD1,2 and Olga Sherman, BS, PharmD3
Abstract Objective: To report 2 cases in which point-of-care international normalized ratios (POC-INRs) measured using a Hemochron Jr. Signature Elite device (International Technidyne Corporation) were inaccurate in rivaroxaban-treated patients. Case Summaries: Therapy in an 86-year-old man with atrial fibrillation was converted from warfarin to rivaroxaban 15 mg twice daily because of a deep venous thrombotic event despite an INR of 2.4, which was within the therapeutic range. One week later a POC-INR was inadvertently measured, which was 6.3. In light of the POC-INR being markedly elevated, a laboratory test for INR was performed, which gave a result of 2.74. Therapy in a 66-year-old man was converted from war-farin to rivaroxaban 15 mg twice daily because of unstable INRs and a pulmonary embolism despite a therapeutic INR. Seven days after rivaroxaban was started, the patient’s POC-INR was 9.2; simultaneously measured laboratory-determined INR was 2.0. For both patients, coagulation tests performed on follow-up visits revealed continued discordance between the POC and laboratory assays. Discussion: Rivaroxaban is an oral factor Xa inhibitor with a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. When patients’ therapy is switched from rivaroxaban to warfarin, it is recommended that the drugs be given concurrently until the INR is 2.0 or higher, to ensure adequate anticoagulation during this well-recognized vulnerable period for stroke. POC testing is a common method of INR assessment in clinical practice. During ROCKET-AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), POC-INRs were measured exclusively with the INRatio device (Hemosense), and values above 4 were seen very rarely (0.25%), which indicates that the values determined in our patients were highly unusual. Conclusions: Our 2 patients receiving rivaroxaban had POC-INRs elevated beyond what was expected; these measurements were discordant from INRs simultaneously measured via the laboratory. A prospective evaluation assessing the accuracy of other commonly used POC-INR devices in patients receiving rivaroxaban would determine whether our findings extend to other devices. Until that time, laboratory measurement of INR or POC-INR using an INRatio device is recommended when patients’ therapy is transitioned from rivaroxaban to warfarin. Keywords rivaroxaban, point-of-care INR, INR, anticoagulation, factor Xa inhibitor, deep vein thrombosis
Rivaroxaban is an oral direct factor Xa inhibitor approved for use in the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism.1,2 Rivaroxaban has a predictable pharmacokinetic profile, allowing for a fixeddose regimen to be administered without the need for routine coagulation monitoring.1,2 The international normalized ratio (INR) is elevated by rivaroxaban (mean value 1.4 at 12-15 hours after the last rivaroxaban dose),3 but does not provide a valid measure of its anticoagulant activity.1-3 In clinical practice, when patients’ therapy is switched from rivaroxaban to warfarin, this period has been identified during clinical development as high risk for stroke.1,2,4 During this vulnerable transition
period, it is recommended that rivaroxaban be given concurrently until the INR is 2.0 or higher1,2 to ensure adequate
1
Medical Program, James J Peters VA Medical Center, Bronx, NY Department of Cardiology, Mt. Sinai School of Medicine, New York, NY 3 Pharmacy Program, James J Peters VA Medical Center 2
Corresponding Author: Lawrence Baruch, MD, Director of Echocardiography, Medical Program, James J Peters VA Medical Center, Bronx, NY; Assistant Professor of Medicine, Department of Cardiology, Mt. Sinai School of Medicine, New York, NY. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV OF MONTANA on April 5, 2015
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Baruch and Sherman Table 1. Point-of-Care and Corresponding Laboratory-Determined INRs. Pt.
Time
Rivaroxaban Dose
Timing of INR Measurement After Last Dose
POC-INR
Laboratory INR
1 2
Week 1 Week 2 Week 4 Week 7 Week 8 Day 1 Day 15
15 mg bid 20 mg/day 20 mg/day 20 mg/day 15 mg/day 15 mg bid 20 mg/day
2 hours 14 hours 14 hours 14 hours 14 hours 2 hours 3 hours
6.3 2.3 4.5 4.8 3.4 9.2 7.9
2.74 1.4 1.83 2.18 1.8 2.0 1.78
INR = international normalized ratio; POC = point-of-care.
anticoagulation.4 Point-of-care (POC) testing is a common method of INR assessment in clinical practice. We report on 2 patients receiving rivaroxaban who had multiple POC-INRs that were elevated well beyond what was expected. These INRs were calculated using a Hemochron Jr. Signature Elite device (International Technidyne Corporation).
Case Reports Case 1 An 86-year-old male with atrial fibrillation, a history of deep vein thrombosis (DVT), and placement of a Greenfield filter more than 20 years ago presented with recurrent right superficial femoral and popliteal DVT. His INR 2 days prior to the DVT diagnosis was 2.4. He was referred to our anticoagulation clinic for rivaroxaban as he experienced a venous thrombotic event despite having an INR in the therapeutic range while on warfarin. His warfarin was discontinued the night before his regularly scheduled clinic visit. His POC-INR the morning of the clinic visit was 2.9 and rivaroxaban 15 mg twice daily was initiated. One week later, at a regularly scheduled clinic visit, a POC-INR inadvertently measured 2 hours after the patient had taken rivaroxaban was 6.3. In light of the markedly elevated POC-INR, the INR was measured via laboratory testing (also 2 hours after the patient had taken rivaroxaban), which gave a result of 2.74. Coagulation tests performed on follow-up visits revealed continued discordance between POC and laboratory assays (Table 1).
Case 2 A 66-year-old man with a history of DVT was followed in our anticoagulation clinic. His therapy was converted from warfarin to rivaroxaban because his INRs were unstable and he experienced a pulmonary embolism while receiving warfarin. On the day after therapy was switched from warfarin to rivaroxaban 15 mg twice daily, he was
admitted with gastrointestinal bleeding. Consequently, all anticoagulants were stopped for 5 days. On the day of discharge, his laboratory-determined INR was 0.91. On the night after discharge, the patient took his prescribed 15-mg evening dose of rivaroxaban with dinner. The following morning, at 6 AM, he took his prescribed 15-mg morning dose of rivaroxaban. At a scheduled anticoagulation clinic visit that morning, the POC-INR was 9.2; the INR measured simultaneously via laboratory testing was 2.0. Coagulation tests performed on a follow-up visit revealed continued discordance between the POC and laboratory assays (Table 1).
Discussion These 2 cases highlight the potential inaccuracy of POC devices in assessing the INR in patients receiving rivaroxaban. Both patients had unexpected unusually high POCINRs (>6), values that occurred at a rate of only 1 in 400 assessments in ROCKET-AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).3 Moreover, 6 of the 7 POC-INRs were greater than 3, a finding seen in only 0.7% of assessments in ROCKET-AF. Patient 2 had unusually high POC-INRs of 7.9 and 9.2, which were inconsistent with values seen in ROCKET-AF.3 This was in contrast to the corresponding laboratory-determined INRs, which were consistent with the values in ROCKET-AF.3 The inaccuracy of the POC device was not an isolated occurrence, as it was noted on 7 different occasions (each time both tests were performed) over a period of weeks. Falsely elevated INRs may affect patient care, as they lead to inappropriate downward adjustments of therapy and inadequate anticoagulation. This will be most common and of greatest clinical significance when transitioning patients’ therapy from rivaroxaban to warfarin, as those patients commonly undergo assessment of INR with a POC device to assess the adequacy of anticoagulation with warfarin. This transition period has been identified in ROCKET-AF
Downloaded from aop.sagepub.com at UNIV OF MONTANA on April 5, 2015
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Annals of Pharmacotherapy 47(9)
as a high-risk period for stroke, even in the absence of falsely elevated INRs,1,2,4 and has led to a boxed warning in the US prescribing information.1 European Medicines Agency documents state that when rivaroxaban is discontinued “the INR may be reliably done 24 hours after the last dose.”2 Our findings would call into question this recommendation when the INR is measured with the Hemochron Jr. POC device. None of the clinical conditions associated with high concentrations of rivaroxaban secondary to altered metabolism (eg, renal insufficiency or the use of P-glycoprotein inhibitors) were present in either of these patients.1 Neither patient had antiphospholipid antibodies, a lupus anticoagulant, or a hematocrit less than 20% or greater than 55%, conditions known to affect the accuracy of the Hemochron device.5 The samples were collected by a medical assistant with certification and extensive experience in performing POC-INR testing, ensuring a high quality of blood specimens, which could also affect the accuracy of the POC-INR. We recognize the limitations to our findings, most notably, the small sample size of 7 INRs derived from 2 patients. The laboratory-measured INRs were all performed with a single device, ACL Advance (Instrumentation Laboratory Company), with RecombiPlasTin 2G used to initiate clotting. The international sensitivity index (ISI) of our POC device, 1.0, is slightly higher than the ISI for our laboratory method, 0.98, which may result in slight differences in the INR. These limitations are largely offset by the fact that our findings were repeated on multiple occasions, the values were dramatically inconsistent with those seen in ROCKET-AF, and the laboratory-measured INRs were consistent with those in ROCKET-AF. Our findings are not inconsequential, as they could affect patient management, especially during the period of transition from rivaroxaban to warfarin, which places patients at high risk for stroke. Our findings do not extend to the INR device used universally in ROCKET-AF, the INRatio (Hemosense). Moreover, the effect of rivaroxaban on other commercially available POC-INR devices is unknown. Based on our findings, until the accuracy of other POCINR devices in rivaroxaban-treated patients is known, we advocate laboratory INR testing or the use of the POC INRatio device in situations in which rivaroxaban could
affect the INR. Our findings are particularly important when switching patients’ therapy from rivaroxaban to warfarin, where a falsely elevated INR would result in a decrease in the dose of warfarin, inadequate anticoagulation, and increased risk of stroke. A prospective evaluation assessing the accuracy of commonly used POC-INR devices, other than the INRatio, in patients receiving rivaroxaban would determine whether our findings extend to other devices. Clinicians should be aware that routine monitoring of coagulation is not indicated in patients receiving rivaroxaban and that the INR does not provide any representation of rivaroxaban’s anticoagulant effect. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Prescribing information. Xarelto (rivaroxaban). www.xarel tohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100 (accessed 2013 Jan 22). 2. Product information (EPAR). Xarelto (rivaroxaban). www .ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000944/WC500057108.pdf (accessed 2013 Jan 22). 3. Janssen Pharmaceuticals. FDA draft briefing document. www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/drugs/CardiovascularandRenalDrugs AdvisoryCommittee/ucm270796.pdf (accessed 2013 Jan 22). 4. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol 2013;61:651-8. 5. Package insert. Hemochron Jr. Whole Blood Microcoagulation Systems. www.itcmed.com/getattachment/41799766-2bdc49df-9f34-554fcc6938f7/ITC-HEMOCHRON-CuvettePackage-Inserts-PT-Assay-DE-.aspx (accessed 2011 Mar 30).
Downloaded from aop.sagepub.com at UNIV OF MONTANA on April 5, 2015
