Coagulation and Transfusion Medicine / Bleeding and Therapy With INR >9 Bleeding Risks and Response to Therapy in Patients With INR Higher Than 9 Monica B. Pagano, MD, 1 and Wayne L. Chandler, MD 2 Key Words: International normalized ratio; Anticoagulant treatment; Warfarin treatment CME/SAM Upon completion of this activity you will be able to: discuss mortality in different patient groups having an international normalized ratio (INR) higher than 9. list the factors associated with bleeding in patients receiving warfarin with an INR higher than 9. describe the effect of different therapies on INR for inpatients receiving warfarin with an initial INR higher than 9. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 616. Exam is located at www.ascp.org/ajcpcme. Abstract An international normalized ratio (INR) higher than 9 is associated with a high risk of bleeding, yet most studies have focused on outpatients with lower INR. We retrospectively analyzed diagnosis, bleeding, treatment, and mortality in 162 patients with INR higher than 9, including inpatients and outpatients with and without warfarin treatment. Patients without anticoagulant treatment with INR higher than 9 had a poor prognosis, 67% experienced bleeding and 74% died. Among outpatients receiving warfarin with INR higher than 9, 11% had bleeding, but none died. Among inpatients receiving warfarin, 35% had bleeding and 17% died. Factors associated with bleeding were older age, renal failure, and alcohol use. Withholding warfarin or giving vitamin K treatment was ineffective at reducing the INR within 24 hours, whereas plasma infusion immediately dropped the INR to 2.4 ± 0.9. Because of underlying disease, comorbidities, and medications, hospitalized patients with INR higher than 9 may not respond quickly to withholding warfarin or vitamin K treatment, and plasma infusion may be needed to reduce INR and the risk of bleeding within 24 hours. The most significant side effect of warfarin treatment is an increased risk of bleeding. 1 Outcomes associated with major bleeding in patients taking warfarin are worse than in patients not taking warfarin. 2 International normalized ratio (INR) fluctuations are common because of drug interactions that modify warfarin metabolism, 3,4 changes in dietary vitamin K intake, 5 or unintentional errors in warfarin dosing. Close monitoring of INR is necessary to avoid both underand overanticoagulation. 6,7 INR higher than 4 has been associated with an increased risk of bleeding, 8 and the risk of intracranial hemorrhage increases approximately 2-fold for every 1 unit rise in INR. 9 INR greater than 9 is associated with a particularly high risk of bleeding, with up to 20% of patients with INR higher than 9 bleeding within the next week, 10 20-fold higher than patients with INR lower than 9. 11 Well-controlled trials of warfarin have reported an annual risk of bleeding of about 0.5% per year, but real-world studies have found bleeding risks up to 6-fold higher. 12 Studies on correcting excessive anticoagulation with warfarin typically evaluated outpatients only and often excluded patients based on comorbidities, other medications, age, and other factors. 10,13-17 Current guidelines to correct excess vitamin K antagonist (VKA) associated anticoagulation in patients with INR higher than 10 and with no evidence of bleeding recommend giving vitamin K, and recommend 4-factor prothrombin complex concentrate rather than plasma for major VKAassociated bleeding. 18 Vitamin K treatment response has not been evaluated in hospitalized patients with INR higher than 9. We reviewed 162 patients, including both outpatients and inpatients, with an INR higher than 9, and describe herein their bleeding rates, bleeding risk factors, presence of 546 Am J Clin Pathol 2012;138:546-550 Downloaded 546 from https://academic.oup.com/ajcp/article-abstract/138/4/546/1760821
Coagulation and Transfusion Medicine / Original Article comorbidities, and response to different treatment modalities to reverse the warfarin effect. Materials and Methods The study was approved by the University of Washington (Seattle) human subjects office. A retrospective analysis was performed of patient charts with INR values higher than or equal to 9 during the period January 1, 2008, to June 10, 2009. Inpatients and outpatients were included and incomplete charts were excluded, resulting in a total of 162 patients in the study. Data Collection Data included the following: gender, age, reason for admission, INR collection date, initial INR result, and where available, INR result 24 hours after treatment, patient location, anticoagulation indication and duration, warfarin dose, platelet count, history of bleeding, chronic heart failure, renal failure, stroke, hypertension, cancer, and alcohol use. Alcohol use was defined as the intake of 1 or more alcoholic beverages per day. Treatments included warfarin cessation, vitamin K administration, and plasma infusion. One patient with trauma received recombinant factor VII in addition to plasma, and none of the patients received factor concentrates. Statistical Analysis A logistic model was used to estimate the effect of several predictors on the probability of bleeding. The relationship between the predictors and the occurrence of bleeding was assumed to follow a nonlinear, logistic function based on the weights of the 10 variables used to predict the probability of bleeding, namely, male sex, age, renal failure, congestive heart failure, hypertension, alcohol use, bleeding history, cancer, stroke, and warfarin dose (in log scale). Results are given as the mean ± standard deviation (SD) unless otherwise noted. The unpaired t test was used to determine individual differences between groups. Results Patient Characteristics Of 162 patients with INR higher than 9, 36 (22%) were outpatients and 126 (78%) were inpatients. Table 1 shows anticoagulant and fibrinolytic therapy in patients with INR higher than 9. All of the outpatients with INR higher than 9 were receiving warfarin. Of the inpatients with INR higher than 9, 37% were receiving warfarin; 15%, direct thrombin inhibitors; 3%, tissue plasminogen activator; and 45% were not receiving any anticoagulant or fibrinolytic therapy. Patients with INR higher than 9 receiving warfarin were on average 59 years old, with a mean INR of 10.6 ± 1.3. Patients with INR higher than 9 not receiving warfarin were on average 50 years old, with a mean INR of 11.0 ± 1.3. The lower average age of patients with INR higher than 9 not receiving warfarin primarily reflects the population of patients with trauma with INR higher than 9 with an average age of 30 years. Diagnosis, Bleeding, Treatment, and Mortality in Patients Not Receiving Warfarin All patients not receiving warfarin with INR higher than 9 were inpatients. Table 2 shows the primary diagnosis and number of patients with reported bleeding. The majority of patients (71%) not receiving warfarin who had an INR higher than 9 were also not receiving any other anticoagulant or fibrinolytic therapy. These patients typically had some form of liver failure, shock, or trauma. Of the patients with acute or chronic liver failure and INR higher than 9, 46% had bleeding, typically treated with blood products, and 64% died. All patients undergoing liver transplantation with INR higher than 9 reported bleeding and were treated with blood products, of whom 18% died. Patients were admitted with shock and INR Table 1 Anticoagulant and Fibrinolytic Therapy in Patients With INR Higher Than 9 Group Anticoagulant No. (% of Total) Outpatients Warfarin 36 (22) Inpatients Warfarin 46 (28) Inpatients Direct thrombin inhibitor * 19 (12) Inpatients Tissue plasminogen activator 4 (3) Inpatients None 57 (35) Total 162 (100) INR, international normalized ratio. * Three patients received argatroban, while 16 received bivalirudin. Table 2 Diagnosis and Bleeding for Inpatients Not Receiving Warfarin With INR Higher Than 9 No. (% Bleeding, No. Diagnosis of Total) (% With Diagnosis) Liver failure/liver transplant 22 (28) 16 (73) Shock 21 (26) 9 (43) Trauma 15 (19) 14 (93) HIT 13 (16) 4 (31) Thrombosis * 9 (11) 3 (33) Total 80 (100) 46 (58) HIT, heparin-induced thrombocytopenia; INR, international normalized ratio. * Thrombosis included ischemic stroke (n = 3), intracardiac thrombosis/disseminated intravascular coagulation (n = 1), limb ischemia (n = 3), and massive pulmonary embolism (n = 2). Downloaded from https://academic.oup.com/ajcp/article-abstract/138/4/546/1760821 Am J Clin Pathol 2012;138:546-550 547 547 547
Pagano and Chandler / Bleeding and Therapy With INR >9 higher than 9 for a number of reasons, including resuscitation after cardiac arrest, sepsis, heart failure, and drug overdose. Of patients with shock, 43% were reported to have bleeding, which was treated with blood products, but 90% died. Essentially all patients with trauma with INR higher than 9 had bleeding, of whom most were treated with blood products, and 1 with plasma and recombinant factor VIIa, but all died. Overall, INR higher than 9 in patients not receiving an anticoagulant was a bad prognostic sign; of these, 67% experienced bleeding and 74% died. The patients diagnosed with heparin-induced thrombocytopenia and INR higher than 9 were all receiving a direct thrombin inhibitor (3 received argatroban and 16 bivalirudin), 31% reported bleeding, and 23% died (1 patient of heart failure and 2 of pulmonary embolism). Patients with no bleeding were generally treated by stopping the drug. Most of the patients with bleeding with a diagnosis of heparin-induced thrombocytopenia were undergoing cardiopulmonary bypass using the direct thrombin inhibitor bivalirudin. All of these patients were treated with blood products during surgery. The inpatients not receiving warfarin with thrombosis and INR higher than 9 were receiving a direct thrombin inhibitor or fibrinolytic therapy, 33% reported bleeding while 11% died. Typically they were treated with a combination of stopping the drug and blood products. Diagnosis, Bleeding, and Treatment in Patients Receiving Warfarin Of the patients receiving warfarin who had an INR higher than 9, 44% were outpatients. Of these, 11% reported bleeding that was typically treated with vitamin K. Outpatients with INR higher than 9 who did not have bleeding were treated by withholding warfarin in 36% and vitamin K in 64%. Platelet counts were available on 17 of 36 outpatients with INR higher than 9, all of which were normal (328 ± 125 10 3 /µl [328 ± 125 10 9 /L]). Follow-up on the outpatients was limited, but none died soon after the high INR was noted and none received blood products. The association between common comorbidities and bleeding for all 82 patients receiving warfarin with INR higher than 9 is shown in Table 3. The factors associated with an increased risk of bleeding were older age, the presence of renal failure, and alcohol use. In contrast, a history of cancer was associated with a reduced risk of bleeding. Treatment of Inpatients Receiving Warfarin With INR Higher Than 9 Sixteen of the 46 inpatients receiving warfarin with INR higher than 9 were admitted for bleeding, whereas the other 30 patients were admitted for other reasons including infection or sepsis, thrombosis, cancer, and congestive heart failure Table 4. Platelet counts were available on all inpatients with INR higher than 9 (232 ± 98 10 3 /µl [232 ± 98 10 9 /L]). Only 3 inpatients with INR higher than 9 had platelet counts less than 100 10 3 /µl (100 10 9 /L), of whom only 1 had bleeding (retroperitoneal hemorrhage associated with an abdominal aortic aneurysm). Overall mortality was 17% for the inpatients receiving warfarin with INR higher than 9. Figure 1 shows the effect of different forms of treatment on inpatients taking warfarin who had an INR higher than 9. There was no difference in the initial INR for the 3 treatment groups (withholding warfarin, vitamin K administration, and plasma infusion). On average, patients treated with vitamin K were given 5 mg (range, 1-10 mg). On average, patients treated with plasma were given 4 units of fresh frozen plasma (range, 2-6 units). There was no significant difference in the INR after 24 hours of treatment between withholding warfarin and vitamin K administration (P =.20). Infusion of plasma significantly reduced the INR compared with vitamin K or withholding warfarin (P <.001). Among the inpatients receiving warfarin with INR higher than 9 and bleeding at admission, 1 was treated by withholding warfarin (6%), 2 were treated with vitamin K (13%), and 13 received plasma infusion (81%). None of these patients experienced rebleeding and there were no deaths related to Table 3 Comorbidities and Other Factors Associated With Increased Bleeding in Patients Receiving Warfarin With INR Higher Than 9 No. (% Association With Comorbidities (n = 82) of Total) Increased Bleeding Alcohol use 22 (27.2) 0.009 Renal dysfunction 29 (35.8) 0.036 Cancer 20 (24.7) NS Congestive heart failure 26 (32.1) NS History of bleeding 9 (11.1) NS History of stroke 9 (11.1) NS Other Factors Age 0.005 Male 41 (50) NS INR, international normalized ratio; NS, not significant. Table 4 Diagnosis for Inpatients Receiving Warfarin With INR Higher Than 9 Diagnosis No. (% of Total) Bleeding 16 (35) Infection/sepsis 9 (20) Thrombosis* 5 (11) Cancer 4 (9) Congestive heart failure 3 (6) High INR 3 (6) Other 6 (13) Total 46 (100) INR, international normalized ratio; NS, not significant. * Thrombosis included ischemic stroke (n = 5) and limb ischemia (n = 1). 548 Am J Clin Pathol 2012;138:546-550 Downloaded 548 from https://academic.oup.com/ajcp/article-abstract/138/4/546/1760821
Coagulation and Transfusion Medicine / Original Article bleeding episodes. For inpatients receiving warfarin with INR higher than 9 but no bleeding at admission, treatment included withholding warfarin in 3 (10%), vitamin K in 17 (57%), and plasma infusion in 10 (33%). There was 1 episode of fatal intracranial hemorrhage in the vitamin K group in a patient with INR higher than 9 after treatment. INR 14 12 10 8 6 Discussion Supratherapeutic INR is a common occurrence in patients receiving warfarin treatment. 19 Garcia et al 11 showed that the risk of major bleeding in outpatients with an INR of 5 to 9 was 0.5% in the first 2 weeks, compared with 10% when the INR was higher than 9. Crowther et al 10 reported that up to 21% of patients with INR higher than 9 experienced bleeding within the next 7 days. In this study, we evaluated 162 patients with INR higher than 9 during a 17-month period. We separated our data into 2 major groups, patients with INR higher than 9 who were either receiving warfarin or not receiving warfarin. We further separated the group not receiving warfarin into those receiving another anticoagulant or fibrinolytic drug vs those not taking any other antithrombotic medications. For outpatients (all receiving warfarin), the incidence of bleeding was 11%, similar to the rate seen in prior studies. 11 The incidence of bleeding in all patients with INR higher than 9 was 38%, higher than in previous studies. This difference reflects the inclusion of hospitalized patients with INR higher than 9, including patients receiving warfarin, those receiving other anticoagulants, and those receiving no anticoagulants. Prior studies have reported that older age was a risk factor for bleeding with warfarin therapy and that alcohol use was associated with an increased risk of intracranial hemorrhage. 9,20 We found that in patients with INR higher than 9 who were receiving warfarin, older age, renal failure, and alcohol use were all associated with an increased risk of bleeding. Patients with INR higher than 9 not receiving warfarin or any other anticoagulants generally had a severe underlying illness, typically shock after resuscitation for cardiac arrest, severe trauma, liver failure, or liver transplantation. These patients had a high rate of bleeding (67%), were typically treated with plasma infusion, and had a high mortality rate (74%). Although bleeding was common in this group, patients typically died of other causes. The other group of patients with INR higher than 9 and not receiving warfarin were patients receiving direct thrombin inhibitors or fibrinolytic therapy. Bleeding was still common in this group (32%), but the mortality rate was lower (18%). Prolonged INR in patients receiving direct thrombin inhibitors may be because of a combination of direct thrombin inhibitor effects and low factor levels. Determining the specific cause of INR higher than 9 in 4 2 0 Withhold Warfarin Vitamin K Plasma Infusion Figure 1 Effect of different therapies on international normalized ratio (INR) for inpatients receiving warfarin with INR higher than 9. The black bars show the mean and standard deviation for the initial INR. The gray bars show INR 24 hours after the start of different treatments. patients receiving direct thrombin inhibitors requires separate specific tests for both direct thrombin inhibitor effect that is not affected by low factor levels, such as a plasma diluted thrombin time, and for factor levels not affected by direct thrombin inhibitors, such as a chromogenic factor X level. 21-23 Vitamin K can successfully correct an excess of anticoagulation; the response depends on the dose of vitamin K and on the presence of normal liver function. Previous studies evaluating vitamin K response typically included only outpatients and often excluded patients with renal and liver dysfunction. 10,13-17 In this study, we tracked the effect of treatment for INR higher than 9 in hospitalized patients receiving warfarin. We found that withholding warfarin had no effect on INR in the first 24 hours and that treatment with vitamin K produced a small decrease in INR by 24 hours, but that the effect was highly variable among patients and that the INR at 24 hours was not significantly different from withholding warfarin. A prior study on outpatients receiving VKA with INR higher than 10 used INR of less than 5 as a indication of successful treatment with vitamin K. 14 Using this criterion, withholding warfarin was unsuccessful at reversing INR higher than 9 for inpatients and vitamin K was successful in only 8 (42%) of 19 patients. In contrast, infusion of plasma produced an immediate decrease in INR, with significantly lower INR at 24 hours than did withholding warfarin or vitamin K administration. All of the patients with INR higher than 9 treated with plasma had an INR less than 5 after treatment (mean INR, 2.4). Conclusions from this study are limited by the observational and not randomized prospective nature of the data, lack of protocol for treatment decisions made by individual physicians, and potential influence of confounding variables. Downloaded from https://academic.oup.com/ajcp/article-abstract/138/4/546/1760821 Am J Clin Pathol 2012;138:546-550 549 549 549
Pagano and Chandler / Bleeding and Therapy With INR >9 Care needs to be taken when choosing a therapy for INR higher than 9 in hospitalized patients. Because of other comorbidities such as liver disease and other treatments such as antibiotics that potentially prolong INR, 24 hospitalized patients may not respond to withholding warfarin or administration of vitamin K as quickly as expected from studies based on carefully selected outpatients. A decision on whether to use plasma infusion to reverse INR higher than 9 should include consideration of the high risk of bleeding, up to 20% in the next 7 days with INR higher than 9, other comorbidities, medications, and age. What works in an otherwise healthy outpatient may not be sufficient in an elderly inpatient with multiple medical problems. From the 1 Department of Laboratory Medicine, University of Washington, Seattle, WA, and 2 the Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, Texas. 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Unreliability of the international normalized ratio for monitoring warfarin therapy in patients with lupus anticoagulants. Pharmacotherapy. 2004;24:838-842. 23. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin. Pharmacotherapy. 2005;25:157-164. 24. Penning-Van Beest FJ, Koerselman J, Herings RMC. Risk of major bleeding during concomitant use of antibiotic drugs and coumarin anticoagulants. J Thromb Haemost. 2008;6:284-290. 550 Am J Clin Pathol 2012;138:546-550 Downloaded 550 from https://academic.oup.com/ajcp/article-abstract/138/4/546/1760821