International Normalized Ratio In Patients Research Articles

Apixaban as a Secondary Prophylaxis Agent for Patent Foramen Ovale-Associated Stroke.

Background: The purpose of this case report is to describe a case of switching warfarin to apixaban in a patient on anticoagulant prophylaxis for a patent foramen ovale (PFO)-associated stroke. Case Summary: An 86-year-old Afro-Latina female with a past medical history of cerebrovascular accident (CVA) in 2012 secondary to PFO and diagnosed Atrial Fibrillation (AF). Patient was switched from warfarin to apixaban after 3months of labile international normalized ratio (INR) levels. The patient's INR was monitored at a pharmacist-led anticoagulation clinic. As the patient's INR remained subtherapeutic while on warfarin, a shared decision was made to switch the patient to apixaban 2.5mg twice daily due to consistently painful enoxaparin injections, inconsistent vitamin K intake, frequent clinic visits and unstable renal function. Patient tolerated the anticoagulant switch well and reported satisfaction with decreased clinic visits and variable vitamin K diet. At 12months post-switch, the patient's complete blood count remains stable, no reported signs and symptoms of bleeding, and no new CVA or venous thromboembolism (VTE) events identified. Based on an improvement in renal function, the dose was increased to 5mg twice daily.

Accuracy and Precision of Point-of-Care International Normalized Ratio in Patients With Liver Disease.

To determine if the CoaguChek XS Pro Point-of-Care (POC) device can accurately and precisely measure the international normalized ratio (INR) compared with the gold standard laboratory INR in pediatric and adult patients with liver disease. This prospective cohort study included 15 pediatric patients without liver disease, 13 pediatric patients with liver disease, and 17 adult patients with liver disease. The accuracy of the POC INR values was determined using the correlation and Bland-Altman limits of agreement. The accuracy of the coagulometer INR was assessed by calculating the proportion of POC INR measurements that were ≤15% of their corresponding laboratory INR. A comparison of INR measurements showed an excellent correlation in pediatric patients without liver disease ( r = 0.82), pediatric patients with liver disease ( r = 0.89), and adult patients with liver disease ( r = 0.96). Fourteen (93%) POC INR values were ≤15% in pediatric patients without liver disease from its paired laboratory INR. All 13 paired measurements were ≤15% in pediatric patients with liver disease. In adult patients with liver disease, 12 (71%) POC INR values were ≤15% of their paired laboratory INR. In patients with liver disease, the CoaguChek XS Pro provides an accurate measure of the INR compared to laboratory INR measurements.

Clinical Impact of the Time in Therapeutic Range on Early Hospital Readmission in Patients with Acute Heart Failure Treated with Oral Anticoagulation in Internal Medicine

Patients with heart failure (HF) often present with non-valvular atrial fibrillation and require oral anticoagulation with coumarin anticoagulants such as acenocoumarol. The objective of this study was to evaluate the relationship between time in therapeutic range (TTR) and the risk of early readmission. A retrospective descriptive study was carried out on hospitalized patients with a diagnosis of HF between 2014 and 2018 who had adverse effects due to oral anticoagulation with acenocoumarol (underdosing, overdosing, or hemorrhage). Clinical, analytical, therapeutic, and prognostic variables were collected. TTR is defined as the duration of time in which the patient's International Normalized Ratio (INR) values were within a desired range. Early readmission was defined as readmission within 30 days after hospital discharge. Patients were divided into two groups depending on whether or not they had a TTR less than 60% (TTR < 60%) over the 6 months prior to the adverse event. In the cohort of 304 patients, the mean age was 82 years, 59.9% of the patients were female, and 54.6% had a TTR < 60%. Patients with TTR < 60% had a higher HAS-BLED score (4.04 vs. 2.59; P < 0.001) and INR (6 vs. 5.31; P < 0.05) but lower hemoglobin (11.67 vs. 12.22 g/dL; P < 0.05). TTR < 60% was associated with early readmission after multivariate analysis (OR: 2.05 (CI 95%: 1.16-3.61)). They also had a higher percentage of hemorrhagic events and in-hospital mortality but without reaching statistical significance. Patients with HF and adverse events due to acenocoumarol often have poor INR control, which is independently associated with a higher risk of early readmission.

ACC releases guide for management of bleeding from oral anticoagulants

In a new report on expert consensus decision pathways, the American College of Cardiology (ACC) offers up practical suggestions for managing bleeding in patients on oral anticoagulants. The report, released on August 4, includes information on the use of new reversal strategies and guidance on when to consider reinitiating therapy. Most health systems will find the guide to be a valuable resource for ensuring that processes in their organization are based on the most current information, said Daniel M. Witt, PharmD, FCCP, BCPS, clinical professor and vice chair of the department of pharmacotherapy at the University of Utah College of Pharmacy. He noted that the easy-to-follow diagrams in the decision pathway will be useful for systems trying to implement principles of anticoagulation therapy stewardship recently proposed by the Anticoagulation Forum. According to the decision pathway, the first step is for clinicians to assess the severity of bleeding in patients on oral anticoagulants and characterize it as major or nonmajor. Major bleeding is defined as meeting one or more of the following factors: bleeding in a critical site, hemodynamic instability, overt bleeding with a hemoglobin drop of 2 g/dL or more, or administration of two or more units of packed red blood cells. Patients who do not meet these criteria are considered to have a nonmajor bleeding event. Laboratory assessments such as prothrombin (PT), activated partial thromboplastin time (aPTT), or an international normalized ratio (INR) in those receiving warfarin are also helpful in determining anticoagulant activity. For major bleeding events that are life threatening or at a critical site, ACC recommends that the oral anticoagulant and any antiplatelet agents be stopped and airway and large-bore I.V. access be secured. It also recommends reversal agents. However, ACC noted that obtaining and administering reversal agents must not delay resuscitation (e.g., volume) and local hemostatic measures. Patients with nonmajor bleeding that requires hospitalization, a surgical/procedural intervention, or a transfusion should also have their oral anticoagulant stopped and managed with local and supportive care measures. The availability of reversal agents in recent years has provided clinicians more options in managing patients who experience bleeding events, especially with direct-acting oral anticoagulants (DOACs). ACC has a flow diagram within their guide that discusses considerations for reversal/hemostatic agents in those with major bleeding events based on the specific oral anticoagulant. For patients taking warfarin or other vitamin K antagonists, ACC recommends the use of vitamin K in addition to varying doses of 4F-PCC based on the patient's INR. If 4F-PCC is not available, then plasma is listed as an alternative. For those on dabigatran, 5 g of IV idarucizumab is recommended; PCC or aPCC are listed as alternatives if idarucizumab is not available. Clinicians should use andexanet alfa for patients taking apixaban and rivaroxaban; if it's not available, PCC or aPCC can be used as alternatives. Finally, for betrixaban and edoxaban, ACC recommends the use of off-label, high-dose andexanet alfa, with PCC or aPCC as alternatives. If there is a known recent ingestion within 2 to 4 hours of any of the DOACs, clinicians can consider administering activated charcoal. “A particularly useful aspect of this decision pathway is [the] consideration of resuming anticoagulation therapy once the bleeding stops,” said Witt. “Too many times the fear of recurrent bleeding leads to patients suffering paradoxical thromboembolic complications because anticoagulation therapy was not resumed in the face of an ongoing indication for thrombosis prevention. According to ACC, clinicians can restart anticoagulation if it provides a net clinical benefit after a bleeding event. The guide noted that there are several conditions for which the anticoagulant would no longer be indicated, such as a temporary indication (e.g., post-surgical prophylaxis); nonvalvular atrial fibrillation with a CHA2DS2-VASc score of less than two in men and less than three in women; or first-time provoked venous thromboembolism more than 3 months ago. However, other conditions may warrant ongoing anticoagulation, so providers should consider the net clinical benefit of oral anticoagulation, with timing of initiation based on both the thrombotic risk and rebleeding risk. The decision to restart anticoagulation should be made with input from both the patient and clinical team via “shared clinical decision making.” Patients should be educated on the risks (e.g., bleeding signs) and benefits (e.g., decreased risk of a thrombotic event) of restarting oral anticoagulation.

Effect of Alteplase Administration on International Normalized Ratio in Patients With Acute Ischemic Stroke.

Alteplase may elevate international normalized ratio (INR) results, although the exact rate of elevation occurrence is not firmly established in the literature. The purpose of this study is to determine the occurrence rate of INR elevation following alteplase administration. We also aimed to determine what factors are independently associated with the development of elevated INR following alteplase administration for ischemic stroke. We conducted a multicenter, retrospective, cohort study of patients who received alteplase for acute ischemic stroke. Patients were screened for baseline INR measurement and a repeat value within 24 hours of alteplase administration. The primary outcome was the percent of patients who experienced ≥0.4-point increase in INR. Secondary outcomes included the rate of adverse bleeding events and identification of factors independently associated with elevated INR following alteplase administration. Two hundred and sixty-one patients were included, with 44 (16.9%) patients having an INR increase of 0.4 or more. Patients with an INR increase ≥0.4 experienced a nonstatistically significant increase in bleeding episodes (8.8% vs 18.2%; P = .10). We identified African American race (odds ratio, 3.48, 95% confidence interval, 1.5-7.6; P = .002) as an independent predictor of INR increase ≥0.04. An INR elevation is common following receipt of alteplase for ischemic stroke. Those of African American race were at increased risk of INR elevation; however, more studies are needed to determine whether these patients are at a higher bleeding risk as a result of INR elevation.

A prospective, multi-center cohort study: investigating the ability of warfarin-treated patients to predict their INR

In practice, warfarin-treated patients may share insight regarding their international normalized ratio (INR) value before it is measured. The accuracy and potential utility of these predictions have not been evaluated. To (1) test how accurately patients can predict their INR; (2) identify demographic factors associated with their ability to predict their INR accurately; and (3) identify demographic factors associated with the patient's INR being in the therapeutic range. A prospective, multi-center cohort study enrolled patients from eight anticoagulation clinics in Iowa. Inclusion criteria were: age ≥ 18years, warfarin use ≥ 60days, INR goal of 2.0-3.0, and expected warfarin use > 6months. Subjects completed a data collection form during enrollment and before each INR measurement. Data included demographics, a set of medication taking beliefs and practices, self-reported adherence, past INR values, INR prediction and reason(s) for the prediction. There were 87 subjects enrolled with 372 INR measurements. The mean (SD) number of INRs per subject was 4.3 (1.8). Thirty percent of subjects reported they could tell when their INR is out of goal range. Patients predicted that 90.5% of their INRs would be within goal range, although only 65.5% of INRs were therapeutic. Patients correctly predicted a low INR as low or high INR as high in only 9.4% of out of range instances. A set of demographic characteristics and medication beliefs were not associated with prediction accuracy or percentage of INR measurements in range (PINRR). Most patients did not give a reason for their predicted result. For those that did, the most common factor was perceived stability at current dose. While some patients believed they could predict when their INR was out of range, only few were able to do so. Most patients assumed a therapeutic INR and missed when their INR was high or low. Patients should be advised against modifying their warfarin dose without consulting the provider that manages their therapy. ClinicalTrials.gov number, NCT 02764112.

Effect of Ramadan Fasting on the International Normalized Ratio in Patients with Mechanical Prosthetic Heart Valves

Background: Maintaining a therapeutic range of International Normalized Ratio (INR) in patients with mechanical prosthetic heart valves is of paramount importance. The effect of religious Fasting and altered lifestyle pattern during the Holy month of Ramadan on the INR stability has not been previously studied in the Saudi population. Objectives: We aimed to evaluate the effect of Ramadan fasting on the INR stability in patients using warfarin anticoagulation for mechanical prosthetic heart valves. Design: Data were extracted retrospectively from a specialized anticoagulation clinic electronic database and were anlysed in a case-control manner, where Ramadan INR of each study subject was compared to his/her own pre-Ramadan INR level. Setting: Prosthetic Valve Anticoagulation Clinic at King Abdul-Aziz Cardiac Center, Riyadh. Materials and methods: Using Point-Of-Care (POC) testing, the first INR level during Ramadan as compared to the average baseline INR readings over the last 3 months before Ramadan. The study was conducted between July 29th and August 20th, 2015, which corresponds to the month of Ramadan, 1436 Hejra Calendar. Several exclusion criteria were applied to minimize the effects of potential confounding factors. Main Outcome measures: Paired t-test was used to detect any statistically significant difference in the INR level between Ramadan and pre-Ramadan readings, in the overall study cohort and among pre-specified study subgroups. Results: One-hundred and fourteen (114) consecutive patients fulfilled the inclusion criteria. Mean age was 48.4±13.6 years and males constituted 58% of cases. Low target (INR: 2.0-3.0) and high target (INR: 2.5-3.5) therapeutic ranges represented 35% and 65% respectively. Mean INR level was 2.81 at baseline and 2.75 during Ramadan with no statistically significant difference between them (P=NS). Achieving the desired target INR level before Ramadan was feasible in 62.5% and 64.8% of the low and high INR target groups respectively. However, maintaining the desired INR level during Ramadan was feasible in 67.5% and 51.3% of the low and high target INR groups respectively (P= 0.07). Duration of anticoagulation, warfarin dose, and adherence scale did not contribute significantly to the primary outcome. Conclusion: Ramadan fasting and its associated lifestyle changes in the Saudi community may aggravate the INR fluctuations in warfarin-treated patients. During Ramadan, warfarin-treated patients are more prone to develop supra-therapeutic INR and therefore they deserve careful attention and closer INR monitoring.

Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients

BackgroundMany patients with heart failure need anticoagulants, including warfarin. Good control is particularly challenging in heart failure patients, with <60% of international normalized ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications. This study aimed to evaluate the effect of a patient-specific tailored intervention on anticoagulation control in patients with heart failure. MethodsPatients with heart failure taking warfarin therapy (n = 145) were randomized to either standard care or a 1-time intervention assessing potential risk factors for lability of INR, in which they received patient-specific instructions. Time in therapeutic range (TTR) using Rosendaal's linear model was assessed 3 months before and after the intervention. ResultsThe patient-tailored intervention significantly increased anticoagulation control. The median TTR levels before intervention were suboptimal in the interventional and control groups (53% vs 45%, P = .14). After intervention the median TTR increased significantly in the interventional group compared with the control group (80% [interquartile range, 62%-93%] vs 44% [29%-61%], P <.0001). The intervention resulted in a significant improvement in the interventional group before versus after intervention (53% vs 80%, P <.0001) but not in the control group (45% vs 44%, P = .95). The percentage of patients with a TTR ≥60%, considered therapeutic, was substantially higher in the interventional group: 79% versus 25% (P <.0001). The INR variability (standard deviation of each patient's INR measurements) decreased significantly in the interventional group, from 0.53 to 0.32 (P <.0001) after intervention but not in the control group. ConclusionsPatient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure.

A Korean Multi-Center Survey about Warfarin Management before Gastroenterological Endoscopy in Patients with a History of Mechanical Valve Replacement Surgery.

BackgroundGuidelines for esophagogastroduodenoscopy (EGD) in the West allow the continued use of warfarin under therapeutic international normalized ratio (INR) level. In Korea, no guidelines have been issued regarding warfarin treatment before EGD. The authors surveyed Korean cardiac surgeons about how Korean cardiac surgeons handle warfarin therapy before EGD using a questionnaire. Participants were requested to make decisions regarding the continuation of warfarin therapy in two hypothetical cases.MethodsThe questionnaire was administered to cardiac surgeons and consisted of eight questions, including two case scenarios.ResultsThirty-six cardiac surgeons at 28 hospitals participated in the survey, and 52.7% of the participants chose to stop warfarin before EGD in aortic valve replacement patients without risk factors for thromboembolism. When the patient’s INR level was 2, 31% of the participants indicated that they would choose to continue warfarin therapy. For EGD with biopsy, 72.2% of the participants chose warfarin withdrawal, and 25% of the participants chose heparin replacement. In mitral valve replacement patients, 47.2% of the participants chose to discontinue warfarin, and 22.2% of the participants chose heparin replacement. For EGD with biopsy in patients with a mitral valve replacement, 58.3% of the participants chose to stop warfarin, and 41.7% of the participants chose heparin replacement.ConclusionThis study demonstrated that attitudes regarding warfarin treatment for EGD are very different among Korean surgeons. Guidelines specific to the Korean population are required.

Stability of International Normalized Ratios in Patients Taking Long-term Warfarin Therapy.

Stability of International Normalized Ratios in Patients Taking Long-term Warfarin Therapy.

Evaluation of Time in Therapeutic Range (TTR) in Patients with Non-Valvular Atrial Fibrillation Receiving Treatment with Warfarin in Tehran, Iran: A Cross-Sectional Study.

Anticoagulant control is assessed by Time in Therapeutic Range (TTR). For a given patient, TTR is defined as the duration of time in which the patient's International Normalized Ratio (INR) values were within a desired range. To assess TTR in patients receiving treatment with warfarin for non-valvular atrial fibrillation at a referral center for cardiovascular diseases in Tehran, Iran. Over 6 months, we enrolled eligible patients presenting to Shaheed Rajaie Hospital in Tehran for regular INR testing. Demographic data, medical history, and current medications were determined for all participants. TTR was assessed by the Rosendaal method. A total of 470 patients (mean age 58.0±14.2 years, 60.2% women) underwent 1450 INR measurements. The mean TTR was calculated as 54.9±11.9%. Of the sample patients, 37.3% were in the good control category (TTR > 70%), 24.6% were in the intermediate category (50% < TTR < 70%), and 38.1% were in the poor control category (TTR < 50%). The number of current medications above four was a significant predictor of poor control (OR = 2.06; 95% CI, 1.87, 2.23). The mean TTR of the studied patients (54.9%) was below the good control range. The quality of anticoagulant therapy with warfarin in Iranian patients was poorer than that reported in European countries. Based on these results, research considering the causes of poor TTR among Iranian patients is recommended.

Influence of CYP2C9 polymorphism on the fall in International Normalized Ratio in patients interrupting warfarin therapy before elective surgery

Patients on warfarin are normally required to stop treatment for a fixed number of days prior to an invasive procedure. However, the anticoagulant activity of warfarin subsides at different rates among different patients. The aim of this study was to investigate the potential influence of CYP2C9 polymorphism on the variable rate of fall in the International Normalized Ratio (INR) in patients withdrawing from warfarin treatment prior to elective surgery. One hundred and fifty-two patients aged 43-93years were recruited. Demographic data on age, height, weight, gender, daily warfarin dose, indication for anticoagulation therapy, medical diagnosis, surgical operation planned and concomitant medication were recorded. A blood sample was taken for later CYP2C9 genotyping. For patients with two CYP2C9 variant alleles (CYP2C9*2*2 or CYP2C9*2*3), the odds of having an INR of ≥1.5 before the planned day of surgery were 8.64 times greater (95% confidence interval [CI]2.25-33.25) than for other patients. Multiple regression analysis revealed that the rate of fall in the INR was reduced in the presence of two CYP2C9 variant alleles, as well as increasing patient age, weight and number of comorbidities, and increased with increasing initial INR (F5,132 =242.9, P<0.0001), all of which accounted for ~90% of the interindividual variability in the fall in INR. A genotype-guided protocol to tailor warfarin withdrawal according to an individual patient's CYP2C9 genotype could reduce cancellation or delays of planned procedures, and could also be beneficial when transitioning patients from warfarin to one of the new oral anticoagulants.

Low Doses of Acetaminophen Prolonged Prothrombin Time and Increased International Normalized Ratio in Patients Receiving Long-Term Therapy

Abstract Objectives: Acetaminophen is one of the safest and effective antipyretic and analgesic medications. Long term administration of this medication appeared to interfere with the activity of two key enzymes of the vitamin K cycle. The primary end point of this study was to evaluate the chronic effect of acetaminophen on Prothrombin Time (PT) and International Normalized Ratio (INR) parameters. Methods: Prospective, longitudinal , double-blind, placebo-controlled study was performed in Kurdistan region of Iraq, patients suffering from mild headache were prepared to take acetaminophen 500 mg twice daily for at least (8) months. PT, INR, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured for both patient and control groups before drug administration and then every month. Results: The main consequence of the study was the difference in mean PT and INR between control group and group receiving acetaminophen long term therapy for 8 months. In patients on acetaminophen (1 g/day), the mean observed PT and INR were significantly elevated during therapy period. The significant differences in mean PT started from the second month of therapy (12.910 ± 0.098) in patients on acetaminophen versus (12.083 ± 0.077) in control participants (P<0.01). The maximum variations of mean PT was observed after eight months in patients on acetaminophen compared with the control participants (18.903 ± 0.184 vs. 12.300 ± 0.066, P< 0.01). Likewise the mean observed INR was significantly increased after the second month of treatment (1.123 ± 0.013) in patients on acetaminophen versus (1.006 ± 0.101) in control subjects (P<0.01). As well, maximum variations of mean INR observed after eight months in patients on acetaminophen compared with the control participants (2.084 ± 0.033 vs. 1.036 ± 0.008, P<0.01). There was a significant difference of mean ALT observed during the latest three months of study period in patients on acetaminophen compared with the control participants (P<0.01). However a significant value of both PT and INR in all patients rose markedly during the eight months of acetaminophen therapy. Conclusion: The clinical findings of this study support that chronic administration of acetaminophen at low dose (Ig/day) induce a highly significant elevation of PT and INR parameters in all patients participated in this study.

Warfarin-induced skin necrosis.

Warfarin is a frequently used oral anticoagulant in the treatment and prevention of various medical conditions. One uncommon adverse effect that can occur following the initiation of therapy is warfarin-induced skin necrosis. Because it is a rare effect with an undetermined pathophysiology of disease, the treatment is not well established. A 52-year-old female was prescribed warfarin and enoxaparin for a newly diagnosed deep vein thrombosis (DVT) in the left lower extremity. On day 4 of therapy, the patient had a supra-therapeutic international normalized ratio (INR), prompting the discontinuation of enoxaparin and a decrease in the warfarin dose. The patient returned to the emergency department on day 7 of treatment with a purple, cold, and extremely painful right foot with punctate areas of necrosis and petechiae proximal to the discoloration. The patient's INR was found to be 10.64. Following the diagnosis of warfarin-induced skin necrosis, the patient was administered vitamin K intravenously and fresh frozen plasma (FFP) to reverse the effects of warfarin and promote protein C and S synthesis. Once the patient's INR was no longer supratherapeutic, subcutaneous enoxaparin was re-started as treatment for the known recent DVT. The patient's necrotic foot began to improve and she was discharged home with an anticipated full recovery. Based on the proposed pathophysiology of disease, adequate bridge therapy may decrease the likelihood of developing this life-threatening condition. Early recognition and treatment with intravenous vitamin K, FFP or 4-factor prothrombin complex concentrate, and continued wound care are essential to prevent further complications.

Warfarin-induced skin necrosis.

Warfarin is a frequently used oral anticoagulant in the treatment and prevention of various medical conditions. One uncommon adverse effect that can occur following the initiation of therapy is warfarin-induced skin necrosis. Because it is a rare effect with an undetermined pathophysiology of disease, the treatment is not well established. A 52-year-old female was prescribed warfarin and enoxaparin for a newly diagnosed deep vein thrombosis (DVT) in the left lower extremity. On day 4 of therapy, the patient had a supra-therapeutic international normalized ratio (INR), prompting the discontinuation of enoxaparin and a decrease in the warfarin dose. The patient returned to the emergency department on day 7 of treatment with a purple, cold, and extremely painful right foot with punctate areas of necrosis and petechiae proximal to the discoloration. The patient's INR was found to be 10.64. Following the diagnosis of warfarin-induced skin necrosis, the patient was administered vitamin K intravenously and fresh frozen plasma (FFP) to reverse the effects of warfarin and promote protein C and S synthesis. Once the patient's INR was no longer supratherapeutic, subcutaneous enoxaparin was re-started as treatment for the known recent DVT. The patient's necrotic foot began to improve and she was discharged home with an anticipated full recovery. Based on the proposed pathophysiology of disease, adequate bridge therapy may decrease the likelihood of developing this life-threatening condition. Early recognition and treatment with intravenous vitamin K, FFP or 4-factor prothrombin complex concentrate, and continued wound care are essential to prevent further complications.

Elevated International Normalized Ratio in a patient concurrently using warfarin and vismodegib

A case report of a sharp rise in International Normalized Ratio (INR) values during a patient's concomitant use of warfarin and the antineoplastic agent vismodegib is presented. About three weeks after he was prescribed vismodegib for skin cancer, a 78-year-old Caucasian man whose INR had been stable during nine months of warfarin use was found to have a critical INR value (9.5) during a visit to a pharmacy anticoagulation clinic. After clinic interventions including brief suspensions of warfarin therapy and an incremental 36% decrease in the weekly dose, the patient's INR returned to a high-normal value over the next few weeks, and treatment with warfarin was resumed. One week later, the man was admitted to the emergency department for altered mental status and loss of consciousness, which were thought to be unrelated to anticoagulation therapy. The patient died in the hospital shortly thereafter of unknown causes. At the time of death, laboratory values were stable, the most recent INR was 1.8, and the patient was hemodynamically stable and on a non-intensive care ward. Assessment with the Drug Interaction Probability Scale indicated a probable interaction between warfarin and vismodegib. Since its introduction in 2012, vismodegib has been implicated as a possible factor in seven reports of patient deaths. Concurrent use of vismodegib and warfarin was deemed the probable cause of acute INR elevation in this case, suggesting the need for close monitoring of INR values in patients receiving this combination of drugs.

Inadvertent Exaggerated Anticoagulation Following Use of Bismuth Subsalicylate in an Enterally Fed Patient Receiving Warfarin Therapy

We report a case of an inadvertent increase in the international normalized ratio (INR) after the addition of bismuth subsalicylate for the treatment of diarrhea in an enterally fed patient receiving warfarin therapy. A 56-year-old Caucasian female presented to the trauma intensive care unit (ICU) with multiple lower extremity fractures. Warfarin was initiated for deep vein thrombosis prophylaxis due to the patient's inability to ambulate. The target INR was 2-3. Continuous intragastric enteral feeding was withheld 1 hour before and 1 hour after intragastric administration of warfarin. Bismuth subsalicylate 30 mL every 4 hours was prescribed for diarrhea. Within 3 days after starting bismuth subsalicylate therapy, the patient's INR increased from 2.56 to 3.54 and minor bleeding was noted from the patient's tracheostomy site. No significant change in warfarin dosage, variability in vitamin K intake, or medications that potentially alter warfarin metabolism were present during the unexpected rise in INR. When the bismuth subsalicylate was discontinued, the patient's INR stabilized into the target range on the same warfarin dose given at the time of the supratherapeutic INR. Salicylate displaces warfarin from plasma protein binding sites and may result in a significant increase in INR secondary to redistribution of warfarin to the free active form. Evaluation of this case report using the Drug Interaction Probability Scale and Naranjo Adverse Drug Reaction Probability Scale yielded scores consistent with a probable adverse drug interaction. Bismuth subsalicylate exaggerates warfarin's anticoagulant response and its concurrent use during warfarin therapy should be avoided.

Supratherapeutic International Normalized Ratio Due to Reduced Vitamin K Intake Secondary to Prolonged Vomiting in a Patient on Warfarin

To report a case of prolonged vomiting during warfarin therapy, leading to an elevated international normalized ratio (INR). A 32-year-old female with a history of cyclic vomiting syndrome since early childhood and bilateral pulmonary emboli diagnosed 4 months prior to this acute event presented to the clinic for routine monitoring of warfarin therapy. The warfarin dose had been maintained at 35 mg/wk for 3½ months (INR 2-3.5), but it was increased to 37.5 mg/wk because the INR had trended down to the low goal range over the preceding month. At presentation, the patient reported a 15-day history of vomiting with minimal oral intake that required intravenous fluids to prevent dehydration. The INR was 4.7; warfarin was withheld, and oral vitamin K 5 mg as well as subcutaneous vitamin K 10 mg was administered the following day. The INR then decreased to 1.3. Therapy was transitioned to subcutaneous enoxaparin 1 mg/kg every 12 hours for the duration of the patient's anticoagulation therapy. Multiple reports have demonstrated malabsorption of warfarin and decreased INR response in the presence of underlying gastrointestinal disease. Despite a prolonged episode of cyclic vomiting syndrome, our patient had an elevated INR. In normal circumstances, warfarin is rapidly absorbed from the gastrointestinal tract and reaches maximum serum concentrations in approximately 90 minutes. Studies have shown that although the presence of food does not affect overall absorption of the medication, it can decrease the rate of absorption. Our patient was vomiting 20-30 minutes after oral dose administration. Because the patient was not consuming food, absorption of warfarin was potentially prompt, thus contributing to the elevated INR. The variability of vitamin K in the diet also can have significant impact on the response to warfarin. Our patient's INR had been stable while she consumed 3 servings each week of foods rich in vitamin K. This consumption was abruptly discontinued with the onset of the cyclic vomiting syndrome. We believe that decreased intake and retention of oral vitamin K-containing foods from the diet due to the prolonged vomiting coupled with the rapid onset of absorption resulted in a notably increased INR and subsequent bruising in our patient. In the presence of prolonged vomiting, warfarin therapy requires more frequent monitoring than usual to detect fluctuations in INR that may increase the risk of adverse events.

Effect of Transdermal Isopropyl Alcohol on the International Normalized Ratio in Five Warfarin‐Treated Patients

Warfarin, an anticoagulant with a narrow therapeutic window, is largely metabolized by cytochrome P450 2C9. Isopropyl alcohol has been shown to inhibit the activity of this enzyme. Use of topical isopropyl alcohol as a rubefacient may place patients at risk for systemic exposure. Isopropyl alcohol's effect on the international normalized ratio (INR) has not been well characterized. We describe five patients who experienced INR elevations after topical application of isopropyl alcohol. Each patient's INR was therapeutic for at least seven visits prior to becoming supratherapeutic. All patients confirmed drug adherence and denied medication or dietary changes. Seventy percent isopropyl alcohol was used in all cases over a large body surface area of intact skin multiple times daily for several days. All patients experienced a 10% or greater increase in their INR compared to previous levels. On discontinuation of isopropyl alcohol, each patient's INR returned to and remained in therapeutic range for the next 2 months. Prediction of isopropyl alcohol's effect of the INR is confound by several factors, notably the BSA covered, concentration of alcohol in the product, contact time with the skin, and skin integrity. It is important that clinicians inquire about the use of isopropyl alcohol and educate patients about its potential risk in those receiving warfarin therapy.

The Potential Effects of Dicloxacillin on Warfarin Management

Objective: To illustrate the effect that dicloxacillin may have on the anticoagulant properties of warfarin. Case Summary: A 69-year-old white male presented to the emergency department following a motor vehicle accident. He had been receiving a stable dose of warfarin of approximately 35–37.5 mg/wk for more than 2 years for atrial fibrillation. Computed tomography and magnetic resonance imaging revealed a 1 × 1.3 cm lesion in the anterior aspect of the pancreatic body. During a subsequent hospital stay for a distal pancreatectomy and splenectomy, the patient began a 6-week course of dicloxacillin to treat osteomyelitis of the elbow. During the course of treatment, the patient's warfarin dose was increased by 114% to reach a therapeutic international normalized ratio (INR) approximately 11 days after the antibiotic was discontinued. Discussion: Compared with previously published cases documenting the interaction between dicloxacillin and warfarin, to our knowledge, this is the first case to comprehensively assess and document other factors that potentially influenced the patient's INR. At every clinic visit, the patient was assessed for several factors that could have contributed to fluctuations in INR, none of which proved to have a significant effect. Conclusions: The addition of dicloxacillin to our patient's stable warfarin regimen resulted in a significant interaction that placed the patient at risk for thromboembolic complications. Careful monitoring of INR from the start of dicloxacillin therapy until 2 weeks after its discontinuation should be considered in patients who are taking warfarin and require dicloxacillin therapy.