Supratherapeutic International Normalized Ratio Research Articles

Ischemic stroke in the setting of supratherapeutic International Normalized Ratio following coronavirus disease 2019 infection: a case report

BackgroundSARS-CoV-19 infection is associated with an increased risk of thrombotic events. We present a case of acute middle cerebral artery ischemic stroke in a patient with SARS-CoV-19 infection despite being on warfarin with supratherapeutic INR (International Normalized Ratio).Case presentationA 68-year-old Caucasian female with multiple comorbidities was admitted to the hospital with symptoms of upper respiratory tract infection. A rapid antigen test confirmed the diagnosis of COVID-19 pneumonia, and intravenous remdesivir was initiated. On the fifth day of admission, the patient experienced sudden onset confusion, slurred speech, left-sided hemiplegia, right-sided eye deviation, and left-sided facial droop. Imaging studies revealed an occlusion of the distal anterior M2 segment of the right middle cerebral artery, and an MRI of the brain confirmed an acute right MCA infarction. Notably, the patient was receiving warfarin therapy with a supratherapeutic INR of 3.2.ConclusionsThis case report highlights the potential for thromboembolic events, including stroke, in patients with COVID-19 infection, even when receiving therapeutic anticoagulation therapy. Healthcare providers should be vigilant for signs of thrombosis in COVID-19 patients, particularly those with pre-existing risk factors. Further research is necessary to understand the pathophysiology and optimal management of thrombotic complications in COVID-19 patients.

Safety of Vitamin K in mechanical heart valve patients with supratherapeutic INR: A systematic review and meta-analysis.

Patients who had mechanical heart valves and an international normalized ratio (INR) of >5.0 should be managed by temporary cessation of vitamin K antagonist. This study aimed to investigate the safety of low-dose vitamin K1 in patients with mechanical heart valves who have supratherapeutic INR. CINAHL, Cochran Library, Clinical trial.gov, OpenGrey, PubMed, ScienceDirect, and Scopus were systematically searched from the inception up to October 2021 without language restriction. Studies comparing the safety of low-dose vitamin K1 treatment in patients with placebo or other anticoagulant reversal agents were included. We used a random-effect model for the meta-analysis. Publication bias was determined by a funnel plot with subsequent Begg's test and Egger's test. From 7529 retrieved studies, 3 randomized control trials were included in the meta-analysis. Pooled data demonstrated that low-dose vitamin K was not associated with thromboembolism rate (risk ratio [RR] = 0.94; 95% CI: 0.19-4.55) major bleeding rate (RR = 0.58; 95% CI: 0.07-4.82), and minor bleeding rate (RR = 0.60; 95% CI: 0.07-5.09). Subgroup and sensitivity analysis demonstrated the nonsignificant effect of low-dose vitamin K on the risk of thromboembolism. Publication bias was not apparent, according to Begg's test and Egger's test (P = .090 and 0.134, respectively). The current evidence does not support the role of low-dose vitamin K as a trigger of thromboembolism in supratherapeutic INR patients with mechanical heart valves. Nevertheless, more well-designed studies with larger sample sizes are required to justify this research question.

Massive warfarin overdose management in an adolescent patient

Introduction Warfarin is a widely used oral anticoagulant with established reversal guidelines in the setting of a supratherapeutic international normalized ratio (INR). Limited literature exists on managing acute warfarin overdoses in patients who are not chronically anticoagulated. Case A 15-year-old male, with no indication for anticoagulation, presented to a pediatric emergency department after an acute 1,000 mg warfarin ingestion. He had no significant complaints upon presentation aside from a mild intermittent headache. His past medical history was significant for anxiety, depression, Tourette syndrome, attention deficit hyperactivity disorder, and polysubstance misuse. Computed tomography of his head was unremarkable and serum acetaminophen, salicylate, and ethanol concentrations were negative. Approximately 16 h post-ingestion, his INR was 1.9 with an increase to 3.3 by 26 h. The regional poison center was consulted and recommended, consistent with the CHEST guidelines, holding treatment with vitamin K until INR was >10 or if signs or symptoms of bleeding occurred. The patient was admitted for monitoring and by hospital day (HD) #4, his INR had risen to >11.8 at which point oral vitamin K 10 mg was administered. On HD #7, the patient was deemed stable for transfer to inpatient psychiatry after repeat INRs of 2.9 and 3.4. Discussion Case reports have demonstrated early administration of vitamin K can temporarily lower INR and prevent detection of rebound. The CHEST warfarin reversal guidelines describe the risks and benefits with respect to bleeding and thrombosis in the non-intentional overdose patient. Application and extrapolation of these guidelines to acute overdose in patients who lack an indication for anticoagulation may or may not be warranted. Conclusion While established clinical guidance exists on reversing a supratherapeutic INR in patients chronically anticoagulated with warfarin, the risks and benefits of extrapolating this approach are unclear in those who lack an indication for anticoagulation.

ANTICOAGULANT DRUG INDUCED SUPRA THERAPEUTIC INR AND ITS MANAGEMENT

This paper has the management of Drug Induced Supra therapeutic INR and a case presentation of 33-year-old Male patient who was on oral anticoagulant (Vitamin K antagonist-VKA) and antiplatelet therapy presented with supra-therapeutic international normalized ratio (INR) with history of Single episode of blood stained Sputum. The patient is known case of posterior circulation stroke with left ventricular clot, Cortical venous sinus thrombosis with left parietal hematoma and secondary seizure, ischemic heart disease (IHD) status post Percutaneous Transluminal Coronary Angioplasty (PTCA) to LAD with left ventricular ejection fraction (LVEF) - 30% and hyper-homocysteinemia. The patient presented with history of single episode of blood stain sputum and with no other complaints. His routine blood investigation revealed INR of 9.50 hence the patient was admitted and treated accordingly. Patients INR returned to normal after appropriate medical management. Patient was discharged with a titrated dose, advised on treatment, education and adherence counselling.

Deranged Haemostasis: Rifampin-Induced Coagulopathy

Prothrombin time (PT), first used in 1935, is the most commonly employed marker of coagulopathy to assess bleeding tendency. It is a screening test and measures the time in seconds to the formation of a clot after platelet-poor plasma has been mixed with a thromboplastin reagent consisting of tissue factor, lipids and calcium chloride ions. The International Normalized Ratio (INR) is a standardized number based on the PT of the patient. It is used by clinicians to measure the effectiveness of anticoagulants and to guide therapy. Drugs such as warfarin can affect the level of or the metabolism of vitamin K in the body, which can impact PT and INR levels. A supratherapeutic INR is rare in a patient not on therapy with vitamin K inhibitors and with preserved liver function. Here we describe an elderly man with a supratherapeutic INR, secondary to the use of rifampin. Antibiotic-induced coagulopathy is an extremely rare complication. To the authors’ knowledge, this is a unique case of rifampin-induced coagulopathy with no other associated complications of disseminated intravascular coagulation. A literature review revealed a small number of cases of rifampicin-induced coagulopathy. A high index of suspicion and knowledge is essential for the diagnosis and management of such cases.LEARNING POINTSGiven the unpredictability and rarity of rifampicin-induced coagulopathy in clinical practice, clinicians should be aware of the possibility of bleeding or drug-induced thromboembolic events with antibiotics.Early recognition and withdrawal of the offending agent are key to the successful management of this condition.Clinicians should be aware of the possible side effects of administered drugs and their possible interactions.

Pharmacist-Managed Anticoagulation Services for Warfarin Management in Tertiary Hospitals: The Egyptian Experience

Background: Warfarin is widely regarded as the main anticoagulant in lowering the risk of thromboembolism. This study used indicators to compare pharmacist-managed anticoagulation services, using a well-prepared protocol, with physician-managed anticoagulation services. Methods: A retrospective prospective pilot study was conducted to compare patient outcomes before and after transitioning patients to pharmacist-managed anticoagulation services, comparing the proportion of those with therapeutic international normalized ratio (INR), subtherapeutic INR, and supratherapeutic INR, as well as their bleeding occurrences as indicators of assuring quality care. Results: A significant improvement in anticoagulation management was noted in the transition to pharmacist-managed anticoagulation services. The proportion of those with subtherapeutic INR decreased from 61.8% to 11.8% (p < 0.001), those with supratherapeutic INR decreased from 20.6% to 2.9% (p < 0.001), those with therapeutic INR increased from 17.6% to 85.3% (p < 0.001), and the occurrence of bleeding decreased from 11.8% to 0.0%, without significant difference in warfarin doses (median from 4 before the transition to 5 after); in addition, the time to reach therapeutic INR decreased from 12-24 weeks to 2-8 weeks after transitioning to pharmacist-managed anticoagulation services. Conclusion: Pharmacist-managed anticoagulation services are considered safer and more effective than physician-managed anticoagulation services alone in terms of patients’ adherence and satisfaction, which provide an excellent opportunity for quality assurance care.

The Impact of Pharmacist-Managed Service on Warfarin Therapy in Patients after Mechanical Valve Replacement.

Objective To evaluate the impact of pharmacist interventions on international normalized ratio (INR) control during the warfarin initiation phase after mechanical valve replacement. Methods This was a retrospective cohort study conducted in a cardiovascular surgery ward in a tertiary hospital from August 1, 2015, to July 31, 2019. Patients aged ≥20 years who were admitted for mechanical valve replacement were enrolled in this study and further classified into conventional and pharmacist-managed warfarin therapy (PMWT) groups. All participants were prospectively followed up until the first outpatient appointment after valve replacement. The effectiveness outcomes were time in therapeutic range (TTR), time to therapeutic INR, number of patients with therapeutic INR at discharge and at first outpatient appointment, and length of hospital stay. The safety outcome was the number of patients with any supratherapeutic INR during the hospital stay. Multivariate logistic regression analyses were also used to determine the predictors of a therapeutic INR at discharge or with any supratherapeutic INR during admission. Results A total of 39 and 33 patients were enrolled in the conventional and PMWT groups, respectively. At discharge, 18 patients (46.2%) in the conventional group and 24 patients (72.7%) in the PMWT group had achieved the therapeutic INR (P=0.023). Compared to the conventional group, fewer patients in the PMWT group had supratherapeutic INR during hospital stay (35.9% vs. 9.0%, P=0.008). No significant differences were found in TTR, time to therapeutic INR, number of patients with therapeutic INR at return appointment, and length of stay between the study groups. In the multivariate regression analyses, PMWT predicted achieving therapeutic INR at discharge (odds ratio (OR) and 95% confidence interval (CI), 3.14 [1.08–9.14]) and was inversely associated with supratherapeutic INRs during admission (OR = 0.21 [0.05–0.82]). Conclusions Among patients admitted for mechanical valve replacement, the implementation of PMWT was associated with optimal therapeutic INR at discharge and no supratherapeutic INR during admission. Therefore, pharmacist participation is essential for improving the quality of warfarin therapy.

The Immediate Effect of COVID-19 Vaccination on Anticoagulation Control in Patients Using Vitamin K Antagonists.

Background In January 2021, the Dutch vaccination program against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was started. Clinical studies have shown that systemic reactions occur in up to 50% of vaccine recipients. Therefore, COVID-19 vaccination could affect anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications. Aims This article investigates whether the BNT162b2 vaccine affects anticoagulation control in outpatients using vitamin K antagonists (VKAs). Methods A case-crossover study was performed in a cohort of outpatient VKA users from four Dutch anticoagulation clinics who received a BNT162b2 vaccine. International normalized ratio (INR) results and VKA dosages before the first vaccination, the reference period, were compared with those after the first and second vaccination. Results A total of 3,148 outpatient VKA users were included, with a mean age (standard deviation) of 86.7 (8.7) years, of whom 43.8% were male, 67.0% used acenocoumarol, and 33.0% phenprocoumon. We observed a decrease of 8.9% of INRs within range in the standard intensity group (target INR 2.0–3.0). There was both an increased risk of supratherapeutic (odds ratio [OR] = 1.34 [95% confidence interval [CI] 1.08–1.67]) and subtherapeutic levels (OR = 1.40 [95% CI 1.08–1.83]) after first vaccination. In the high-intensity group (target INR 2.5–3.5), the risk of a supratherapeutic INR was 2.3 times higher after first vaccination (OR = 2.29 [95% CI 1.22–4.28]) and 3.3 times higher after second vaccination (OR = 3.25 [95% CI 1.06–9.97]). Conclusion BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with VKAs, so it is advisable to monitor the INR shortly after vaccination, even in stable patients.

Does ramadan fasting affect the therapeutic and clinical outcomes of warfarin? a systematic review and meta-analysis.

Warfarin's therapeutic effect is affected by many factors, including diet modifications. The impact of Ramadan fasting on warfarin is controversial. The aim of this systematic review and meta-analysis was to investigate the effect of Ramadan fasting on patients taking warfarin. A literature search was done in PubMed, WOS, Scopus, and Embase from inception to May 24, 2021. All relevant studies measuring the international normalized ratio (INR), time in therapeutic range (TTR), or the number of patients within therapeutic range before, during, and after Ramadan were assessed by full-text screening for achieving all of the inclusion criteria. We used the Newcastle-Ottawa Scale for quality assessment and RevMan 5.4 software for meta-analysis. A total of five studies with 446 patients were included in the meta-analysis. The patients served as their own control. Our pooled analyses showed no significant difference during Ramadan compared to pre-Ramadan (MD: 0.08; 95% CI: - 0.00, 0.15; P = 0.06) and post-Ramadan (MD: - 0.00; 95% CI: - 0.14, 0.14; P = 1.00, respectively). There was only a significant increase in the risk ratio of supratherapeutic INR when comparing post-Ramadan vs. pre-Ramadan (RR: 1.69; 95% CI: 1.22, 2.33; P = 0.001). However, there was no significant risk for supratherapeutic INR during Ramadan compared to pre-Ramadan or post-Ramadan; the number of patients within the therapeutic range of INR during Ramadan compared to pre-Ramadan; and TTR during Ramadan, pre-Ramadan, and post-Ramadan. Ramadan fasting did not affect INR level, TTR, or the number of patients within the therapeutic range before, during, and after Ramadan. However, there was a possibility of achieving a supratherapeutic INR post-Ramadan compared to pre-Ramadan. Therefore, INR monitoring and warfarin dose adjustments accordingly are recommended after Ramadan.

Warfarin-Related Nephropathy Manifested as Diffuse Mesangial Proliferative Glomerulonephritis

Warfarin is associated with anticoagulant-related nephropathy (ARN), one of the potential side effects. This is evidenced by a progressively increasing number of detected cases of deterioration in the kidney function even in patients with normal baseline function (GFR {glomerular filtration rate}) in addition to the chronic kidney disease (CKD) patients who are already vulnerable to ARN. There has been a clinical correlation in a rapid decline of kidney function and international normalized ratio (INR) levels of greater than three. ARN is a significant but underdiagnosed complication of anticoagulation that is associated with increased renal morbidity and all-cause mortality. We want to emphasize the importance of monitoring kidney function regularly and adjusting the appropriate doses of warfarin. We present a case of a 57-year-old female who was on warfarin for the mechanical aortic valve, presented with acute kidney injury and supratherapeutic INR. Her renal biopsy showed diffuse mesangial proliferative glomerulonephritis.

Time in therapeutic range of anticoagulation among patients with atrial fibrillation and cerebral amyloid angiopathy

Atrial fibrillation (AF) and cerebral amyloid angiopathy (CAA) present risks of ischemic stroke and intracerebral hemorrhage (ICH). Vitamin K antagonist use is associated with fluctuations in international normalized ratio (INR), which predispose to a higher bleeding risk. Patients with a diagnosis of AF and ICH while on a vitamin K antagonist were identified using the Rochester Epidemiology Project. Sixty patients were identified (mean age 81.3 years; 24 men). Thirty-three (55%) exhibited characteristics consistent with possible (n = 25) or probable (n = 8) CAA. Mean time in therapeutic range in the 30 days preceding ICH was 55.4%, with no difference between CAA and non-CAA patients. Mean time spent above therapeutic range (INR > 3.0) was 17.7%, with no difference between CAA and non-CAA patients. Following ICH, 21 (35%) died within 30 days, with total mortality at 76.7% after 176.4 person-years of follow-up (mean 2.9 years). Time in therapeutic range in the 30 days prior to ICH had no significant impact on 7-day mortality, nor risk of recurrent ICH or ischemic stroke. Patients with warfarin-related ICH were often outside of the therapeutic range within the month preceding hemorrhage but more frequently were subtherapeutic. Even with careful avoidance of supratherapeutic INR, vitamin K antagonist use in CAA patients is unlikely to have a major effect in preventing ICH and must be used with caution.

Drive-up INR testing and phone-based consultations service during COVID-19 pandemic in a pharmacist-lead anticoagulation clinic in Qatar: Monitoring, clinical, resource utilization, and patient- oriented outcomes.

BackgroundCoronavirus disease 2019 (COVID‐19) pandemic has resulted in unprecedented pressure on healthcare systems and led to widespread utilization of telemedicine or telehealth services. Combined with teleclinics, using drive‐up fingerstick International normalized ratio (INR) testing was recommended to decrease exposure risk of anticoagulation patients.ObjectiveTo evaluate the impact of transitioning from clinic‐based anticoagulation management services to drive‐up and phone‐based services during COVID‐19 pandemic in Qatar.MethodsThe study comprised of two components: a retrospective cohort study of all eligible patients who attended anticoagulation clinic over 1‐year period (6 months before and 6 months after service transition) and a cross‐sectional survey of eligible patients who agreed to provide data about their satisfaction with the new service. Monitoring parameters, clinical outcomes, and resource utilization related to warfarin therapy were compared before and after service transition. Patients' experience was explored through a structured survey.ResultsThere was no statistically significant difference between clinic‐based and phone‐based anticoagulation services in mean time and number of visits within therapeutic range (P = .67; P = .06 respectively); mean number of extreme subtherapeutic and supratherapeutic INR values (P = .32 and P = .34, respectively); incidence of thromboembolic complications and warfarin related hospitalization. There was one reported bleeding and one emergency visit (0.9%) in the phone‐based group vs none in the clinic‐based group. Frequency of INR testing and compliance to attending clinics appointments declined significantly (P = .002; P = .001, respectively). Overall, patients were highly satisfied with the new service. The majority of patients found it better (51.6%) or just as good as the traditional service (44.5%). Patients who preferred the new service were significantly younger than their counterparts (P = .005).ConclusionThe service of drive‐up INR testing and phone‐based consultations was shown to be comparable to traditional anticoagulation service, a finding that supports maintaining such services as part of the new normal after the pandemic is over.

Side-Effects of COVID-19 on Patient Care: An INR Story.

BackgroundNumerous studies have documented reduced access to patient care due to the COVID-19 pandemic including access to a diagnostic or screening tests, prescription medications, and treatment for an ongoing condition. In the context of clinical management for venous thromboembolism, this could result in suboptimal therapy with warfarin. We aimed to determine the impact of the pandemic on utilization of International normalized ratio (INR) testing and the percentage of high and low results.MethodsINR data from 11 institutions were extracted to compare testing volume and the percentage of INR results ≥3.5 and ≤1.5 between a pre-pandemic period (January-June 2019, period 1) and a portion of the COVID-19 pandemic period (January-June 2020, period 2). The analysis was performed for inpatient and outpatient cohorts.ResultsTesting volumes showed relatively little change in January and February, followed by a significant decrease in March, April and May, and then returned to baseline in June. Outpatient testing showed a larger percentage decrease in testing volume compared to inpatient testing. At 10 of the 11 study sites we observed an increase in the percentage of abnormal high INR results as test volumes decreased, primarily among outpatients.ConclusionThe COVID-19 pandemic impacted INR testing among outpatients which may be attributable to several factors. Increased supratherapeutic INR results during the pandemic period when there was reduced laboratory utilization and access to care is concerning because of the risk of adverse bleeding events in this group of patients. This could be mitigated in the future by offering drive through testing and/or widespread implementation of home INR monitoring.

Effectiveness of the Alfalfa App in Warfarin Therapy Management for Patients Undergoing Venous Thrombosis Prevention and Treatment: Cohort Study.

BackgroundOver the years, the internet has enabled considerable progress in the management of chronic diseases, especially hypertension and diabetes. It also provides novel opportunities in online anticoagulation management. Nevertheless, there is insufficient evidence regarding the effectiveness of online anticoagulation management.ObjectiveThis study explored the effectiveness and safety of warfarin management via the Alfalfa app, so as to provide evidence in support of anticoagulant management through online services.MethodsIn this retrospective, observational cohort study, 824 patients were included. In the offline group, patients went to the hospital clinic for warfarin management. In the Alfalfa app group, patients reported the dose of warfarin, current international normalized ratio (INR) value, and other related information through the Alfalfa app. Physicians or pharmacists used the app to adjust the dose of warfarin and determined the time for the next blood INR testing. Patients completed INR testing by point-of-care at home or hospital. The primary outcome of the study was the percentage of time in therapeutic range (TTR). Secondary outcomes included minor and major bleeding events, thrombotic events, warfarin-related emergency department visits, hospital admissions, and high INR values.ResultsThe TTR and percentage of INR values in the range were significantly higher in the Alfalfa app group than in the offline group (79.35% vs 52.38%, P<.001; 3314/4282, 77.39% vs 2005/4202, 47.72%, P<.001, respectively). Patients managed via the Alfalfa app had lower rates of subtherapeutic (172/4282, 4.02% vs 388/4202, 9.23%; P<.001), supratherapeutic (487/4282, 11.37% vs 882/4202, 20.99%; P<.001), and extreme subtherapeutic INR values (290/4282, 6.77% vs 910/4202, 21.66%; P<.001). Additionally, the Alfalfa app group had lower incidences of major bleeding (2/425, 0.5% vs 12/399, 3.0%; P=.005), warfarin-related emergency department visits (13/425, 3.1% vs 37/399, 9.3%; P<.001), and hospital admissions (1/425, 0.2% vs 12/399, 3.0%; P=.001) compared with the offline group. However, the Alfalfa app group had a higher incidence of minor bleeding than the offline group (45/425, 10.6% vs 20/399, 5.0%; P=.003). There were similar incidences in extreme supratherapeutic INR values (19/4282, 0.44% vs 17/4202, 0.40%; P=.78) and thromboembolic events (1/425, 0.2% vs 1/399, 0.3%; P=.53) between the two groups.ConclusionsWarfarin management is superior via the Alfalfa app than via offline services in terms of major bleeding events, warfarin-related emergency department visits, and hospital admissions.

Effectiveness of Telepharmacy Versus Face-to-Face Anticoagulation Services in the Ambulatory Care Setting: A Systematic Review and Meta-analysis.

Effectiveness of anticoagulation services managed via telepharmacy (TP) has not been clearly demonstrated. This systematic review and meta-analysis compares the effectiveness of TP anticoagulation services to face-to-face (FTF) anticoagulation services in the ambulatory care setting. A literature search for studies assessing the effectiveness of TP services was conducted using PubMed, EMBASE, and Cochrane Central databases, from inception through November 18, 2020. Studies that compared TP with FTF anticoagulation services in the ambulatory care setting were included. Outcomes of interest included thromboembolic events, major bleeding, minor bleeding, any bleeding, warfarin international normalized ratio (INR) time in therapeutic range (TTR), frequency of extreme INR, anticoagulation-related emergency department visits, anticoagulation-related hospitalization, any hospitalization, and mortality. Relative risk (RR) and weighted mean difference were calculated using the DerSimonian and Laird random-effects model. Overall, 11 studies involving 8395 patients were included in the systematic review, and 9 studies were included in the pooled meta-analysis. Compared with FTF service, TP was associated with a lower risk of any bleeding and any hospitalization, with RRs of 0.65 (95% CI = 0.47 to 0.90; P = 0.01) and 0.59 (95% CI = 0.39 to 0.87; P = 0.01), respectively. There was no statistically significant difference in TTR or the risk of extreme supratherapeutic INR, major bleeding, minor bleeding, or thromboembolic events between the 2 groups. TP appears to be at least as effective as FTF anticoagulation services. Findings from this study support the utilization of TP practice models in ambulatory care anticoagulation management.

A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional.

Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies. Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype. The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.

Evaluation of dosing and safety outcomes of low-dose prophylactic warfarin in children after cardiothoracic surgery.

Prophylactic warfarin with an International Normalized Ratio (INR) goal of 1.5 to 2.0 is one antithrombotic therapy utilized in children after cardiothoracic surgery (CTS); published sources suggest a dose of 0.1 mg/kg per day to achieve this goal. However, few studies have evaluated dosing in this population. The purpose of this study was to evaluate dosing and safety outcomes in children receiving warfarin after CTS. A descriptive, retrospective review was conducted to evaluate warfarin dosing and INR outcomes in patients 18 years of age or younger who underwent CTS and received prophylactic warfarin with an INR goal of 1.5 to 2.0 from January 2014 through December 2018. The primary objective was to determine the median initial warfarin dose. Secondary objectives included identifying the percentage of documented INR values that were outside the therapeutic range, the percentage of patients with therapeutic INRs at discharge, and the 30-day readmission rate. Twenty-six patients were included in the review. The median initial warfarin dosage was 0.07 mg/kg/d (interquartile range [IQR], 0.05-0.10 mg/kg/d). Of the total of 177 INR values collected during the entire study period, 67 (37.9%) were therapeutic, 64 (36.2%) were subtherapeutic, and 46 (26.0%) were supratherapeutic. Eighteen patients (69.2%) had at least 1 supratherapeutic INR at any point during the study period, most frequently on days 2 through 4 of therapy. At discharge, 11 patients (42.3%) had therapeutic INRs. Four patients (15.4%) were readmitted within 30 days, with bleeding documented in 2 patients during their readmission. The majority of patients received an initial warfarin dose less than that specified in published recommendations but still had a supratherapeutic INR at least once during the study period. When initiating warfarin after CTS, a dosage of <0.1 mg/kg per day and frequent monitoring may be needed to achieve an INR goal of 1.5 to 2.0.

Incidence of Major Bleeding Associated with International Normalized Ratio Greater Than 4.0 in a Cohort of Mechanical Circulatory Support Device Patients

To study the frequency by which a significantly elevated international normalized ratio (INR) may be associated with a major bleeding event in mechanical circulatory support device (MCS) patients. A retrospective review of mechanical circulatory support device recipients was performed for the years 9/2013-5/2018. The incidence of significant bleeding was determined using the MOMENTUM 3 major adverse event bleeding definition. The incidence of bleeding within 30 days of an INR>4.0 was assessed. Sixty-Four MCS patients (36 Heartware, 18 Heartmate II, 7 Heartmate III, 3 total artificial heart) were reviewed for INR data over the study period. Only ten patients never had any INR values above 4.0. A total of 217 INR measurements were found to be greater than 4.0. There was a total of 56 major bleeding events in 33 patients during the study period. Eleven patients experienced 17 major bleeding events associated with INR>4.0, however 39 bleeds did not register an INR>4.0. The incidence of bleeding and high INR as measured by positive predictive value was 8.3% with a sensitivity of 0.306. The negative predictive value for freedom from bleeding with INR<4.0 was 99.5% with a specificity of 0.968. The average time to bleed after a measured INR>4.0 was 10.3 +/- 10.0 days. Both the bleeding and the non-bleeding groups had an average total number of INR values>4.0 for the study period of 3.9 +/- 3.5. There were 9 gastrointestinal bleeds (GIB), and 6 non GIBs that required transfusion, as well as 2 intracranial hemorrhages (ICH) in the elevated INR group. No bleeds within a month of an INR>4.0 group were fatal, whereas two ICHs in the INR<4.0 group were fatal. A single elevated INR>4.0 did not correlate strongly with an incidence of major bleeding in the subsequent 30 days. The amount of time to bleeding events after an elevated INR is also quite variable making the forecasting of potential bleeding difficult. Further study is warranted to improve our understanding of the link between the frequency, amount of time, and individual significance of supratherapeutic INR and bleeding complications.

The Magnitude of the Warfarin‐Amiodarone Drug‐Drug Interaction Varies With Renal Function: A Propensity‐Matched Cohort Study

Amiodarone inhibits warfarin metabolism and is associated with major bleeding during warfarin therapy. Managing this drug-drug interaction (DDI) is challenging because of substantial interpatient variability in DDI magnitude. Because renal dysfunction induces changes in drug metabolism and protein binding that could alter cytochrome P450 inhibition mechanisms, we hypothesized that renal dysfunction alters the impact of the warfarin-amiodarone DDI. We tested this question in a propensity-matched cohort study of hospitalized patients with atrial fibrillation. Patients were queried from an electronic health record database. Renal function was estimated with creatinine clearance (CrCl). Warfarin response was measured with the warfarin sensitivity index (WSI), a dose-normalized international normalized ratio (INR) measure, and was modeled with multilevel mixed-effects linear regression. Time to supratherapeutic INR (>4) was modeled using Cox regression. Propensity score matching resulted in 4,518 patients administered amiodarone and 4,518 controls. Amiodarone's effect on warfarin response varied threefold across the renal function range, increasing WSI by 36% in patients with normal renal function (CrCl 115mL/minute), but by only 11.8% in patients with severe renal dysfunction (CrCl 15mL/minute). Similarly, amiodarone had a strong effect in patients with normal renal function (hazard ratio (HR) 1.80; 1.23, 2.64), but a negligible effect on supratherapeutic INR hazard in patients with severe renal dysfunction (HR 1.01; 0.75, 1.37). These results suggest that renal function is a novel factor that explains substantial variability in the warfarin-amiodarone DDI. This information could inform warfarin dosage adjustment and monitoring and may have implications for the selection of oral anticoagulation agents in patients treated with amiodarone.

Supratherapeutic International Normalized Ratio causing Nephropathy: A Rare Adverse Effect of Warfarin

There are many common causes of nephropathy (abnormal pathology of kidneys) such as diabetes, hypertension, autoimmune, and drugs. Amongst the drugs, warfarin has recently been recognized to cause nephropathy in rare cases. Warfarin-related nephropathy (WRN) is clinically defined as an increase in serum creatinine of 0.3 mg/dl within one week of international normalized ratio (INR) being greater than 3.A 61-year-old male was referred by his primary care physician (PCP) for having complaints of elevated creatinine associated with hematuria for one month. On evaluation with computed tomography (CT) of the abdomen/pelvis, it was revealed that he had small non-obstructing stones. The creatinine had increased from a baseline of 2.03 mg/dl to 6.8 mg/dl. Hemoglobin (Hb) had decreased from a baseline of 12.8 gm/dl to 8.1 gm/dl, the INR was 3.52. On subsequent days, the patient's renal function did not improve with fluids and supportive measures. Workup was unremarkable; therefore, a kidney biopsy was done. The biopsy specimen concluded the diagnosis of WRN. The patient was started on prednisone without any effect and then intermittent hemodialysis.Our case highlights the rare instance in which the cause of nephropathy is warfarin. If an early diagnosis had been made, the patient might have had a better prognosis; therefore, it is essential to have a high index of clinical suspicion when a patient presents with supratherapeutic INR and acute kidney injury (AKI) not getting better.