Over-anticoagulated Patients Research Articles

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24h. One hundred and eighty-one patients with an index INR>6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P=0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P<0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.

Frequency and cost of acute surgical admissions in over-anticoagulated patients: over-anticoagulation in the community.

Anticoagulation treatment in the community is common. This investigation was undertaken to determine the frequency of patient surgical admission with conditions associated with over-anticoagulation in the community and the surgical resource required to effectively and safely manage these patients acutely. Hospital discharge data on individual patients admitted to Waitemata District Health Board hospitals between December 2014 and November 2015 inclusive were reviewed. Data were extracted on individual patients with relevant ICD-10 codes (D683, Y442, Y443). Individual records for patients admitted to general surgery were then reviewed and costing information related to admissions extracted. A total of 551 patients were admitted in a 12-month period (4.8 admissions/1000 warfarin users and 2.4 admissions/1000 dabigatran users) for conditions associated with over-anticoagulation, with 35 admitted to the general surgery service, of whom 29 were taking warfarin and six taking dabigatran. A total of 21 patients were admitted with haemorrhagic conditions, and 14 over-anticoagulated patients were admitted with general surgical conditions requiring treatment. All patients were managed by withholding anticoagulant medication, 12 required formal reversal, three required red cell transfusion and four haemostatic procedures. The average hospital stay was 4 days, with inpatient costs of NZ$3500. Management of patients admitted with over-anticoagulation in the community is a significant surgical workload; however, acute management is usually straightforward.

Influence of VKORC1 gene polymorphisms on the effect of oral vitamin K supplementation in over-anticoagulated patients

Significant inter-individual variability on the effect of vitamin K to reverse overanticoagulation has been identified. Genetic polymorphisms of the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene might explain in part this variability. The objective of this study was to evaluate the influence of VKORC1 -1639G>A and 3730G>A polymorphisms on the effect of oral vitamin K supplementation in overanticoagulated patients. We performed an interventional trial of oral vitamin K supplementation in over-anticoagulated outpatients (international normalized ratio [INR]≥4). Subjects received vitamin K (2.5-5.0mg) according to baseline INR and were genotyped by real time polymerase chain reaction (PCR). INR values were determined at 3, 6, 24 and 72h after supplementation. We evaluated 33 outpatients, 61% were males, with a mean age of 62±12years old. There was a significant decrease in INR values over time for both polymorphisms after oral vitamin K. At 3h after supplementation, patients carrying the G allele for the -1639G>A polymorphism had a greater decrease in INR values compared to AA patients (p<0.05 for difference among groups; p<0.001 for time variation; p=0.001 for time×group interaction), with differences of -1.01 for GG versus AA (p=0.003) and -0.84 for GA versus AA (p=0.024). Mean INR value at 24h was 1.9±0.6 and at 72h was 2.1±0.7, with no differences among genotypes. No significant interaction was identified between the 3730G>A polymorphism and vitamin K supplementation. Our study indicated that the VKORC1 -1639G>A polymorphism plays a role in the response to acute vitamin K supplementation in over-anticoagulated patients, with faster decrease of INR value in patients carrying the G allele.

Pharmacogenetic tests could be helpful in predicting of VKA maintenance dose in elderly patients at treatment initiation

Several studies have linked mutations in the genes encoding cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) to a reduced VKA dose requirement and an increased risk of bleeding. Nevertheless, implementation of genotyping as a routine practice is still controversial. Our study was conducted in order to investigate the impact of genetic factors, presence of VKORC1-c.1639A, CYP2C*2 and CYP2C*3 among outpatients referred to Anticoagulation Service due to extremely unstable anticoagulant therapy. From 2008 to 2011, 68 patients, mean age 65.9, were included in the study. They were referred from primary care physicians due to inability to sustain the therapeutic range in the period of initiation of anticoagulant therapy. Genotyping results showed that 17 (25%) of them were carriers of both CYP2C9 and VKORC1 variant alleles, 38 (55.9%) were carriers of VKORC1 c.1639AA, 6 (8.8%) were carriers of CYP2C9 variant alleles, while 7 (10.3%) of them were carriers of wild type alleles. INR control upon admission showed that 34 (50%) of them were over-anticoagulated, while 12 (17.6%) of them had subsequent bleeding complications. Among over-anticoagulated patients, 32 were carriers of mutated alleles in both CYP2C9 and VKORC1 gene or VKORC1 alone, while 2 of patients carried wild type alleles. In addition to presence of CYP2C9 or VKORC 1 alleles, older age was an important factor related to a lower dose and risk for over-anticoagulation. Genotype (CYP2C9/VKORC1) and age are the most important factors that could predispose an extreme response and subsequent bleeding complications during the initiation of VKA.

The clinical significance of differences between point-of-care and laboratory INR methods in over-anticoagulated patients

IntroductionPatients receiving warfarin are at increased risk of bleeding when their International Normalised Ratio (INR) >4.5. Although not standardised above 4.5 the INR is measured in over-anticoagulated patients, consequently we have examined the reliability of INR results ≥4.5. We assessed: the relationship between different prothrombin time systems for INRs >4.5; the relationships between the INR and levels of vitamin K-dependent coagulation factors (VKD-CF) and thrombin generation test (TGT) parameters; and the impact that variation in results would have on warfarin dosing. MethodsINRs were performed using a CoaguChek XS Plus point-of-care (POC) device (measuring range 0.6-8.0). For POC INRs ≥4.5, laboratory INRs were also measured using a recombinant tissue factor (rTF) and a rabbit brain (RBT) thromboplastin. ResultsThere was good correlation between POC (INR ≥4.5, <8.0) and Lab INRs (rTF n=154, rs=0.87, p<0.0001; RBT n=102, rs=0.76, p<0.0001); and significant correlations between each of the VKD-CF and the INR, the strongest being with FVII (POC INR rs=-0.53 p<0.0001; Lab rTF-INR rs=-0.70 p<0.0001). TGT peak thrombin and ETP also showed good correlations with INR values (R2>0.71). Using POC and Lab rTF-INR, 109/154 (71%), or POC and Lab RBT-INR 75/102 (74%) results exhibited dosage concordance and/or were within 0.5 INR units. In the remaining patients variation in warfarin dosing was generally slight. ConclusionsOur data suggest that CoaguChek XS Plus INRs >4.5 and <8.0 are comparable to laboratory INRs (both methods) and it is probably unnecessary to perform laboratory INRs for clinical management of patients with INRs >4.5 including those >8.0.

Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy

Dietary vitamin K is thought to be an important factor that interferes with anticoagulation stability, but the clinical applicability of this interaction has not been evaluated adequately in prospective studies. In a randomized controlled trial that enrolled outpatients with a recent international normalized ratio (INR) outside the therapeutic target, we compared 2 strategies to optimize long-term oral anticoagulation: (1) a conventional approach based on changes in anticoagulant prescription and (2) a dietary vitamin K-guided strategy based on simple modifications of the amount of vitamin K-rich foods ingested per week. The primary efficacy end point was the percentage of patients who achieved a prespecified INR target at 90 days after randomization. Study population (n=132) predominantly included men with mechanical heart prostheses (58%) or atrial fibrillation (35%). Over time, patients allocated to the vitamin K-guided strategy reached the prespecified INR more frequently so that after 90 days of follow-up, 74% were on target compared with 58% of patients managed conventionally (P=0.04). Patients allocated to the dietary vitamin K-guided strategy had the same magnitude and direction of INR variation as those observed with the conventional approach in the short term (15 days) for both underanticaogulated and overanticoagulated patients. Minor bleeding or use of parenteral vitamin K were also marginally less frequent in patients managed according to the dietary intervention (1 [1.5%] versus 7 [11%]; P=0.06). A vitamin K-guided management strategy to adjust long-term oral anticoagulation is feasible and safe and may result in an increased chance of reaching target levels of INR.

T1954 Pre-Endoscopic Proton Pump Inhibitors in Non-Variceal Upper Gastrointestinal Bleeding; Continuous Infusion vs. Bolus

Aim: to evaluate the influence of anticoagulant therapy upon the course of non-variceal UGB. Methods: From January 2006 to Juny 2007 we carried out a cohort study of consecutive patients admitted in hospital due to UGB shown by haematemesis or melena. Upper gastrointestinal endoscopy was performed during the first 12 hours of admission. Three cohorts were defined: patients receiving vitamin K antagonists (AC), patient with antiplatelet treatment (AP) and patients without anticoagulant therapy (noACAP) as control group. The AC cohort was evaluated according to excess of anticoagulant treatment(INR>o<3). Outcome was assessed by: a) number of days in hospital; b) mortality rate; c) need for urgent surgery; and d) rebleeding. The measure of the association between antithrombotic therapy and the course of UGB was adjusted for confounders (age, sex, comorbidity, and the use of NSAIDs and PPIs at the time of UGB presentation). Other evaluated parameters were: etiology of UGB, initial hemodynamic severity, excess of anticoagulation, initial hemoglobin and blood transfusions. Results: A total of 392 consecutive patients were included. Forty-three were AC, 107 AP and 242 noACAP patients. In the AC cohort, 25 patients (58%) were overanticoagulated. The mean age was 64±19 years (64% men) and AC and AP patients were older than the controls. Significant comorbidity other than diabetes or hypertension was significantly greater in the AC cohort than in the noACAP cohort. Peptic lesions were more frequent in the AP cohort, and hemoglobin upon admission was lower in the AC cohort. There were no significant differences in terms of sex, previous use of PPIs, hemodynamic alterations, or number of units of packed red blood cells transfused. There were no significant differences among groups in terms of rebleeding (AC:11.6%. AP: 7.5%. NoACAP:9.1%), the need for urgent surgery (AC:2.3%. AP: 1.9%. NoACAP:1.2%) or mortality rate (AC:4.7%. AP:5.6%. NoACAP:5.8%). There were no differences in clinical outcome among overanticoagulated patients and the rest of them (INR<3). The number of days in hospital was greater in the AC cohort (4.81 more days; 95%CI 2.83-6.79, p<0.001). After adjusting for age and comorbidity, the increase in days in hospital among the AC patients was 3.24 days (95%CI: 1.22-5.26). CONCLUSION: Anticoagulated patients, including overanticoagulated patients, have similar clinical course that those without this treatment. Nevertheless, anticoagulation is associated with a longer hospital stay. This is partially explained by the older age and increased comorbidity of the patients subjected to such treatment.

Appraisal of current vitamin K dosing algorithms for the reversal of over‐anticoagulation with warfarin: the need for a more tailored dosing regimen

Warfarin is the most commonly prescribed oral anticoagulant in the UK for the treatment and prevention of thromboembolic disorders. Vitamin K administration is an effective way of reversing excessive anticoagulation. Over-anticoagulated patients present with a wide range of international normalized ratio (INR) values and may respond differently to a fixed dose of vitamin K. Current dosing algorithms for vitamin K administration in the non-urgent treatment of over-anticoagulation do not take this variability in response into account. Consequently, over a third of over-anticoagulated patients still remain outside their target INR 24 h after treatment. Such patients are therefore prone to either haemorrhage (if the patient is still over-anticoagulated) or thromboembolism (if the INR reversal is over-corrected). A number of factors such as patient age, body weight, co-morbidity, frailty, warfarin daily dose and CYP2C9 and VKORC1 polymorphism could affect response to vitamin K and thus the rate and extent of INR reversal. There is a need for a more individualized approach to the reversal of over-anticoagulation in asymptomatic or mildly haemorrhagic patients in order to improve the safety of warfarin therapy.

The use of vitamin K in patients on anticoagulant therapy: a practical guide.

Anticoagulation with antivitamin K (AVK) is very effective for primary and secondary prevention of thromboembolic events. However, questions persist about the risks and management of over-anticoagulation. For reversal of excessive anticoagulation by warfarin, AVK withdrawal, oral or parenteral vitamin K administration, prothrombin complex or fresh frozen plasma may be used, depending on the excess of anticoagulation, the existence and site of active bleeding, patient characteristics and the indication for AVK. In over-anticoagulated patients, vitamin K aims at rapid lowering of the international normalized ratio (INR) into a safe range to reduce the risk of major bleeding and therefore improving patient outcome without exposing the patient to the risk of thromboembolism due to overcorrection, resistance to AVK, or an allergic reaction to the medication. The risk of bleeding increases dramatically when the INR exceeds 4.0-6.0, although the absolute risk of bleeding remains fairly low, <5.5 per 1000 per day. Patient characteristics, including advanced age, treated hypertension, history of stroke, and concomitant use of various drugs, affect the risk of bleeding. The absolute risk of thromboembolism associated with overcorrection appears to be in the same range as the risk of bleeding due to over-anticoagulation. The use of vitamin K in patients with warfarin over-anticoagulation lowers excessively elevated INR faster than withholding warfarin alone; however, it has not been clearly demonstrated that vitamin K treatment does, in fact, lower the risk of major hemorrhage. As vitamin K administration via the intravenous route may be complicated by anaphylactoid reactions, and via the subcutaneous route by cutaneous reactions, oral administration is preferred. A dose of 1-2.5mg of oral phytomenadione (vitamin K(1)), reduces the range of INR from 5.0-9.0 to 2.0-5.0 within 24-48 hours, and for an INR >10.0, a dose of 5mg may be more appropriate. Overcorrection of the INR or resistance to warfarin is unlikely if the above doses of vitamin K are used. Vitamin K is less effective for over-anticoagulation after treatment with acenocoumarol or phenprocoumon than after treatment with warfarin.

Identificación de factores responsables de anticoagulación oral excesiva en pacientes ambulatorios con cardiopatía

Few studies have attempted to investigate the clinical course or identify factors responsible for excessive anticoagulation in patients with heart disease. To determine the incidence of excessive anticoagulation in outpatients with heart disease treated with acenocoumarol, analyze the factors related with over-anticoagulation, and identify bleeding complications. This 7-month prospective observational study included consecutive outpatients anticoagulated with acenocoumarol. They were seen in an anticoagulation unit. The high INR group of 55 over-anticoagulated patients had at least one test with INR > 5. The control group of 49 patients had INR results strictly within therapeutic range. A total of 3,683 INR determinations were made in 512 patients. Seventy-seven tests had an INR > 5 (a 2% overall incidence of high-INR). In the group of 55 INR < 5 patients, 31% had more than one INR determination > 5 during follow-up. Multivariate analysis identified four variables as independent predictors of over-anticoagulation: artificial heart valve, poor treatment compliance, addition of potentially interactive new drugs, and illness in the last month. The high-INR group patients had more bleeding episodes (21.8 vs 4.08%; p = 0.008), one of which was major. The incidence of excessive oral anticoagulation in our outpatient population was similar to that reported in other studies. Patients with INR > 5 had more total bleeding complications, mostly minor. It is recommended to proceed carefully with oral anticoagulant therapy in patients with an artificial heart valve, suspected poor treatment compliance, addition of potentially interactive new drugs, and illness in the last month.

Levels of vitamin K-dependent procoagulant and anticoagulant proteins in over-anticoagulated patients.

Coumarin anticoagulants impair the biological activity of the vitamin K-dependent procoagulant and anticoagulant proteins. There are no reports that focus on the levels of these proteins in over-anticoagulated patients. Therefore, we determined the levels of factor II, factor VII, factor IX and factor X, protein C and protein S in 25 randomly selected over-anticoagulated patients (International Normalized Ratio >/= 6.0) and in 25 matched, therapeutically anticoagulated patients with an International Normalized Ratio within the therapeutic zone. Furthermore, to study a possible effect of the cause of over-anticoagulation, coagulant levels were compared between 16 over-anticoagulated patients with fever in the preceding 2 weeks and 24 over-anticoagulated patients with stable congestive heart failure. The pattern of procoagulant level reductions in the three groups of over-anticoagulated patients was largely the same as in therapeutically anticoagulated patients: factor X was the lowest and factor IX the highest. The difference was that, in over-anticoagulated patients, factor VII was relatively low among the procoagulant factors compared with therapeutically anticoagulated patients. Protein C was lower than protein S in over-anticoagulated patients with congestive heart failure, but was similar to protein S in the other study groups. In over-anticoagulated patients with fever, the vitamin K-dependent coagulation proteins except factor X were significantly lower than in over-anticoagulated patients with congestive heart failure, especially factor VII and protein S.

The management of coumarin-induced over-anticoagulation Annotation.

The management of coumarin-induced over-anticoagulation Annotation.

Body Weight Affects Response to Vitamin K in Over-Anticoagulated Patients

One way to correct the common problem of excessive anticoagulation with warfarin is to administer vitamin K subcutaneously. However, patient response

Influence of body weight on response to subcutaneous vitamin K administration in over-anticoagulated patients

PURPOSE: To determine the influence of body weight on the international normalized ratio (INR) response to a fixed dose of vitamin K in overanticoagulated patients. METHODS: Retrospective review of records of patients who received 1 mg of vitamin K subcutaneously to correct excessive INR. Dose of vitamin K in milligrams per kilograms plotted against change in INR in 24 hours. RESULTS: Fifteen patients were identified who met all inclusion criteria. Linear regression analysis plotted INR response at 24 hours versus dose of vitamin K adjusted for body weight. Pearson’s product moment correlation ( R = 0.85) indicated a significant relationship between INR response at 24 hours to an adjusted body weight dose of subcutaneous vitamin K ( P = 0.0000523). A strong correlation ( r = 0.69) also existed between INR response at 24 hours and the actual body weight dose of subcutaneous vitamin K ( P = 0.004). CONCLUSIONS: In overanticoagulated patients, variability in response to vitamin K may be explained by variability in body weight. Dosing vitamin K according to body weight may result in a more predictable INR response.

Incidence of clinically significant endoscopic findings in over-anticoagulated patients with upper GI bleeding

Incidence of clinically significant endoscopic findings in over-anticoagulated patients with upper GI bleeding

Anticoagulation therapy.

Despite refinements and standardization in the use of anticoagulants, many problems remain for clinicians. Dr. Crowther describes appropriate starting and maintenance doses of warfarin, factors accounting for inter- and intra-observer variability and importantly, the management of the over-anticoagulated patients and bleeding patients. Dr. White compares unfractionated heparin (UFH) and low molecular weight heparin (LMWH) and addresses whether there truly are differences in the efficacy and safety of different LMWH's for both arterial and venous indications. Dr. Ortel discusses the management of the problem patient who requires anticoagulants, the management of heparin-induced thrombocytopenia, the pregnant patient, the obese patient, patients who have renal insufficiency and/or liver disease, patients with malignant disease, and other challenging patient populations.

Preventing ischemic stroke in patients with prior stroke and transient ischemic attack : a statement for healthcare professionals from the Stroke Council of the American Heart Association.

Stroke, the third leading cause of death in the United States, is a leading cause of adult neurological disability and accounts for the greatest number of hospitalizations for neurological disease. Although treatment of acute stroke has the potential of reducing death and disability, it is likely that prevention will more effectively reduce the ravages of stroke. The patient who is recovering from a mild stroke or who has had a recent transient ischemic attack (TIA) is at high risk of stroke recurrence, physical and intellectual disability, long-term institutionalization, and death. There is substantial evidence from observational epidemiological studies and clinical trials that recurrent ischemic stroke can be prevented (Table 1⇓). Control of risk factors is important for prevention of a first stroke and is practical after ischemic stroke and TIA have occurred. Identification of the specific ischemic stroke mechanism, eg, TIA or minor stroke ipsilateral to a moderate or severe internal carotid stenosis, guides decision making with regard to recurrent stroke prevention therapy (Table 2⇓). A patient with symptomatic cerebrovascular disease is likely to have other cardiovascular diseases or is predisposed to develop them. Preventive measures should complement reduction in risk of atherothrombotic events in the coronary arteries and other arterial territories. Certain nonmodifiable characteristics identify persons at high risk of stroke and stroke recurrence. These include advancing age, male sex, and black and Hispanic race-ethnic backgrounds. Some risk factors, however, such as elevated blood pressure, cigarette smoking, obesity, impaired glucose tolerance, and physical inactivity, are modifiable. Other conditions, ie, prior cardiovascular diseases such as coronary heart disease with angina or prior myocardial infarction, valvular heart disease, congestive heart failure, atrial fibrillation, increased left ventricular mass, and certain other echocardiographic abnormalities, identify persons at increased risk who may be treated with antithrombotic therapy. More recently, other modifiable risk …

Audit of the frequency and clinical response to excessive oral anticoagulation in an out-patient population.

A retrospective review of over-anticoagulated patients with critical international normalized ratios (INRs) was undertaken in a large outpatient laboratory. In the six-month study period, 85 prothrombin times (PTs) were identified with an INR of > or = 6.0, an overall incidence of elevated PTs of 0.2% or two per 1,000 INR tests. Complete follow-up data was available on 65 patients. When compared to an age- and gender-matched control group without INR > or = 6.0, high-INR patients were significantly more likely to manifest the presence of alcoholism or liver disease, to have been anticoagulated for less than six months, to have experienced more frequent warfarin dosage changes, and to have had the addition of a medication known to interact with warfarin. In the high-INR group, a likely cause for the specific critical INR was identified in 44 patients (68%). Drug interactions followed by compliance problems were the most common factors identified. The 13 patients (20%) who received vitamin K therapy experienced no difference in the clinical outcome compared with those managed conservatively. Conservative management of critically high INR values appeared to be as efficacious as intervention with vitamin K therapy.

Conservative Treatment of Overanticoagulated Patients

To determine the outcome of over-anticoagulated patients who were treated with vitamin K and those who were treated conservatively by holding doses and increasing monitoring frequency. A secondary objective was to compare conservative management with American College of Chest Physicians (ACCP) treatment guidelines when followed. Retrospective chart review of all patients with international normalized ratios (INRs) of 6 or greater and concurrently receiving warfarin between November 1993 and February 1994. A Veterans Affairs Medical Center providing inpatient and outpatient care. Patients receiving warfarin are managed by an established anticoagulation clinic. Fifty-one consecutive patients receiving warfarin who had an INR of 6 or greater were reviewed. Data collection included INR, risks for bleeding, indication for anticoagulation, interventions, and patient outcomes. INRs ranged from 6.1 to 81.8. Forty-eight patients (94%) did not receive vitamin K; they were treated by withholding doses and increasing monitoring frequency. One developed minor bleeding. Three patients (6%) received vitamin K. Two of these patients died of unrelated problems. The third patient required 47 days of heparin therapy prior to achieving therapeutic oral anticoagulation. This trial showed that conservative treatment of nonbleeding overanticoagulated patients is safe. A prospective trial comparing the ACCP guidelines with a conservative approach is needed.