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1.  Point-of-Care International Normalized Ratio (INR) Monitoring Devices for Patients on Long-term Oral Anticoagulation Therapy 
Executive Summary
Subject of the Evidence-Based Analysis
The purpose of this evidence based analysis report is to examine the safety and effectiveness of point-of-care (POC) international normalized ratio (INR) monitoring devices for patients on long-term oral anticoagulation therapy (OAT).
Clinical Need: Target Population and Condition
Long-term OAT is typically required by patients with mechanical heart valves, chronic atrial fibrillation, venous thromboembolism, myocardial infarction, stroke, and/or peripheral arterial occlusion. It is estimated that approximately 1% of the population receives anticoagulation treatment and, by applying this value to Ontario, there are an estimated 132,000 patients on OAT in the province, a figure that is expected to increase with the aging population.
Patients on OAT are regularly monitored and their medications adjusted to ensure that their INR scores remain in the therapeutic range. This can be challenging due to the narrow therapeutic window of warfarin and variation in individual responses. Optimal INR scores depend on the underlying indication for treatment and patient level characteristics, but for most patients the therapeutic range is an INR score of between 2.0 and 3.0.
The current standard of care in Ontario for patients on long-term OAT is laboratory-based INR determination with management carried out by primary care physicians or anticoagulation clinics (ACCs). Patients also regularly visit a hospital or community-based facility to provide a venous blood samples (venipuncture) that are then sent to a laboratory for INR analysis.
Experts, however, have commented that there may be under-utilization of OAT due to patient factors, physician factors, or regional practice variations and that sub-optimal patient management may also occur. There is currently no population-based Ontario data to permit the assessment of patient care, but recent systematic reviews have estimated that less that 50% of patients receive OAT on a routine basis and that patients are in the therapeutic range only 64% of the time.
Overview of POC INR Devices
POC INR devices offer an alternative to laboratory-based testing and venipuncture, enabling INR determination from a fingerstick sample of whole blood. Independent evaluations have shown POC devices to have an acceptable level of precision. They permit INR results to be determined immediately, allowing for more rapid medication adjustments.
POC devices can be used in a variety of settings including physician offices, ACCs, long-term care facilities, pharmacies, or by the patients themselves through self-testing (PST) or self-management (PSM) techniques. With PST, patients measure their INR values and then contact their physician for instructions on dose adjustment, whereas with PSM, patients adjust the medication themselves based on pre-set algorithms. These models are not suitable for all patients and require the identification and education of suitable candidates.
Potential advantages of POC devices include improved convenience to patients, better treatment compliance and satisfaction, more frequent monitoring and fewer thromboembolic and hemorrhagic complications. Potential disadvantages of the device include the tendency to underestimate high INR values and overestimate low INR values, low thromboplastin sensitivity, inability to calculate a mean normal PT, and errors in INR determination in patients with antiphospholipid antibodies with certain instruments. Although treatment satisfaction and quality of life (QoL) may improve with POC INR monitoring, some patients may experience increased anxiety or preoccupation with their disease with these strategies.
Evidence-Based Analysis Methods
Research Questions
1. Effectiveness
Does POC INR monitoring improve clinical outcomes in various settings compared to standard laboratory-based testing?
Does POC INR monitoring impact patient satisfaction, QoL, compliance, acceptability, convenience compared to standard laboratory-based INR determination?
Settings include primary care settings with use of POC INR devices by general practitioners or nurses, ACCs, pharmacies, long-term care homes, and use by the patient either for PST or PSM.
2. Cost-effectiveness
What is the cost-effectiveness of POC INR monitoring devices in various settings compared to standard laboratory-based INR determination?
Inclusion Criteria
English-language RCTs, systematic reviews, and meta-analyses
Publication dates: 1996 to November 25, 2008
Population: patients on OAT
Intervention: anticoagulation monitoring by POC INR device in any setting including anticoagulation clinic, primary care (general practitioner or nurse), pharmacy, long-term care facility, PST, PSM or any other POC INR strategy
Minimum sample size: 50 patients Minimum follow-up period: 3 months
Comparator: usual care defined as venipuncture blood draw for an INR laboratory test and management provided by an ACC or individual practitioner
Outcomes: Hemorrhagic events, thromboembolic events, all-cause mortality, anticoagulation control as assessed by proportion of time or values in the therapeutic range, patient reported outcomes including satisfaction, QoL, compliance, acceptability, convenience
Exclusion criteria
Non-RCTs, before-after studies, quasi-experimental studies, observational studies, case reports, case series, editorials, letters, non-systematic reviews, conference proceedings, abstracts, non-English articles, duplicate publications
Studies where POC INR devices were compared to laboratory testing to assess test accuracy
Studies where the POC INR results were not used to guide patient management
Method of Review
A search of electronic databases (OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database) was undertaken to identify evidence published from January 1, 1998 to November 25, 2008. Studies meeting the inclusion criteria were selected from the search results. Reference lists of selected articles were also checked for relevant studies.
Summary of Findings
Five existing reviews and 22 articles describing 17 unique RCTs met the inclusion criteria. Three RCTs examined POC INR monitoring devices with PST strategies, 11 RCTs examined PSM strategies, one RCT included both PST and PSM strategies and two RCTs examined the use of POC INR monitoring devices by health care professionals.
Anticoagulation Control
Anticoagulation control is measured by the percentage of time INR is within the therapeutic range or by the percentage of INR values in the therapeutic range. Due to the differing methodologies and reporting structures used, it was deemed inappropriate to combine the data and estimate whether the difference between groups would be significant. Instead, the results of individual studies were weighted by the number of person-years of observation and then pooled to calculate a summary measure.
Across most studies, patients in the intervention groups tended to have a higher percentage of time and values in the therapeutic target range in comparison to control patients. When the percentage of time in the therapeutic range was pooled across studies and weighted by the number of person-years of observation, the difference between the intervention and control groups was 4.2% for PSM, 7.2% for PST and 6.1% for POC use by health care practitioners. Overall, intervention patients were in the target range 69% of the time and control patients were in the therapeutic target range 64% of the time leading to an overall difference between groups of roughly 5%.
Major Complications and Deaths
There was no statistically significant difference in the number of major hemorrhagic events between patients managed with POC INR monitoring devices and patients managed with standard laboratory testing (OR =0.74; 95% CI: 0.52- 1.04). This difference was non-significant for all POC strategies (PSM, PST, health care practitioner).
Patients managed with POC INR monitoring devices had significantly fewer thromboembolic events than usual care patients (OR =0.52; 95% CI: 0.37 - 0.74). When divided by POC strategy, PSM resulted in significantly fewer thromboembolic events than usual care (OR =0.46.; 95% CI: 0.29 - 0.72). The observed difference in thromboembolic events for PSM remained significant when the analysis was limited to major thromboembolic events (OR =0.40; 95% CI: 0.17 - 0.93), but was non-significant when the analysis was limited to minor thromboembolic events (OR =0.73; 95% CI: 0.08 - 7.01). PST and GP/Nurse strategies did not result in significant differences in thromboembolic events, however there were only a limited number of studies examining these interventions.
No statistically significant difference was observed in the number of deaths between POC intervention and usual care control groups (OR =0.67; 95% CI: 0.41 - 1.10). This difference was non-significant for all POC strategies. Only one study reported on survival with 10-year survival rate of 76.1% in the usual care control group compared to 84.5% in the PSM group (P=0.05).
Summary Results of Meta-Analyses of Major Complications and Deaths in POC INR Monitoring Studies
Patient Satisfaction and Quality of Life
Quality of life measures were reported in eight studies comparing POC INR monitoring to standard laboratory testing using a variety of measurement tools. It was thus not possible to calculate a quantitative summary measure. The majority of studies reported favourable impacts of POC INR monitoring on QoL and found better treatment satisfaction with POC monitoring. Results from a pre-analysis patient and caregiver focus group conducted in Ontario also indicated improved patient QoL with POC monitoring.
Quality of the Evidence
Studies varied with regard to patient eligibility, baseline patient characteristics, follow-up duration, and withdrawal rates. Differential drop-out rates were observed such that the POC intervention groups tended to have a larger number of patients who withdrew. There was a lack of consistency in the definitions and reporting for OAT control and definitions of adverse events. In most studies, the intervention group received more education on the use of warfarin and performed more frequent INR testing, which may have overestimated the effect of the POC intervention. Patient selection and eligibility criteria were not always fully described and it is likely that the majority of the PST/PSM trials included a highly motivated patient population. Lastly, a large number of trials were also sponsored by industry.
Despite the observed heterogeneity among studies, there was a general consensus in findings that POC INR monitoring devices have beneficial impacts on the risk of thromboembolic events, anticoagulation control and patient satisfaction and QoL (ES Table 2).
GRADE Quality of the Evidence on POC INR Monitoring Studies
CI refers to confidence interval; Interv, intervention; OR, odds ratio; RCT, randomized controlled trial.
Economic Analysis
Using a 5-year Markov model, the health and economic outcomes associated with four different anticoagulation management approaches were evaluated:
Standard care: consisting of a laboratory test with a venipuncture blood draw for an INR;
Healthcare staff testing: consisting of a test with a POC INR device in a medical clinic comprised of healthcare staff such as pharmacists, nurses, and physicians following protocol to manage OAT;
PST: patient self-testing using a POC INR device and phoning in results to an ACC or family physician; and
PSM: patient self-managing using a POC INR device and self-adjustment of OAT according to a standardized protocol. Patients may also phone in to a medical office for guidance.
The primary analytic perspective was that of the MOHLTC. Only direct medical costs were considered and the time horizon of the model was five years - the serviceable life of a POC device.
From the results of the economic analysis, it was found that POC strategies are cost-effective compared to traditional INR laboratory testing. In particular, the healthcare staff testing strategy can derive potential cost savings from the use of one device for multiple patients. The PSM strategy, however, seems to be the most cost-effective method i.e. patients are more inclined to adjust their INRs more readily (as opposed to allowing INRs to fall out of range).
Considerations for Ontario Health System
Although the use of POC devices continues to diffuse throughout Ontario, not all OAT patients are suitable or have the ability to practice PST/PSM. The use of POC is currently concentrated at the institutional setting, including hospitals, ACCs, long-term care facilities, physician offices and pharmacies, and is much less commonly used at the patient level. It is, however, estimated that 24% of OAT patients (representing approximately 32,000 patients in Ontario), would be suitable candidates for PST/PSM strategies and willing to use a POC device.
There are several barriers to the use and implementation of POC INR monitoring devices, including factors such as lack of physician familiarity with the devices, resistance to changing established laboratory-based methods, lack of an approach for identifying suitable patients and inadequate resources for effective patient education and training. Issues of cost and insufficient reimbursement strategies may also hinder implementation and effective quality assurance programs would need to be developed to ensure that INR measurements are accurate and precise.
For a select group of patients who are highly motivated and trained, PSM resulted in significantly fewer thromboembolic events compared to conventional laboratory-based INR testing. No significant differences were observed for major hemorrhages or all-cause mortality. PST and GP/Nurse use of POC strategies are just as effective as conventional laboratory-based INR testing for thromboembolic events, major hemorrhages, and all-cause mortality. POC strategies may also result in better OAT control as measured by the proportion of time INR is in the therapeutic range and there appears to be beneficial impacts on patient satisfaction and QoL. The use of POC devices should factor in patient suitability, patient education and training, health system constraints, and affordability.
anticoagulants, International Normalized Ratio, point-of-care, self-monitoring, warfarin.
PMCID: PMC3377545  PMID: 23074516
2.  Factors determining patients’ intentions to use point-of-care testing medical devices for self-monitoring: the case of international normalized ratio self-testing 
To identify factors that determine patients’ intentions to use point-of-care medical devices, ie, portable coagulometer devices for self-testing of the international normalized ratio (INR) required for ongoing monitoring of blood-coagulation intensity among patients on long-term oral anticoagulation therapy with vitamin K antagonists, eg, warfarin.
A cross-sectional study that applied the technology-acceptance model through a self-completed questionnaire, which was administered to a convenience sample of 125 outpatients attending outpatient anticoagulation services at a district general hospital in London, UK. Data were analyzed using descriptive statistics, factor analyses, and structural equation modeling.
The participants were mainly male (64%) and aged ≥ 71 years (60%). All these patients were attending the hospital outpatient anticoagulation clinic for INR testing; only two patients were currently using INR self-testing, 84% of patients had no knowledge about INR self-testing using a portable coagulometer device, and 96% of patients were never offered the option of the INR self-testing. A significant structural equation model explaining 79% of the variance in patients’ intentions to use INR self-testing was observed. The significant predictors that directly affected patients’ intention to use INR self-testing were the perception of technology (β = 0.92, P < 0.001), trust in doctor (β = −0.24, P = 0.028), and affordability (β = 0.15, P = 0.016). In addition, the perception of technology was significantly affected by trust in doctor (β = 0.43, P = 0.002), age (β = −0.32, P < 0.001), and affordability (β = 0.23, P = 0.013); thereby, the intention to use INR self-testing was indirectly affected by trust in doctor (β = 0.40), age (β = −0.29), and affordability (β = 0.21) via the perception of technology.
Patients’ intentions to use portable coagulometers for INR self-testing are affected by patients’ perceptions about the INR testing device, the cost of device, trust in doctors/clinicians, and the age of the patient, which need to be considered prior to any intervention involving INR self-testing by patients. Manufacturers should focus on increasing the affordability of INR testing devices for patients’ self-testing and on the potential role of medical practitioners in supporting use of these medical devices as patients move from hospital to home testing.
PMCID: PMC3536357  PMID: 23300344
oral anticoagulation; INR self-testing; technology-acceptance model; trust in doctor; home testing; affordability; structural equation modeling
3.  Multivariate relationships between international normalized ratio and vitamin K-dependent coagulation-derived parameters in normal healthy donors and oral anticoagulant therapy patients 
Thrombosis Journal  2003;1:7.
Background and objectives
International Normalized Ratio (INR) is a world-wide routinely used factor in the monitoring of oral anticoagulation treatment (OAT). However, it was reported that other factors, e. g. factor II, may even better reflect therapeutic efficacy of OAT and, therefore, may be potentialy useful for OAT monitoring. The primary purpose of this study was to characterize the associations of INR with other vitamin K-dependent plasma proteins in a heterogenous group of individuals, including healthy donors, patients on OAT and patients not receiving OAT. The study aimed also at establishing the influence of co-morbid conditions (incl. accompanying diseases) and co-medications (incl. different intensity of OAT) on INR.
Design and Methods
Two hundred and three subjects were involved in the study. Of these, 35 were normal healthy donors (group I), 73 were patients on medication different than OAT (group II) and 95 were patients on stable oral anticoagulant (acenocoumarol) therapy lasting for at least half a year prior to the study. The values of INR and activated partial thromboplastin time (APTT) ratio, as well as activities of FII, FVII, FX, protein C, and concentration of prothrombin F1+2 fragments and fibrinogen were obtained for all subjects. In statistical evaluation, the uni- and multivariate analyses were employed and the regression equations describing the obtained associations were estimated.
Of the studied parameters, three (factors II, VII and X) appeared as very strong modulators of INR, protein C and prothrombin fragments F1+2 had moderate influence, whereas both APTT ratio and fibrinogen had no significant impact on INR variability. Due to collinearity and low tolerance of independent variables included in the multiple regression models, we routinely employed a ridge multiple regression model which compromises the minimal number of independent variables with the maximal overall determination coefficient. The best-fitted two-component model included FII and FVII activities and explained 90% of INR variability (compared to 93% in the 5-component model including all vitamin K-dependent proteins). Neither the presence of accompanying diseases nor the use of OAT nor any other medication (acetylsalicylic acid, statins, steroids, thyroxin) biased significantly these associations.
Among various vitamin K-dependent plasma proteins, the coagulation factors II, VII and X showed the most significant associations with INR. Of these variables, the two-component model, including factors II and VII, deserves special attention, as it largely explains the overall variability observed in INR estimates. The statistical power of this model is validated on virtue of the estimation that the revealed associations are rather universal and remain essentially unbiased by other compounding variables, including clinical status and medical treatment. Further, much broader population studies are needed to verify clinical usefulness of methods alternate or compounding to INR monitoring of OAT.
PMCID: PMC317378  PMID: 14969588
International Normalized Ratio (INR) of prothrombin time; clotting factors; protein C; prothrombin fragment F1+2; multivariate analysis
4.  Safety and effectiveness of point-of-care monitoring devices in patients on oral anticoagulant therapy: a meta-analysis 
Open Medicine  2007;1(3):e131-e146.
Point-of-care devices (POCDs) for monitoring long-term oral anticoagulation therapy (OAT) may be a useful alternative to laboratory-based international normalized ratio [INR] testing and clinical management.
To determine clinical outcomes of the use of POCDs for OAT management by performing a meta-analysis. Previous meta-analyses on POCDs have serious limitations.
Data sources
PubMed, the Cochrane Library, DIALOG, MEDLINE, EMBASE, BIOSIS Previews and PASCAL databases.
Study selection
Randomized controlled trials of patients on long-term OAT, comparing anticoagulation monitoring by POCD with laboratory INR testing and clinical management.
Data extraction
1) rates of major hemorrhage; 2) rates of major thromboembolic events; 3) percentage of time that the patient is maintained within the therapeutic range; 4) deaths. Outcomes were compared using a random-effects model. Summary measures of rates were determined. The quality of studies was assessed using the Jadad scale.
Data synthesis
Seventeen articles (16 studies) were included. Data analysis showed that POCD INR testing reduced the risk of major thromboembolic events (odds ratio [OR] = 0.51; 95% confidence interval [CI] 0.35–0.74), was associated with fewer deaths (OR = 0.58; 95% CI = 0.38–0.89), and resulted in better INR control compared with laboratory INR testing. No significant difference between the two management modalities with respect to odds ratios for major hemorrhage was found.
Quality scores varied from 1 to 3 (out of a maximum of 5). Only 3 studies defined how thromboembolic events would be diagnosed, casting doubt on the accuracy of the reporting of thromboembolic events. The studies suggest that only 24% of patients are good candidates for self-testing and self-management. Compared with patients managed with laboratory-based monitoring, POCD patients underwent INR testing at a much higher frequency and received much more intensive education on OAT management.
The use of POCDs is safe and may be more effective than laboratory-based monitoring. However, most patients are not good candidates for self-testing and self-management. Patient education and frequency of testing may be the most important factors in successful PODC management. Definitive conclusions about the clinical benefits provided by self-testing and self-management require more rigorously designed trials.
PMCID: PMC3113217  PMID: 21673942
5.  A sensitivity comparison of the Quick and Owren prothrombin time methods in oral anticoagulant therapy 
Hematology Reviews  2009;1(2):e15.
Prothrombin time (PT) is the leading test for monitoring oral anticoagulation therapy (OAT). According to the World Health Organization recommendation, International Normalized Ratio (INR) results obtained from the same patient samples with the major PT methods (Quick and Owren) should be the same when the therapeutic range is the same. In our study blood samples were obtained from 207 OAT patients. We analyzed the samples using two Quick and two Owren PT (combined thromboplastin) reagents for INR and assessed the sensitivity and true coagulation activity using a new-generation PT method. The INR values with the Quick PT and Owren PT methods were very similar around the normal range, while unacceptable differences were seen within the therapeutic range and at higher INR values. The Quick PT results as INR are clearly lower than those given by Owren PT and the difference increases toward higher INR. The new PT method functions well with both Owren PT reagents, and we can calculate the true active INR. The Quick PT methods show no sensitivity to coagulation inhibition measurement. The harmonization of the INR is an important goal for the safety of OAT patients. More accurate INR results reduce morbidity and mortality, and the therapeutic ranges should be similar worldwide. In this study we found unacceptable differences in INR results produced by the two PT methods. The new method showed a lack of sensitivity to Quick PT. For the global harmonization of OAT therapy and for INR accuracy only the more sensitive Owren PT method should be used.
PMCID: PMC3222250
International Normalized Ratio; oral anticoagulant therapy; prothrombin time; warfarin.
6.  Security and cost comparison of INR self-testing and conventional hospital INR testing in patients with mechanical heart valve replacement 
International normalized ratio (INR) self-testing can improve the management of anticoagulation therapy with warfarin for the patients following mechanical heart valve replacement. Several reviews and studies have demonstrated self-management as an option to improve patient’s outcome considerably after mechanical heart valve replacement. We sought to analyze the security, economy and discuss the prospect of self-testing of anticoagulation therapy in patients following mechanical heart valve replacement in China, and evaluate the accuracy and stability of CoaguChek XS portable INR-testing device.
This was a prospective self-controlled clinical study conducted with 526 patients receiving oral warfarin anticoagulation therapy after mechanical heart valve replacement in the period of Mar.1, 2012 – Nov.1, 2012 in Cardiovascular Surgery Department of West China Hospital of Sichuan University. The same patient performed INR testing with CoaguChek XS portable coagulometer (group1) and central lab (group 2) in parallel. The follow-up time was 6 months. Meanwhile, a questionnaire was handed out to survey the expenses required for the re-examination visits to the hospital, time, and anticoagulation complications.
No severe anticoagulation complications occurred in all the patients. No significant difference of the INR results were observed between group 1 and group 2, they showed significant relevance, r = 0.953(p < 0.05). Compared with the conventional method of INR testing in hospital, the portable coagulometer is convenient, quick and less traumatic. Self-testing of anticoagulation therapy reduced the cost and the time required for re-examination.
Results of CoaguChek XS monitor are precise and have a good consistency and stability as compared with traditional laboratory testing. For the patients receiving anticoagulation therapy after mechanical heart valve replacement, the self-testing of anticoagulation therapy with portable coagulometer is a safe choice, and it has a promising future application in China.
PMCID: PMC4308889  PMID: 25592732
Heart valve replacement; Anticoagulation therapy; Portable coagulometer; Self-testing; Cost
7.  A New Generation Prothrombin Time Method for INR 
Prothrombin time (PT) is the leading test for monitoring oral anticoagulation therapy (OAT). We sought to determine INR taking into account only active coagulation factors FII, FVII and FX without inhibition in patient plasmas and calibrator kits.
We measured PT using a combined thromboplastin reagent. The calculation was based on a new PT method, which measures active coagulation factors (F II, F VII, FX) and corrects the errors caused by inactive coagulation factors.
On this basis, an INR result with and without inhibition for individual patient samples was also calculated and applied to 200 plasma samples obtained from OAT patients. Conspicuous variation in inhibition between the four calibration kits was noted. The kinetics of this inhibition was closest to a noncompetitive pattern.
The need of correction for INRs of single patients increases with higher INRs. At the same level of patient INRs the coagulation inhibiton varies markedly.
It has been known that different thromboplastin reagents possess variable sensitivities, but this may depend on sensitivity in inactive coagulation factors. PT methods today measure the sum of active coagulation factors and inhibition of inactive coagulation factors. ISI calibrators contain variable amounts of inactive coagulation factors, which renders harmonisation of INR results.
Application of the Acf-PT (INRAcf) presented in this work develops the PT methodology to measure the true coagulation activity in vivo for patient warfarin therapy without inhibition. INRInh can evidently also be used for the diagnostics and follow-up of certain liver diseases.
PMCID: PMC2709469  PMID: 19662139
PT; prothrombin time; oral anticoagulant therapy; Pivka.
8.  The Clinical Impact of Different Coagulometers on Patient Outcomes 
Advances in Therapy  2014;31(6):639-656.
Long-term anticoagulation therapy using vitamin K antagonists (VKA) is used in millions of patients worldwide to reduce the risk of thrombotic or thromboembolic events. Control and monitoring of VKA therapy is improved by the regular self-measurement of international normalized ratio (INR) using a home monitoring device. This retrospective analysis of a large cohort of patients in the Netherlands seeks to determine whether the choice of INR monitor could have a clinical impact on patient outcomes.
The National Thrombosis Service provides medical supervision, training and support to anticoagulant patients eligible for home-monitoring of INR in the Netherlands. Two INR monitors (CoaguChek XS and INRatio2) have been distributed at random to patients since June 2011, and patient self-testing data (INR measurements and other clinical parameters) have been recorded to measure and improve treatment outcomes. The data have been retrospectively analyzed to determine any effect of the choice of monitor. Univariate and multivariate statistical tests are used to assess any differences between groups in terms of efficacy and safety parameters.
Data from 4,326 patients were collated, and 156,507 INR values were included in the analysis. Over half the patients (54.3%) were being treated for atrial fibrillation, and 77.6% were prescribed acenocoumarol. There were few differences between the patient populations using the two different monitors. Anticoagulant control overall was good, with high percentage of time (87.9%) in the appropriate INR range and low incidence of excessively high or low INR values (0.085/month). Minor clinical events related to safety were low (0.78 per patient-year) and showed few differences between monitors. Mortality rates were similar [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.65–1.70].
Self-testing data from a large cohort of patients in the Netherlands suggest that there is no clinically relevant effect of the choice of coagulation monitor (CoaguChek XS or INRatio2) on the time in therapeutic range (TTR), minor or fatal outcomes of long-term anticoagulation management.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0124-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4082646  PMID: 24895179
Anticoagulation; CoaguChek XS; INRatio2; International normalized ratio (INR); Patient self-monitoring (PSM); Patient self-testing (PST); Point of care (POC) test (POCT); Time in therapeutic range (TTR); Time in target range; Vitamin K antagonist (VKA)
9.  A randomised controlled trial of patient self management of oral anticoagulation treatment compared with primary care management 
Journal of Clinical Pathology  2002;55(11):845-849.
Background: The increase in numbers of patients receiving warfarin treatment has led to the development of alternative models of service delivery for oral anticoagulant monitoring. Patient self management for oral anticoagulation is a model new to the UK. This randomised trial was the first to compare routine primary care management of oral anticoagulation with patient self management.
Aim: To test whether patient self management is as safe, in terms of clinical effectiveness, as primary care management within the UK, as assessed by therapeutic international normalised ratio (INR) control.
Method: Patients receiving warfarin from six general practices who satisfied study entry criteria were eligible to enter the study. Eligible patients were randomised to either intervention (patient self management) or control (routine primary care management) for six months. The intervention comprised two training sessions of one to two hours duration. Patients were allowed to undertake patient self management on successful completion of training. INR testing was undertaken using a Coaguchek device and regular internal/external quality control tests were performed. Patients were advised to perform INR tests every two weeks, or weekly if a dose adjustment was made. Dosage adjustment was undertaken using a simple dosing algorithm.
Results: Seventy eight of 206 (38%) patients were eligible for inclusion and, of these, 35 (45%) declined involvement or withdrew from the study. Altogether, 23 intervention and 26 control patients entered the study. There were no significant differences in INR control (per cent time in range: intervention, 74%; control, 77%). There were no serious adverse events in the intervention group, with one fatal retroperitoneal haemorrhage in the control group. Costs of patient self management were significantly greater than for routine care (£90 v £425/patient/year).
Conclusion: These are the first UK data to demonstrate that patient self management is as safe as primary care management for a selected population. Further studies are needed to elucidate whether this model of care is suitable for a larger population.
PMCID: PMC1769803  PMID: 12401823
oral anticoagulation; patient self management; primary care
10.  Potentially avoidable inpatient nights among warfarin receiving patients; an audit of a single university teaching hospital 
BMC Research Notes  2009;2:41.
Warfarin is an oral anticoagulant (OAT) that needs active management to ensure therapeutic range. Initial management is often carried out as an inpatient, though not requiring inpatient facilities. This mismatch results in financial costs which could be directed more efficaciously. The extent of this has previously been unknown. Here we aim to calculate the potential number of bed nights which may be saved among those being dose optimized as inpatients and examine associated factors.
A 6 week prospective audit of inpatients receiving OAT, at Cork University Hospital, was carried out. The study period was from 11th June 2007 to 20th July 2007. Data was collected from patient's medications prescription charts, medical record files, and computerised haematology laboratory records. The indications for OAT, the patient laboratory coagulation results and therapeutic intervals along with patient demographics were analysed. The level of potentially avoidable inpatient nights in those receiving OAT in hospital was calculated and the potential cost savings quantified. Potential avoidable bed nights were defined as patients remaining in hospital for the purpose of optimizing OAT dosage, while receiving subtherapeutic or therapeutic OAT (being titred up to therapeutic levels) and co-administered covering low molecular weight heparin, and requiring no other active care. The average cost of €638 was taken as the per night hospital stay cost for a non-Intensive Care bed. Ethical approval was granted from the Ethical Committee of the Cork Teaching Hospitals, Cork, Ireland.
A total of 158 patients were included in the audit. There was 94 men (59.4%) and 64 women (40.6%). The mean age was 67.8 years, with a median age of 70 years.
Atrial Fibrillation (43%, n = 70), followed by aortic valve replacement (15%, n = 23) and pulmonary emboli (11%, n = 18) were the commonest reasons for prescribing OAT. 54% had previously been prescribed OAT prior to current admission.
It was confirmed that, there are potentially avoidable nights in patients receiving OAT. The majority of this group were those being commenced on OAT for the first time (p = 0.00002), in the specialities of Cardiology, Cardiothoracic surgery and Care of the Elderly. The potential number of bed nights to be saved is 13 per week for the hospital or 1.1 bed nights per 10,000 general hospital admissions. These were predominantly weekday nights. The estimated cost of avoidable inpatient OAT dose optimization was approximately €8300 per week.
With rising costs and the increasing demands for acute hospital beds, alterations to inpatient management for this group of patients should be considered. Alternatives include increasing the size of current anticoagulation clinics, introduction of POCT (point of care testing) devices and increased GP management. POCT can be justified based upon the publication by Gardiner et al, who showed that 87% of patients find self testing straightforward, 87% were confident in the result they obtained using the devices and 77% preferred self testing.
PMCID: PMC2657894  PMID: 19284662
11.  Is the international normalised ratio (INR) reliable? A trial of comparative measurements in hospital laboratory and primary care settings. 
Journal of Clinical Pathology  1999;52(7):494-497.
AIM: To determine the reliability of international normalised ratio (INR) measurement in primary care by practice nurses using near patient testing (NPT), in comparison with results obtained within hospital laboratories by varied methods. METHODS: As part of an MRC funded study into primary care oral anticoagulation management, INR measurements obtained in general practice were validated against values on the same samples obtained in hospital laboratories. A prospective comparative trial was undertaken between three hospital laboratories and nine general practices. All patients attending general practice based anticoagulant clinics had parallel INR estimations performed in general practice and in a hospital laboratory. RESULTS: 405 tests were performed. Comparison between results obtained in the practices and those in the reference hospital laboratory (gold standard), which used the same method of testing for INR, showed a correlation coefficient of 0.96. Correlation coefficients comparing the results with the various standard laboratory techniques ranged from 0.86 to 0.92. It was estimated that up to 53% of tests would have resulted in clinically significant differences (change in warfarin dose) depending upon the site and method of testing. The practice derived results showed a positive bias ranging from 0.28 to 1.55, depending upon the site and method of testing. CONCLUSIONS: No technical problems associated with INR testing within primary care were uncovered. Discrepant INR results are as problematic in hospital settings as they are in primary care. These data highlight the failings of the INR to standardise when different techniques and reagents are used, an issue which needs to be resolved. For primary care to become more involved in therapeutic oral anticoagulation monitoring, close links are needed between hospital laboratories and practices, particularly with regard to training and quality assurance.
PMCID: PMC501488  PMID: 10605400
12.  Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience 
Blood Transfusion  2012;10(1):87-94.
Prothrombin Complex Concentrates (PCC) are administered to normalise blood coagulation in patients receiving oral anticoagulant therapy (OAT). Rapid reversal of OAT is essential in case of major bleeding, internal haemorrhage or surgery.
The primary end-point was to evaluate whether PCC in our hospital were being used in compliance with international and national guidelines for the reversal of OAT on an emergency basis. The secondary end-point was to evaluate the efficacy and safety of PCC.
Materials and methods
All patients receiving OAT who required rapid reversal anticoagulation because they had to undergo emergency surgery or urgent invasive techniques following an overdose of oral anticoagulants were eligible for this retrospective observational study.
Forty-seven patients receiving OAT who needed rapid reverse of anticoagulation were enrolled in our study. The patients were divided in two groups: (i) group A (n=23), patients needed haemostatic treatment before neurosurgery after a head injury and (ii) group B (n=24), patients with critical haemorrhage because of an overdose of oral anticoagulants. The International Normalised Ratio (INR) was checked before and after infusion of the PCC. The mean INR in group A was 2.7 before and 1.43 after infusion of the PCC; in group B the mean INR of 6.58, before and 1.92 after drug infusion. The use of vitamin K, fresh-frozen plasma and red blood cells was also considered. During our study 22 patients died, but no adverse effects following PCC administration were recorded.
In our study three-factor-PCC was found to be effective and safe in rapidly reversing the effects of OAT, although it was not always administered in accordance with international or national guidelines. The dose, time of administration and monitoring often differed from those recommended. In the light of these findings, we advocate the use of single standard protocol to guide the correct use of PCC in each hospital ward.
PMCID: PMC3258994  PMID: 22044952
prothrombin complex concentrate; oral anticoagulant therapy; reversal of anticoagulation guidelines
13.  Supervised Patient Self-Testing of Warfarin Therapy Using an Online System 
Point-of-care international normalized ratio (INR) monitoring devices simplify warfarin management by allowing selected patients to monitor their own therapy in their homes. Patient self-testing (PST) has been shown to improve the clinical outcomes of warfarin therapy compared to usual care.
To compare management of warfarin therapy using PST combined with online supervision by physicians via a custom system with usual warfarin management, which involved laboratory testing and physician dosing.
Interested patients were recruited via community pharmacies to participate in a warfarin PST training program. Participants were required to have a long-term indication for warfarin, have been taking warfarin for at least 6 months, and have Internet access in their home. The training involved two sessions covering theoretical aspects of warfarin therapy, use of the CoaguChek XS, and the study website. Following training, patients monitored their INR once weekly for up to 3 months. Patients and physicians utilized a secure website to communicate INR values, dosage recommendations, and clinical incidents. Physicians provided a 6-12 month history of INR results for comparison with study results. The percentage of time spent within the therapeutic INR range (TTR) was the primary outcome, with participants acting as their own historical controls. The percentage of INR tests in range and participant satisfaction were secondary outcomes.
Sixteen patients completed training requirements. The mean age of participants was 69.8 (SD 10.1) years. TTR improved significantly from 66.4% to 78.4% during PST (P=.01), and the number of tests within the target range also improved significantly (from 66.0% at prior to the study to 75.9% during PST; P=.04). Patients and physicians expressed a high degree of satisfaction with the monitoring strategy and online system.
PST supported by an online system for supervision was associated with improved INR control compared to usual care in a small group of elderly patients. Further research is warranted to investigate the clinical outcomes and cost-effectiveness of online systems to support patients monitoring medications and chronic conditions in the home.
PMCID: PMC3713938  PMID: 23853350
warfarin; self-care; management; international normalized ratio; Internet; communication
14.  Differences in the INR evaluation of two different thromboplastins in patients with positivity to lupus anticoagulant in ongoing oral anticoagulation 
A possible interference between lupus anticoagulant (LAC), a well characterized clotting inhibitor, in the International Normalized Ratio (INR) determination during oral anticoagulation (OA) has been reported in the literature. Few data are available about the relationship between this kind of interference and the daily clinical management of oral anticoagulation. The aim of the study is to evaluate the role of two different thromboplastins–RecombiPlasTin 2G and HepatoComplex–in the determination of INR values of several patients’ ongoing OA for a previous thrombotic disorder with and without positivity to LAC, and to evaluate possible interferences in the daily therapeutic approach.
Patients and methods:
We selected 16 patients (13 females and 3 males, mean age 59 ± 16 years) with LAC positivity ongoing OA and 11 control subjects (7 females and 4 males, mean age 58 ± 14.5 years) with similar characteristics (ie, ethnic background and weight) with LAC negativity ongoing OA. 165 assays for INR determination were analyzed from both groups. Statistical analysis was performed using STATA 10 software. P values were considered significant if <0.05.
Mean values of INR for patients with LAC positivity were 3.79 ± 1.63 when tested with RecombiPlasTin 2G vs 3.18 ± 1.15 when tested with HepatoComplex (P < 0.001, s); while mean values of INR for patients with antiphospholipid syndrome (APS) with LAC negativity were 3.54 ± 1.39 when tested with RecombiPlasTin 2G vs 3.23 ± 1.14 when tested with HepatoComplex (P < 0.002, s). An INR value > than 4.5 was found in 31/165 samples in 9 subjects, 8 patients with LAC positivity, and 1 control group subject with LAC negativity. There was a great difference in INR values in these subjects if we use the common thromboplastin (ie, RecombiPlasTin 2G) with a INR range varying from 5.14 ± 0.35 vs 3.79 ± 0.38 if we use another thromboplastin (ie, HepatoComplex) (P < 0.001, s). A change in the therapeutic approach for OA is possible in these cases because different INR values were obtained using different thromboplastins.
Our data confirm that INR evaluation does not reveal significant changes also if tested with two different thromboplastins, for patients ongoing OA with and without LAC positivity, when the INR value is < than 4. Over this INR value there is a significant difference in patients with LAC positivity if we use a different thromboplastin for the INR determination. For this reason values obtained by RecombiPlasTin 2G need to be confirmed and matched with another thromboplastin (ie, HepatoComplex). This approach may be useful in order to have a good INR testing for the chronic long-term treatment with OA in particular in patients with LAC positivity.
PMCID: PMC3262322  PMID: 22282684
lupus anticoagulant; oral anticoagulation; INR; thromboplastin; prothrombin time; thrombosis; long-term treatment
15.  Self-monitoring of oral anticoagulation: does it work outside trial conditions? 
Journal of Clinical Pathology  2009;62(2):168-171.
Patient self-monitoring (PSM) of oral anticoagulation therapy (OAT) can improve anticoagulant control, but poor uptake and high dropout rates have prompted suggestions that PSM is suitable for only a minority of patients in the UK.
To determine whether PSM could be a viable alternative to regular hospital anticoagulant clinic attendance, if offered from the start of treatment.
318 consecutive patients referred, for the first time, to an anticoagulation clinic were assessed for eligibility using established criteria. Patients electing for PSM attended training and, following successful assessment, performed a capillary blood INR every two weeks or more frequently if directed to do so by the anticoagulation clinic. Primary outcome measures were uptake of PSM and the percentage time in target therapeutic INR range (TIR) compared to patients electing for routine clinic care.
Of 318 patients referred for OAT, 188 were eligible for PSM. 84 (26%) elected to self-monitor, of whom 72 (23%) remained self-monitoring or had completed their course of treatment at the end of the audit. Self-monitoring patients had significantly better anticoagulant control than those receiving routine hospital anticoagulation clinic care (TIR 71% vs 60%, p = 0.003) and significantly less time outside critical limits, ie, INR <1.5 or >5.0 (0.45% vs 2.04%, p = 0.008).
Patients offered PSM from the start of treatment show increased uptake compared to previous UK studies and a level of oral anticoagulation control comparable to that reported in previous clinical trials.
PMCID: PMC2629005  PMID: 19181634
16.  Communicating the Experience of Chronic Pain and Illness Through Blogging 
Although more individuals are sharing their experiences with chronic pain or illness through blogging (writing an Internet web log), research on the psychosocial effects and motivating factors for initiating and maintaining a blog is lacking.
The objective was to examine via online questionnaire the perceived psychosocial and health benefits of blogging among patients who use this media to communicate their experience of chronic pain or illness.
A 34-item online questionnaire was created, tested, and promoted through online health/disease forums. The survey employed convenience sampling and was open from May 5 to July 2, 2011. Respondents provided information regarding demographics, health condition, initiation and upkeep of blogs, and dynamics of online communication. Qualitative data regarding respondents’ blogging experiences, expectations for blogging, and the perceived effects from blogging on the blogger’s health, interpersonal relationships, and quality of life were collected in the form of written narrative.
Out of 372 respondents who started the survey, 230 completed the entire questionnaire. Demographic data showed survey respondents to be predominantly female (81.8%) and highly educated (97.2% > high school education and 39.6% with graduate school or professional degrees). A wide spectrum of chronic pain and illness diagnoses and comorbidities were represented. Respondents reported that initiating and maintaining an illness blog resulted in increased connection with others, decreased isolation, and provided an opportunity to tell their illness story. Blogging promoted accountability (to self and others) and created opportunities for making meaning and gaining insights from the experience of illness, which nurtured a sense of purpose and furthered their understanding of their illness.
Results suggest that blogging about chronic pain and illness may decrease a sense of isolation through the establishment of online connections with others and increases a sense of purpose to help others in similar situations. Further study involving a larger sample size, a wider range of education levels, and respondents with different types and magnitudes of illnesses will be needed to better elucidate the mechanism of the observed associations in this understudied area.
PMCID: PMC3510726  PMID: 23092747
Blogging; narrative medicine; disease management; Internet; pain; chronic illness; survey; psychosocial support systems; holistic health; selfcare
17.  Personalized versus non-personalized computerized decision support system to increase therapeutic quality control of oral anticoagulant therapy: an alternating time series analysis 
The quality control of oral anticoagulant therapy (OAT) during the initiation and maintenance treatment is generally poor. Physicians' ordering of OAT (especially fluindione and warfarin) can be improved by dose adjustment algorithms, taking into account the results of International Normalized Ratio (INR). Reminders at the point of care, computerized or not, have been demonstrated to be effective in changing physicians prescription behavior.
However, few studies have addressed the benefit of personalized reminders versus non personalized reminders, whereas the personalized reminders require more development to access patient record data and integrate with the computerized physician order entry system.
The Hospital Information System of George Pompidou European Hospital integrates an electronic medical record, lab test and drugs order entry system. This system allows to evaluate such reminders and to consider their implementation for routine use as well as the continuous evaluation of their impact on medical practice quality indicators.
The objective of this study is to evaluate the impact of two types of reminders on overtreatment by oral anticoagulant: a simple reminder of text formatted dose adjustment table and a personalized recommendation for oral anticoagulant dose and next date of INR control, adapted to patient data. Both types of reminders appear to the physician at the moment of drug ordering.
The study is an alternating time series experiment with three 6 months periods, each one including every 2 months according to a Latin square scheme: a control period without any reminder, a period with the simple non personalized reminder, a period with personalized reminder. All patients hospitalized in departments using the computerized physician order entry system and ordered fluindione or warfarin, will be included in the study between November 2004 and May 2006.
Main outcome will be the proportion of overcoagulation, as expressed by the proportion of observation time with INR over 4.5, assuming INR change linearly. Secondary outcome is the incidence of major haemorrhagic events. Data will be collected thanks to Hospital Information Systems databases.
Data will be analyzed taking into account patient and physician clustering effect.
PMCID: PMC526261  PMID: 15456515
18.  Correlation between International Normalized Ratio values and sufficiency of two different local hemostatic measures in anticoagulated patients 
European Journal of Dentistry  2014;8(4):475-480.
The management of patients receiving oral anticoagulant therapy (OAT) undergoing minor oral surgeries is controversial. This study was designed to evaluate the correlation between International Normalized Ratio (INR) values and the sufficiency of two different local hemostatic measures in controlling postextraction bleeding in anticoagulated patients.
Materials and Methods:
One hundred and sixty patients receiving Warfarin OAT were included in this study. Patients were selected so that 80 patients have INR values of ≤2, whereas the remaining patients have the INR values ranging from 2 to 3. Forty patients were then randomly selected from each category to form two equal groups. Forty-five patients who had never been on OAT were selected as a negative control group (group 1). Failure to achieve hemostasis using a pressure pack was managed using either tranexamic acid (group 2) or Ankaferd Blood Stopper (ABS) (group 3).
The INR values of patients included in group 2 and 3 ranged from 1.5 to 3, with a mean of 2.2. No significant difference was recorded between the use of either tranexamic acid or ABS in achieving hemostasis in anticoagulated patients with INR values ranging between 2 and 3 (P = 0.93).
Based on our findings, ABS is a hemostatic agent of good efficacy. The effect of ABS in controlling post-extraction bleeding in anticoagulated patients with INR values ≤3 is comparable to tranexamic acid with no evidence to support the superiority of tranexamic acid over ABS.
PMCID: PMC4253102  PMID: 25512727
Gel foam; postextraction bleeding; tranexamic acid; warfarin; ankaferd
19.  Oral anticoagulation and self-management: analysis of the factors that determine the feasibility of using self-testing and self-management in primary care 
The skills of patients on oral anticoagulants are critical for achieving good outcomes with this treatment. Self-management, or the capacity of patients to control their INR level and adjust their treatment, is an effective strategy of treatment. Capacity of patients to self manage is determined by a range of factors. The identification of these factors would improve the design of self management programmes and in turn increase the number of patients able to self-manage. The objective of our study is to identify those factors that determine the ability of patients on oral anticoagulant therapy to achieve self-management of their treatment.
This will be a three year quasi- experimental prospective study with a control group. 333 patients on anticoagulant therapy from five health centres of the Basque Health Service are to be followed up for a period of six months each after the intervention, to assess their ability to self-test and self-manage. The intervention will consist of a patient training programme involving the provision of information and practical training concerning their condition and its treatment, as well as how to use a portable blood coagulation monitoring device and adjust their anticoagulant dose.
The ease-of-use of this technique lead us to believe that self-management is feasible and will represent an innovative advance that should have a substantial impact on the quality of life of this patients and their families as well as on the health care provision systems.
Trial registration
Osakidetza Protocol Record ISCIII-11/02285, Oral anticoagulation and self-management, Identifier: NCT01878539
PMCID: PMC3765739  PMID: 23968316
Oral anticoagulants; Self-management; Determinants
20.  Canalization effect in the coagulation cascade and the interindividual variability of oral anticoagulant response. a simulation Study 
Increasing the predictability and reducing the rate of side effects of oral anticoagulant treatment (OAT) requires further clarification of the cause of about 50% of the interindividual variability of OAT response that is currently unaccounted for. We explore numerically the hypothesis that the effect of the interindividual expression variability of coagulation proteins, which does not usually result in a variability of the coagulation times in untreated subjects, is unmasked by OAT.
We developed a stochastic variant of the Hockin-Mann model of the tissue factor coagulation pathway, using literature data for the variability of coagulation protein levels in the blood of normal subjects. We simulated in vitro coagulation and estimated the Prothrombin Time and the INR across a model population. In a model of untreated subjects a "canalization effect" can be observed in that a coefficient of variation of up to 33% of each protein level results in a simulated INR of 1 with a clinically irrelevant dispersion of 0.12. When the mean and the standard deviation of vitamin-K dependent protein levels were reduced by 80%, corresponding to the usual Warfarin treatment intensity, the simulated INR was 2.98 ± 0.48, a clinically relevant dispersion, corresponding to a reduction of the canalization effect.
Then we combined the Hockin-Mann stochastic model with our previously published model of population response to Warfarin, that takes into account the genetical and the phenotypical variability of Warfarin pharmacokinetics and pharmacodynamics. We used the combined model to evaluate the coagulation protein variability effect on the variability of the Warfarin dose required to reach an INR target of 2.5. The dose variance when removing the coagulation protein variability was 30% lower. The dose was mostly related to the pretreatment levels of factors VII, X, and the tissue factor pathway inhibitor (TFPI).
It may be worth exploring in experimental studies whether the pretreatment levels of coagulation proteins, in particular VII, X and TFPI, are predictors of the individual warfarin dose, even though, maybe due to a canalization-type effect, their effect on the INR variance in untreated subjects appears low.
PMCID: PMC3215663  PMID: 22082142
Interindividual variability; stochastic model; oral anticoagulant treatment; INR; coagulation cascade; canalization
21.  Increased international normalized ratio level in hepatocellular carcinoma patients with diabetes mellitus 
AIM: To determine the association of diabetes mellitus (DM) and international normalized ratio (INR) level in hepatocellular carcinoma (HCC) patients.
METHODS: Our present study included 375 HCC patients who were treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period from January 2003 to April 2012, and with a hospital discharge diagnosis of HCC. The demographic, clinical, laboratory, metabolic and instrumental features were analyzed. χ2 test, Student’s t test and Mann-Whitney U test were used to compare the differences between HCC patients with and without DM. Unconditional multivariable logistic regression analysis was used to determine the association of DM and INR level in HCC patients. A sub-group analysis was performed to assess the effect of liver cirrhosis or hepatitis B virus (HBV) infection on the results. The Pearson correlation test was used to determine the relationship between INR level and fasting glucose. In addition, association between diabetes duration, and diabetes treatment and INR level was determined considering the potentially different effects.
RESULTS: Of the total, 63 (16.8%) patients were diabetic (diabetic group) and 312 (83.2%) patients were diagnosed without diabetes (non-diabetic group). Their mean age was 56.4 ± 11.0 years and 312 (83.2%) patients were male. Compared with patients without DM, the HCC patients with diabetes were older (59.5 ± 10.3 vs 55.8 ± 11.1, P = 0.015), had a lower incidence of HBV infection (79.4% vs 89.1%, P = 0.033), had increased levels of systolic blood pressure (SBP) (133 ± 17 vs 129 ± 16 mmHg, P = 0.048) and INR (1.31 ± 0.44 vs 1.18 ± 0.21, P = 0.001), had lower values of hemoglobin (124.4 ± 23.9 vs 134.2 ± 23.4, P = 0.003) and had a platelet count (median/interquartile-range: 113/64-157 vs 139/89-192, P = 0.020). There was no statistically significant difference in the percentages of males, overweight or obesity, drinking, smoking, cirrhosis and Child classification. After controlling for the confounding effects of age, systolic blood pressure, hemoglobin, platelet count and HBV infection by logistic analyses, INR was shown as an independent variable [odds ratio (OR) = 3.650; 95%CI: 1.372-9.714, P = 0.010]. Considering the effect of liver cirrhosis on results, a sub-group analysis was performed and the study population was restricted to those patients with cirrhosis. Univariate analysis showed that diabetic patients had a higher INR than non-diabetic patients (1.43 ± 0.51 vs 1.25 ± 0.23, P = 0.041). After controlling for confounding effect of age, SBP, hemoglobin, platelet count and HBV infection by logistic analyses, INR level remained as the sole independent variable (OR = 5.161; 95%CI: 1.618-16.455, P = 0.006). No significant difference in the relationship between INR level and fasting glucose was shown by Pearson test (r = 0.070, P = 0.184). Among the 63 diabetic patients, 35 (55.6%) patients had been diagnosed with DM for more than 5 years, 23 (36.5%) received oral anti-diabetic regimens, 11 (17.5%) received insulin, and 30 (47.6%) reported relying on diet alone to control serum glucose levels. No significant differences were found for the association between DM duration/treatment and INR level, except for the age at diabetes diagnosis.
CONCLUSION: The INR level was increased in HCC patients with DM and these patients should be monitored for the coagulation function in clinical practice.
PMCID: PMC3631993  PMID: 23613635
International normalized ratio; Coagulation function; Diabetes mellitus; Hepatocellular carcinoma; Chinese patients
22.  Oral anticoagulation in elderly patients as secondary prevention of cardioembolic strokes 
Stroke incidence increases with age. Atrial fibrillation (AF) is an important risk factor for ischemic stroke and its incidence also increases with age. However oral anticoagulant therapy (OAT) tends to be underused in the elderly population.
Elderly patients (> = 80 years) with an ischemic stroke admitted in our department between 1/7/2003 and 31/6/2005 were prospectively evaluated. Baseline characteristics, risk factors, treatment and etiology according to TOAST criteria were recorded. Patients treated with OAT were followed up in order to assess any side effect and stroke recurrence. Mean follow-up was of 19.5 months (7-45) from discharge.
Sixty four out of a hundred and fifty nine elderly patients (40.25%) were classified as cardioembolic; mean age was 84.5 years (80-97) and 64.6% were women. AF had been previously identified in 60% of them (16.9% were on OAT and 40.6% on antiplatelet therapy). At discharge, 32 patients (49.2%) were on OAT. In the follow-up 4 patients (12.5%) suffered systemic haemorrhages (3 urinary, 1 gastrointestinal bleeding), with no change in their functional status. Mean INR in this group was 5.9 [3-11] and, in 3 of them, OAT was cancelled. No brain haemorrhages were recorded. Ischemic stroke recurred in 4 patients (INR < 1.8 in 3 of them; the other, INR 2.35). Three patients had died at the end of the follow-up, one of them as a consequence of ischemic stroke recurrence.
Twenty eight point eight of stroke patients admitted in the period of study were >80 years. The high proportion of cardioembolic strokes in this age segment contrasts with the general underuse of OAT as antithrombotic prophylaxis. Our study suggests that OAT is a safe strategy when carefully prescribed, even for elderly patients.
PMCID: PMC2890514  PMID: 20525389
23.  INR reduction after prothrombin complex concentrate (Co-fact©) administration: comparison of INR outcomes in different patient categories at the emergency department 
Co-fact©, prothrombin complex concentrate, is used for restoring the international normalized ratio (INR) in patients on vitamin K antagonists (VKA) presenting with acute bleeding. In this prospective cohort study, we evaluated whether adequate INR values were reached in ED patients using the Sanquin (Federation of Dutch Thrombosis Services) treatment protocol.
We evaluated this protocol for two target INR groups: group 1, target INR ≤ 1.5 (for life-threatening bleeding/immediate intervention); group 2, target INR 1.6-2.1 (in cases of a minor urgent surgery or serious overdosing of anticoagulant). We specifically wanted to identify both under- and over-treated patients. Reversing VKA anticoagulation therapy to unnecessarily low INR values may involve thrombotic risks. Apart from this risk, the patient is also administered an excess amount of the drug. This means unnecessary costs and may present problems with restoring an anticoagulated state at a later time.
In our cohort, the Sanquin dosing protocol was followed for 45/60 patients. It appeared that out of the 41 patients in group 1 (target INR ≤ 1.5), 35 (85%) achieved the goal INR. This occurred more often than for the 19 patients in group 2 (target INR 1.6–2.1), where only 6 (32%) achieved the goal INR. Using the protocol resulted in a positive trend toward better INR reversal in group 1.
In group 2, no relation between using the protocol and achieving the desired INR value was detected. Physicians ignoring the proposed dose of Co-fact© prescribed significantly less Co-fact© (even when correcting for patient weight). It appeared that patients in group 1 had a significantly lower baseline INR than patients in group 2. Group 2 patients, on the other hand, had a baseline INR > 7.5 in 53% of the cases.
In our cohort, for most patients in INR group 2 treated with Co-fact©, the achieved INR value was outside the desired range of 1.6-2.1. The supra-therapeutic range of baseline INR in group 2 may have contributed to the different kind of bleeding witnessed in this patient group.
Our results support the idea that treatment of patients on vitamin K antagonists with Co-fact© could benefit from a slightly different approach, taking into account the INR value to which the patient needs to be reversed.
PMCID: PMC3655866  PMID: 23663356
24.  Use of Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal before Surgical Treatment of Intracranial Hemorrhage 
Oral anticoagulant therapy (OAT) is used to prevent/treat thromboembolism. Major bleeding is common in patients on OAT; eg, warfarin increases intracranial hemorrhage (ICH) risk.
A 71-year-old male on warfarin (to reduce stroke risk) presented at Accident and Emergency Minor Injuries Unit with headache after reportedly sounding ‘drunk’. On triage, the patient appeared lucid and well. However, International Normalized Ratio (INR) was 4.1. Head computed tomography (CT) indicated a large right-sided subdural hematoma. Prothrombin complex concentrate (PCC; Beriplex® P/N, CSL Behring) with vitamin K normalized the INR within minutes of administration. The patient underwent neurosurgery without complications, and was discharged after 5 days, with no residual neurological symptoms.
ICH patients can present with no neurological signs. In OAT patients with headache, INR must be established; if ≥3.0, normalization of INR and head CT are essential. PCC is the best option to rapidly reverse anticoagulation and correct INR pre-surgery.
PMCID: PMC3096433  PMID: 21769259
anticoagulation reversal; Beriplex® P/N; computed tomography; International Normalized Ratio; intracranial hemorrhage; prothrombin complex concentrate
25.  Validity of CoaguChek S for home monitoring of anticoagulant therapy in pediatrics 
CoaguChek S (Roche Diagnostics, Canada) is a portable device designed to monitor international normalized ratio (INR) by capillary puncture. Although the device is used in pediatrics, no study has evaluated its validity in patients of this population.
To evaluate the validity of CoaguChek S as an in-home INR monitor in patients younger than 18 years of age.
Data were based on 129 INR pairs collected from nine patients younger than 18 years of age followed up at an anticoagulation clinic between March 1, 2000, and January 19, 2004. The INRs from both the laboratory and CoaguChek S were used to evaluate concordance between the two methods using the intraclass correlation coefficient.
The overall intraclass correlation coefficient between the CoaguChek S and the laboratory was 0.75 (95% CI 0.66 to 0.82). On average, CoaguChek S underestimated INRs by 0.11±0.54 units compared with those of the laboratory. INRs of 3.5 units and higher obtained with CoaguChek S were, on average, 0.49±1.09 units higher than those obtained in the laboratory.
CoaguChek S appears to be a valid instrument for in-home INR monitoring for most patients younger than 18 years of age, with INR targets of 2.0 to 3.0 followed up by an anticoagulant therapy clinic’s program. However, caution must be used when interpreting INRs higher than 3.5. Parents should perform a second test to confirm all CoaguChek S INR results higher than 4.0.
PMCID: PMC2649171  PMID: 17245482
Anticoagulants; Home monitoring; International normalized ratio; Pediatrics; Patient self-testing

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