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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.  Implant surgery and oral anticoagulant therapy: case report 
Oral & Implantology  2014;7(2):51-56.
This work aims to assess the risks both thromboembolic that bleeding of a management protocol “non-conservative” in patients on oral anticoagulant therapy (OAT) to be undergoing implant surgery.
Materials and methods.
We decided to take a surgical “non-conservative” protocol, to insert four implants in the aesthetic zone, without using flapless surgery and the surgical template. In accordance with the hematologist, the value of INR is lowered and warfarin was replaced with heparin low molecular weight, to have a better coagulation’s control.
The modern guidelines impose a protocol of conservative management in patients with OAT, with minimally invasive surgery, flapless, and use of surgical template to reduce the risk of uncontrolled bleeding. This, thanks to the team-work between dentist and hematologist, thanks to careful adjustment of INR and the use of local haemostatic agents, were not encountered any problems with bleeding or intra or postoperative.
Surgical treatment of patients with OAT is a real problem for the oral surgeon, to treat every time in association with the hematologist. Applying this type of surgical procedure, different from today’s guidelines, in our experience there were no post-operative complications (bleeding or bleeding); osseointegration has not been compromised and the prosthetic rehabilitation was completed successfully.
PMCID: PMC4302744  PMID: 25694802
oral pathology; implant surgery; OAT; protocol “non conservative”
3.  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
4.  Is stopping of anticoagulant therapy really required in a minor dental surgery? - How about in an endodontic microsurgery? 
Nowadays, oral anticoagulants are commonly prescribed to numerous patients for preventing cardiovascular accident such as thromboembolism. An important side effect of anticoagulant is anti-hemostasis. In a major surgery, the oral anticoagulant therapy (OAT) regimen must be changed before the surgery for proper post-operative bleeding control. However, in a minor dental surgery and endodontic surgery, the necessity for changing or discontinuing the OAT is open to debate. In this study, risks of the consequences were weighed and analyzed. In patients who stop the OAT, the occurrence of thromboembolic complication is rare but the result is fatal. In patients who continuing the OAT, post-operative bleeding can be controlled well with the local hemostatic measures. In the endodontic surgery, there are almost no studies about this issue. The intra-operative bleeding control is particularly important in the endodontic surgery because of its delicate and sensitive procedures such as inspection of resected root surface using dental microscope and retrograde filling. Further studies are necessary about this issue in the viewpoint of endodontic surgery.
PMCID: PMC3761118  PMID: 24010076
Anticoagulants; Bleeding control; Endodontic microsurgery; Hemorrhage; Post-operative bleeding; Thromboembolism
5.  Risk of Thromboembolism Following Acute Intracerebral Hemorrhage 
Neurocritical care  2008;10(1):28-34.
Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulant therapy (OAT). While anticoagulated patients have increased severity of bleeding following ICH, they may also be at increased risk for thromboembolic events (TEs) given that they had been prescribed OAT prior to their ICH. We hypothesized that TEs are relatively common following ICH, and that anticoagulated patients are at higher risk for these complications.
Consecutive patients with primary ICH presenting to a tertiary care hospital from 1994 to 2006 were prospectively characterized and followed. Hospital records were retrospectively reviewed for clinically relevant inhospital TEs and patients were prospectively followed for 90 day mortality.
For 988 patients of whom 218 (22%) were on OAT at presentation, median hospital length of stay was 7 (IQR 4–13) days and 90-day mortality was 36%. TEs were diagnosed in 71 patients (7.2%) including pulmonary embolism (1.8%), deep venous thrombosis (1.1%), myocardial ischemia (1.6%), and cerebrovascular ischemia (3.0%). Mean time to event was 8.4 ± 7.0 days. Rates of TE were 5% among those with OAT-related ICH and 8% among those with non-OAT ICH (P = 0.2). After multivariable Cox regression, the only independent risk factor for developing a TE was external ventricular drain placement (HR 2.1, 95% CI 1.1–4.1, P = 0.03). TEs had no effect on 90-day mortality (HR 0.7, 95% CI 0.5–1.1, P = 0.1).
The incidence of TEs in an unselected ICH population was 7.2%. Patients with OAT-related ICH were not at increased risk of TEs.
PMCID: PMC4307935  PMID: 18810667
Cerebral hemorrhage; Warfarin; Venous thrombosis; Pulmonary embolism; Brain ischemia; Myocardial ischemia
6.  Effective and Safe Management of Oral Anticoagulation Therapy in Patients Who Use the Internet-Accessed Telecontrol Tool SintromacWeb 
Despite the existing evidence that highlights the benefits of oral anticoagulation therapy (OAT) self-testing and self-management by patients in comparison with conventional control, significant progress is still needed in the implementation of computer-based, Internet-assisted systems for OAT within health care centers. The telecontrol tool “SintromacWeb” is a previously validated system for OAT management at home, which is currently operative and accessed by patients through a hospital Web portal.
The intent of the study was to assess the effectiveness and safety of OAT management in patients using the SintromacWeb telecontrol system in reference to control in patients using the conventional system (management at the hematology department), in terms of time in therapeutic range (TTR) of International Normalized Ratio (INR).
In this observational prospective study, patients were identified by their physician and divided in two groups according to the OAT management system that they were already using (conventional control or telecontrol with SintromacWeb). For 6 months, patients were required to visit the hematology department every time their physician considered it necessary according to usual clinical practice. Sociodemographic and clinical variables for the study were collected at first visit (baseline) and at those visits closest to 2, 4, and 6 months after first visit.
A total of 173 patients were evaluated, 87 with conventional control and 86 with telecontrol. Follow-up time was a median of 6.3 (range 5.2-8.1) months. The average time of OAT treatment prior to enrollment was 9.2 (SD 6.4) years. Patients in the telecontrol group tested their INR a median of 21 (range 4-22) days versus a median of 35 (range 14-45) days in patients in the conventional control group (P<.001). TTR in the telecontrol group was 107 (SD 37) days versus 94 (SD 37) days in the conventional control group (an increase of 12.6%; P=.02). In all visits, the percentage of TTR was higher in the telecontrol group (at the third visit: 59% vs 48%; P=.01). Higher TTR (positive coefficient) was associated with patients under OAT telecontrol (P=.03). Under-anticoagulation (INR<1.5) and over-anticoagulation (INR>5) were observed in 34 (19.7%, 34/173) and 38 (22.0%, 38/173) patients, respectively (no differences between treatment groups). Seven thrombotic and/or bleeding events were serious, 12 were non-serious, and most of them (5 and 10, respectively) occurred in the conventional control group.
In clinical practice, OAT management with the Internet-based tool SintromacWeb is effective and safe for those patients who are eligible for OAT telecontrol.
PMCID: PMC4420842  PMID: 25900775
oral anticoagulant therapy; International Normalized Ratio; Internet; self-management software; telecontrol; SintromacWeb
7.  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
8.  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
9.  Supporting patients to self-monitor their oral anticoagulation therapy: recommendations based on a qualitative study of patients’ experiences 
The British Journal of General Practice  2015;65(636):e438-e446.
Clinical trials suggest that oral anticoagulation therapy (OAT) self-monitoring is safe and effective, however little is known about the patient experience of this process. There is a lack of understanding about how best to train and support patients embarking on OAT self-monitoring.
To collect in-depth information about patients’ experiences of OAT self-monitoring outside of clinical trial conditions and to produce a set of recommendations on how best to support such patients.
Design and setting
Semi-structured qualitative interviews with patients who self-monitor and live in England.
In total, 26 of the 267 (9.7%) who participated in the Cohort study of Anticoagulation Self-Monitoring (CASM) and were still self-monitoring after 12 months’ follow-up were interviewed. Topics discussed included experiences of OAT self-monitoring, healthcare support, training, and decision making. Framework analysis was used.
Following initial problems using the monitoring device, interviewees described a mostly positive experience. Although less effort was expended attending monitoring appointments with health professionals, effort was required to conduct self-monitoring tests and to interpret and act on the results. Desire to self-manage was variable, especially when dosing advice systems worked promptly and reliably. Interviewees overcame patchy healthcare system knowledge and support of self-monitoring by educating themselves. Family and friends provided support with learning to use the monitor and managing OAT dosage adjustments.
Better, more-consistent training and health-service support would have alleviated a number of problems encountered by these patients who were self-monitoring. This training and support will become even more important if self-monitoring becomes more accessible to the general population of people on OAT.
PMCID: PMC4484944  PMID: 26077266
anticoagulants; primary care; qualitative research; self-monitoring; self-management
10.  Practice nursed-based, individual and video-assisted patient education in oral anticoagulation - Protocol of a cluster-randomized controlled trial 
BMC Family Practice  2011;12:17.
Managing oral anticoagulant treatment (OAT) is a challenge for patients and primary care providers. It requires a high level of patient knowledge and adherence. Studies have shown that insufficient adherence and a low level of patient knowledge about OAT are primary causes for complications. This trial is the first to evaluate the long-term effects of a complex practice nurse-based patient education program in comparison to a patient brochure only.
Methods and design
This trial will be a cluster-randomized controlled trial in 22 general practices (GPs) recruiting 360 patients with OAT. GPs will be randomized into an intervention group or a control group. A baseline questionnaire will assess pre-existing knowledge about OAT. The patients in the intervention group will be educated by a complex education program which consists of a video, a brochure and individual training by a practice nurse. The video gives information about OAT, nutrition, and instructions about how to manage critical situations. The brochure repeats the content of the video. After 4 to 6 weeks, the intervention will be recapitulated. The control group will receive the brochure only. After 6 months, questionnaires will be used in both groups to assess patient knowledge about OAT as well as patients' subjective feelings of safety. Separately, we will evaluate patient records, looking for documented complications and the time spent in the therapeutic range.
This trial will start in January 2011. This trial will evaluate the long-term effectiveness of a video-assisted education program on patients with OAT in comparison to a patient information brochure. Most previous studies have evaluated knowledge directly after an educational intervention. Our trial will look for long-term differences in basic knowledge of OAT. We expect that our complex patient education program effectively increases long-term basic knowledge about OAT. Although the population of our study is too small to observe differences in adverse effects, we expect to discover differences in secondary outcomes, such as the time spent in the therapeutic range.
Trial registration
Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000586
Universal Trial Number (UTN U1111-1118-3464)
PMCID: PMC3089775  PMID: 21477372
11.  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
12.  Safety relevant knowledge of orally anticoagulated patients without self-monitoring: a baseline survey in primary care 
BMC Family Practice  2014;15:104.
Effective and safe management of oral anticoagulant treatment (OAT) requires a high level of patient knowledge and adherence. The aim of this study was to assess patient knowledge about OAT and factors associated with patient knowledge.
This is a baseline survey of a cluster-randomized controlled trial in 22 general practices with an educational intervention for patients or their caregivers. We assessed knowledge about general information on OAT and key facts regarding nutrition, drug-interactions and other safety precautions of 345 patients at baseline.
Participants rated their knowledge about OAT as excellent to good (56%), moderate (36%) or poor (8%). However, there was a discrepancy between self-rated knowledge and evaluated actual knowledge and we observed serious knowledge gaps. Half of the participants (49%) were unaware of dietary recommendations. The majority (80%) did not know which non-prescription analgesic is the safest and 73% indicated they would not inform pharmacists about OAT. Many participants (35-75%) would not recognize important emergency situations. After adjustment in a multivariate analysis, older age and less than 10 years education remained significantly associated with lower overall score, but not with self-rated knowledge.
Patients have relevant knowledge gaps, potentially affecting safe and effective OAT. There is a need to assess patient knowledge and for structured education programs.
Trial registration
Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000586.
Universal Trial Number (UTN U1111-1118-3464).
PMCID: PMC4045910  PMID: 24885192
13.  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
14.  Patients' perspectives on self-testing of oral anticoagulation therapy: Content analysis of patients' internet blogs 
Patients on oral anticoagulant therapy (OAT) require regular testing of the prothrombin time (PT) and the international normalised ratio (INR) to monitor their blood coagulation level to avoid complications of either over or under coagulation. PT/INR can be tested by a healthcare professional or by the patient. The latter mode of the testing is known as patient self-testing or home testing. The objective of this study was to elicit patients' perspectives and experiences regarding PT/INR self-testing using portable coagulometer devices.
Internet blog text mining was used to collect 246 blog postings by 108 patients, mainly from the USA and the UK. The content of these qualitative data were analysed using XSight and NVivo software packages.
The key themes in relation to self-testing of OAT identified were as follows: Patient benefits reported were time saved, personal control, choice, travel reduction, cheaper testing, and peace of mind. Equipment issues included high costs, reliability, quality, and learning how to use the device. PT/INR issues focused on the frequency of testing, INR fluctuations and individual target (therapeutic) INR level. Other themes noted were INR testing at laboratories, the interactions with healthcare professionals in managing and testing OAT and insurance companies' involvement in acquiring the self-testing equipment. Social issues included the pain and stress of taking and testing for OAT.
Patients' blogs on PT/INR testing provide insightful information that can help in understanding the nature of the experiences and perspectives of patients on self-testing of OAT. The themes identified in this paper highlight the substantial complexities involved in self-testing programmes in the healthcare system. Thus, the issues elicited in this study are very valuable for all stakeholders involved in developing effective self-testing strategies in healthcare that are gaining considerable current momentum particularly for patients with chronic illness.
PMCID: PMC3045880  PMID: 21291542
15.  Needs and barriers to improve the collaboration in oral anticoagulant therapy: a qualitative study 
Oral anticoagulant therapy (OAT) involves many health care disciplines. Even though collaboration between care professionals is assumed to improve the quality of OAT, very little research has been done into the practice of OAT management to arrange and manage the collaboration. This study aims to identify the problems in collaboration experienced by the care professionals involved, the solutions they proposed to improve collaboration, and the barriers they encountered to the implementation of these solutions.
In the Netherlands, intensive follow-up of OAT is provided by specialized anticoagulant clinics (ACs). Sixty-eight semi-structured face-to-face interviews were conducted with 103 professionals working at an AC. These semi-structured interviews were transcribed verbatim and analysed inductively. Wagner's chronic care model (CCM) and Cabana's framework for improvement were used to categorize the results.
AC professionals experienced three main bottlenecks in collaboration: lack of knowledge (mostly of other professionals), lack of consensus on OAT, and limited information exchange between professionals. They mentioned several solutions to improve collaboration, especially solutions of CCM's decision support component (i.e. education, regular meetings, and agreements and protocols). Education is considered a prerequisite for the successful implementation of other proposed solutions such as developing a multidisciplinary protocol and changing the allocation of tasks. The potential of the health care organization to improve collaboration seemed to be underestimated by professionals. They experienced several barriers to the successful implementation of the proposed solutions. Most important barriers were the lack motivation of non-AC professionals and lack of time to establish collaboration.
This study revealed that the collaboration in OAT is limited by a lack of knowledge, a lack of consensus, and a limited information exchange. Education was identified as the best way to improve collaboration and considered a prerequisite for a successful implementation of other proposed solutions. Hence, the implementation sequence is of importance in order to improve the collaboration successfully. First step is to establish alignment regarding collaboration with all involved professionals to encounter the lack of motivation of non-AC professionals and lack of time.
PMCID: PMC3268100  PMID: 22192088
16.  Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position 
Patients with mechanical heart valve prostheses must continuously be treated with oral anticoagulants to prevent thromboembolic events related to prosthetesis. These patients should be continually evaluated for the control of oral anticoagulation.
To compare the occurrence of thromboembolic and hemorragic complications in patients with mechanical heart valve prosthesis with one (mono) and two (bi) leaflets in the mitral position in anticoagulant therapy.
We studied the 10-year interval, 117 patients with prosthesis in the mitral position, 48 with prosthetic single leaflet and 69 with two leaflets. We evaluated the occurrence of thromboembolic and hemorrhagic major and minor degree under gravity. The results are presented in an actuarial study and the frequency of occurrence of linear events.
The actuarial survival curves showed that over time, patients with prosthetic heart valve with one leaflet were less free of thromboembolic complications than patients with two leaflet prosthetic valve, while the latter (two leaflet) were less free of hemorrhagic accidents. The linearized frequency of occurrence of thromboembolism were higher in patients with mono leaflet prosthesis. Bleeding rates were higher for patients with bi leaflet prosthetic valve.
Patients with mono leaflet prosthetic heart valve showed that they are more prone to the occurrence of serious thromboembolic events compared to those with bi leaflet prosthetic valve. Patients with bi leaflet prosthetic valve had more bleeding than patients with mono leaflet prosthetic valve, however this difference was restricted to the bleeding of minor nature.
PMCID: PMC4389486  PMID: 24896164
Anticoagulants; Embolism and Thrombosis; Hemorrhage; Heart Valve Prosthesis
17.  A non-experimental study of oral anticoagulation therapy initiation before and after national patient safety goals 
BMJ Open  2014;4(2):e003960.
The Joint Commission revised its National Patient Safety Goals (NPSGs) to include oral anticoagulation therapy (OAT) in 2008. We sought to examine the effect of including OAT in The Joint Commission's NPSGs on historically low rates of OAT initiation for individuals with incident atrial fibrillation (AF).
Southeastern state in the USA.
North Carolina State Health Plan claims data from 944 500 individuals enrolled between 1 January 2006 and 31 December 2010, supplemented with data from the Area Resource File and Online Survey, Certification and Reporting data network. We evaluated OAT initiation before and after the 2008 NPSGs revisions in a retrospective cohort new user design with an AF intervention group and two control groups: a positive control—patients estimated to be at very high risk of thromboembolism (mechanical heart valve and pulmonary embolism); and a negative control—patients with very low perceived risk of thromboembolism (paroxysmal AF). We developed multivariable models using a difference-in-difference parameterisation. Effects were estimated with generalised estimating equations.
Primary outcome measure
OAT initiation, a binary outcome defined as having a prescription drug claim for warfarin within 30 days of the index claim.
OAT initiation was low (26.8%) for eligible individuals with incident AF in 2006–2008 but increased after NPSGs implementation (31.7%, p=0.022). OAT initiation was high but decreased in the positive control group (67.5% vs 62.0%, p=0.003). Multivariate analysis resulted in a relative 11% (95% CI (4% to 18%), p<0.01) increase in OAT initiation for incident AF patients.
We document a substantial increase in guideline concordant OAT initiation in incident AF after the establishment of NPSGs, suggesting that regulatory healthcare agency initiatives can influence clinical practice.
PMCID: PMC3927813  PMID: 24525389
18.  Oral Anticoagulation Therapy in Heart Failure Patients in Sinus Rhythm: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(1):e52952.
Heart failure (HF) patients show high morbidity and mortality rate with increased risk of malignant arrhythmia and thromboembolism. Anticoagulation reduces embolic event and death rates in HF patients with atrial fibrillation, but if antithrombotic therapy is beneficial in patients with HF in sinus rhythm is still debated.
Methodology and Principal Findings
We conducted a systematic review of prospective, randomized controlled trials (RCTs) to assess the efficacy and safety of oral anticoagulant therapies (OATs) compared to antiplatelet treatment in HF patients in sinus rhythm. MEDLINE, Web of Science, CENTRAL and Scopus databases were searched up to May 2012. Four RCTs were identified and a total of 3663 patients were included in the meta-analysis. Patients with both ischemic and non-ischemic HF were included. There was no significant difference in mortality (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.86 to 1.19) between OATs group and antiplatelet drug group. OATs have reduced ischemic stroke risk (OR 0.49, 95% CI 0.32 to 0.74), but have increased major bleeding risk (OR 2.01, 95% CI 1.40 to 2.88) compared to antiplatelet treatment.
In HF patients in sinus rhythm OATs do not show a better risk-benefit profile compared to antiplatelet treatment in cardioembolism prevention. Warfarin and aspirin seem to be similar in reducing mortality. Warfarin reduces the incidence of ischemic stroke, but increases major bleedings. Thus, it is possible to speculate that aspirin prescription be indicated in patients with high risk of bleeding, whereas warfarin could be preferred in patients with high thromboembolic risk.
PMCID: PMC3534653  PMID: 23301006
19.  The prediction role of D-dimer in recurrence of venous thromboembolism 1-year after anticoagulation discontinuing following idiopathic deep vein thrombosis 
After discontinuing oral anticoagulant therapy (OAT), the recurrence of venous thromboembolism (VTE) is greatest in the 1st year and gradually diminishes. D-dimer assay was proposed to be effective in selecting patients with idiopathic DVT. The aim of this study was to determine the rate of VTE recurrence after discontinuing OAT according to the results of D-dimer.
Materials and Methods:
This prospective study was conducted in patients with a first episode of symptomatic proximal deep vein thrombosis (DVT) who had received OAT for at least 3 months. Patients were re-evaluated at 1st, 6th and 12th months of their follow-up. At the first (T0) and 30-day (T1) visits, venous blood samples were taken for D-dimer test. At each follow-up visit, we examined patients for clinical symptoms or signs of recurrent VTE, bleeding, postthrombotic manifestations, adherence to treatment, and concomitant analgesic or antiinflammatory therapy. The endpoint outcomes were VTE recurrence and complete of this survey follow-ups.
A total of 68 eligible patients was enrolled. Four patients (two patients need to use long-term oral anticoagulation, and two patients lost their first follow-up) were excluded. At T0, D-dimer and compression ultrasonongraphy (CUS) was normal in 28 patients (44%). Moreover, 36 patients had abnormal D-dimer but normal CUS. A follow-up of 12 months was available in 44 patients. During the follow-up, three recurrent events were recorded. All Recurrent events were ipsilateral DVT. Among these index cases, all had an abnormal D-dimer at either T0 and/or T1. The recurrence rate was higher in males than in females (8.6% vs. 2.2%, P = 0.04) with an abnormal D-dimer at T0 and/or T1 with a multivariate hazard ratio of 2.1 (95% confidence intervals [CI]: 1.2-5.2; P = 0.02). Patients older than 65 years had a higher rate of events than younger and hazard ratio was about 3.8 (95% CI: 2.1-4.2; P = 0.02). Patients with recurrences had higher mean D-dimer at both T0 and T1 when compared with those without recurrences, but the difference was significant only for D-dimer at T1 (P = 0.03). During the follow-up, two patients died (3%).
Within 12 months follow-up, the risk of recurrence with an abnormal D-dimer, either during or at 1-month after discontinuing OAT, was 4.6% which is much lower to the annual risk of recurrence in most studies with idiopathic and provoked VTE. D-dimer has an acceptable prognostic value in detecting recurrence of idiopathic VTE before discontinuing the anticoagulant therapy.
PMCID: PMC4214014  PMID: 25364355
D-dimer; deep vein thrombosis; recurrent venous thromboembolism; residual vein obstruction
20.  The new oral anti-coagulants and the phase 3 clinical trials - a systematic review of the literature 
Thrombosis Journal  2013;11:18.
Anticoagulation with vitamin K antagonists such as warfarin has historically been used for the long term management of patients with thromboembolic disease. However, these agents have a slow onset of action which requires bridging therapy with heparin and its analogues, which are available only in parenteral route. To overcome these limitations, new oral anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors have been developed. The aim of this article is to systematically review the phase 3 clinical trials of new oral anticoagulants in common medical conditions.
We searched PubMed (Medline) from January 2007 to February 2013 using “Oral anticoagulants”, “New oral anticoagulants”, “Randomized controlled trial”, “Novel anticoagulants”, “Apixaban”, “Rivaroxaban”, “Edoxaban”, “Dabigatran etexilate”, “Dabigatran” and a combination of the above terms. The available evidence from the phase 3 RCTs was summarized on the basis of individual drug and the medical conditions categorized into “atrial fibrillation”, “acute coronary syndrome”, “orthopedic surgery”, “venous thromboembolism” and “medically ill patients”.
Apixaban, rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk, superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding, non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed. Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism. However, compared to enoxaparin, apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients. Additional studies evaluating the specific reversal agents of these new drugs for the management of life-threatening bleeding or other adverse effects are necessary.
Considering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.
PMCID: PMC3766654  PMID: 24007323
Vitamin K antagonists; Oral anticoagulants; Apixaban; Rivaroxaban; Dabigatran; Orthopedic surgery; Knee replacement; Hip replacement; Acute coronary syndrome; Atrial fibrillation; Venous thromboembolism; Critically ill patients; Systematic review
21.  Intracerebral haemorrhage: an often neglected medical emergency 
Intracerebral haemorrhage (ICH) is the deadliest form of stroke, carrying a mortality rate between 30% and 55%, increasing to 67% in patients on oral anticoagulant therapy (OAT). Despite its relevant incidence, the treatment of ICH has been until recently a largely neglected item, addressed by only a few trials. Early treatment of ICH in non-anticoagulated patients with recombinant activated factor VII (rFVII) has been demonstrated to be able to limit the growth of the haematoma, but such a promising result requires further confirmations. In ICH patients receiving OAT a prompt reversal of the anticoagulant effect should be warranted in order to reduce the consequences of this dreadful adverse event. In clinical practice, however, just a small proportion of anticoagulated patients receive this treatment, probably because of the fear of thromboembolic complications. It is now time to check our way of thinking about ICH, regarding and treating it as a compelling medical emergency.
PMCID: PMC2780614  PMID: 17551684
Intracerebral haemorrhage; Oral anticoagulants; Antiplatelet drugs; Recombinant activated factor VII; Emergency medicine
22.  Cohort study of Anticoagulation Self-Monitoring (CASM): a prospective study of its effectiveness in the community 
The British Journal of General Practice  2015;65(636):e428-e437.
Trials show that oral anticoagulation therapy (OAT) substantially reduces thromboembolic events without an increase in major haemorrhagic events, but it is not known whether these results translate into routine practice.
To estimate the current levels of control and adverse events in patients self-monitoring OAT, explore the factors that predict success, and determine whether the level of side effects reported from randomised controlled trials are translated to a non-selected population.
Design and setting
Prospective cohort study in the UK.
Participants were aged ≥18 years and registered with a GP. Main outcomes were the proportion of participants, over 12 months, who were still self-monitoring, had not experienced adverse events, and had achieved >80% of time in therapeutic range (TTR).
In total, 296 participants were recruited; their median age was 61 years and 55.1% were male. Participants were predominately professional or held a university qualification (82.7%). At 12 months, 267 (90.2%) were still self-monitoring. Mean TTR was 75.3% (standard deviation 16.9).Six serious and two minor adverse events were reported by GPs. Only 45.9% of participants received any in-person training at the outset. Increased age (P = 0.027), general wellbeing (EQ-5D visual score, P = 0.020), and lower target international normalised range (INR, P = 0.032) were all associated with high (>80% TTR) levels of control.
The findings show that, even with little training, people on OAT can successfully self-monitor, and even self-manage, their INR. TTR was shown to improve with age. However, widespread use of self-monitoring of INR may be limited by the initial costs, as well as a lack of training and support at the outset.
PMCID: PMC4484943  PMID: 26077267
anticoagulants; primary care; monitoring; self-management; self-monitoring
23.  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
24.  Vitamin E Serum Levels and Bleeding Risk in Patients Receiving Oral Anticoagulant Therapy: a Retrospective Cohort Study 
Hemorrhagic risk assessment is a crucial issue in patients with nonvalvular atrial fibrillation (NVAF) who are receiving oral anticoagulant therapy (OAT). Our aim was to analyze the relationship between vitamin E, which possesses anticoagulant properties, and bleeding events in NVAF patients.
Methods and Results
In this retrospective observational study we analyzed baseline serum cholesterol‐adjusted vitamin E (vit E/chol) levels in 566 consecutive patients (59% males, mean age 73.6 years) receiving OAT followed up for a mean time of 22 months. Mean time in therapeutic INR range (TTR) was 64%. The overall incidence rate of any bleeding event was 9.2/100 person‐years. Compared to patients who did not bleed, those who experienced bleeding events (n=92, 73 minor and 15 major bleedings and 4 cerebral hemorrhages according to International Society on Thrombosis and Haemostasis [ISTH] ) classification) showed a significant difference for history of coronary heart disease (P=0.039), HAS‐BLED score (P=0.002), and vit E/chol levels (P<0.001). Higher vit E/chol serum levels were found in patients who bled compared to those who did not (5.27±1.93 versus 4.48±1.97 μmol/cholesterol; P<0.001), with a progressive increase from minor (5.16±1.91 μmol/mmol cholesterol, P=0.006) to major bleedings (5.72±2.0 μmol/mmol cholesterol, P=0.008). A Cox proportional hazard model demonstrated that serum vit E/chol quartiles (global P=0.0189) and HAS‐BLED scores (P=0.005) predicted bleeding events.
In a NVAF population being treated with warfarin, serum vitamin E predicted hemorrhagic events. Further study is necessary to see if the relationship between serum levels of vitamin E and bleeding is still maintained with the use of new anticoagulants.
Clinical Trial Registration
URL: Unique identifier NCT01882114.
PMCID: PMC3886776  PMID: 24166490
anticoagulation; atrial fibrillation; bleeding; tocopherol
25.  Postoperative nadroparin administration for prophylaxis of thromboembolic events is not associated with an increased risk of hemorrhage after spinal surgery 
European Spine Journal  2003;13(1):9-13.
Aim: To determine the risk of postoperative hemorrhage during a 3-year period of early postoperative administration of nadroparin (Fraxiparin) plus compression stockings in a large cohort of patients who underwent spinal surgery. Methods: A total of 1,954 spinal procedures at different levels (503 cervical, 152 thoracic and 1,299 lumbar), performed between June 1999 and 2002 at the Department of Neurosurgery, Johann-Wolfgang-Goethe University Frankfurt, were included in this study. To prevent venous thromboembolic events (VTE), all patients were routinely treated subcutaneously with 0.3 ml of early (less than 24 h) postoperative nadroparin calcium (Fraxiparin) (2850 IU anti-Xa, Sanofi Winthrop Industrie, France) plus intra- and postoperative compression stockings until discharge. The occurrence of a postoperative hematoma (defined as a hematoma requiring surgical evacuation because of space occupation and/or neurological deterioration) and a deep venous thrombosis (DVT) were recorded in a database and analyzed retrospectively. Results: 13 (0.7%) of the 1,954 spinal operations were complicated by major postoperative hemorrhages. In 5 of the 13 patients (38.5%) the hemorrhage occurred on the day of surgery before the administration of nadroparin. Thus, the hemorrhage rate of patients receiving nadroparin was 0.4% (8/1,949). Ten (77%) of the 13 patients with major postoperative hematoma showed a progressive neurological deficit, which resolved in 6 patients and resulted in a hematoma-related morbidity of 31% (4/13). Only 1 patient (0.05%) in this series developed a clinically evident DVT, and none of the patients suffered from pulmonary embolus during the hospital stay. Conclusion: Although retrospective, this is to date the largest study providing information about the hemorrhage rate associated with early postoperative anticoagulation following spinal surgery. The results confirm that early postoperative pharmacological thromboembolic prophylaxis using nadroparin in patients with spinal surgery is not associated with an increased risk of postoperative hemorrhage.
PMCID: PMC3468029  PMID: 14615928
Spinal surgery; Hemorrhage; Thrombosis; Thromboembolism; Heparin

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