International Normalized Ratio Testing Research Articles

The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. The article describes the antithrombotic effect of VKAs, the monitoring of anticoagulation intensity, the clinical applications of VKA therapy, and the optimal therapeutic range of VKAs, and provides specific management recommendations. Grade 1 recommendations are strong, and indicate that the benefits do, or do not, outweigh the risks, burdens, and costs. Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this article are the following: for dosing of VKAs, we suggest the initiation of oral anticoagulation therapy with doses between 5 and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 2B). In the elderly and in other patient subgroups with an elevated bleeding risk, we suggest a starting dose at < or = 5 mg (Grade 2C). We recommend basing subsequent doses after the initial two or three doses on the results of INR monitoring (Grade 1C). The article also includes several specific recommendations for the management of patients with INRs above the therapeutic range and for patients requiring invasive procedures. For example, in patients with mild to moderately elevated INRs without major bleeding, we suggest that when vitamin K is to be given it be administered orally rather than subcutaneously (Grade 1A). For the management of patients with a low risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before they undergo surgery (Grade 2C). For patients with a high risk of thromboembolism, we suggest stopping warfarin therapy approximately 4 days before surgery, to allow the INR to return to normal, and beginning therapy with full-dose unfractionated heparin or full-dose low-molecular-weight heparin as the INR falls (Grade 2C). In patients undergoing dental procedures, we suggest the use of tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash without interrupting anticoagulant therapy (Grade 2B) if there is a concern for local bleeding. For most patients who have a lupus inhibitor, we suggest a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 2B]. In patients with recurrent thromboembolic events with a therapeutic INR or other additional risk factors, we suggest a target INR of 3.0 (range, 2.5 to 3.5) [Grade 2C]. As models of anticoagulation monitoring and management, we recommend that clinicians incorporate patient education, systematic INR testing, tracking, and follow-up, and good communication with patients concerning results and dosing decisions (Grade 1C+).

Near Patient Monitoring of Anticoagulant Therapy in General Practice

Background and aims: New systems for monitoring anticoagulation in routine clinical practice should be evaluated to inform future service development. The aim of this study was to investigate the workload, patient characteristics and bleeding complications in a nurse run, near patient monitoring service serving a population of 23,368. Methods: Retrospective review of coagulometer and general practice case records. Results: Between 1995 and 2000 workload increased from 154 to 269 consultations per month. Three hundred and forty four patients were followed up during a cumulative period of 664.8 years. The 8 week period prevalence of anticoagulation was 8.6 per thousand patients at the close of the study. The median age at enrolment was 71 years. Eighteen per cent of treatment episodes were started when patients were 80 years or older. The most common indication was non rheumatic atrial fibrillation (NRAF) in 51% of treatment episodes. During the study 49.6% [95% confidence interval (CI) 47.8%–50.6%] of international normalised ratio (INR) tests were within target range and INR was estimated to be within the target range 62% (95% CI 61.8%–62.2%) of the time. INR control varied markedly between individual patients. There were 4 fatal bleeding events (0.6 per hundred patient years) and 14 major bleeding events (2.1/hundred patient years). Conclusion: Demand for anticoagulant therapy with warfarin has increased substantially. Service development is required to ensure that appropriately selected patients have access to adequately resourced monitoring which promotes optimum INR control and a minimum of bleeding complications.

Primary care anticoagulant management using near patient testing.

Indications for anticoagulant treatment are increasing and new approaches to anticoagulant services require a shift from hospital to primary care. To pragmatically test the validity and effectiveness of primary care anticoagulant management using near patient testing. Twelve CoaguCheck monitors were supplied to 16 rural practices that had previously provided supervision of anticoagulant therapy. Practices were required to record data for eligible patients from September 1998 to April 1999 and to forward one blood sample per week to the regional hospital laboratory for parallel testing. Nine practices returned data on 122 patients. Indications for anticoagulation Included atrial fibrillation (n = 56), valve replacement (n = 12) and deep venous thrombosis or pulmonary embolus (n=12). Regression of the mean of 185 paired readings against their difference confirmed the validity of the CoaguCheck monitor (r2 = 0.00 [95% CI -0.38 to 0.38]). There were 692 International Normalised Ratio (INR) tests performed representing an average of 5.7 tests per patient. The desired therapeutic range was provided for 609 (88%) of these tests; 294 (48.3%) were within the desired therapeutic range. Results differed significantly between practices. This study confirmed the validity of anticoagulant management using the CoaguCheck monitor in primary care.

The initial phase of oral anticoagulation with warfarin in outpatients with deep venous thrombosis

Patients with deep venous thrombosis (DVT) treated out of hospital usually start warfarin with the recommended 5 mg loading dose and have their International Normalized Ratio (INR) test performed every 2-3 days. Thus, achievement of the therapeutic range may be more difficult than for inpatients, possibly resulting in extended duration of low molecular weight heparin (LMWH) treatment. We retrospectively examined the charts of 55 DVT outpatients (mean age, 61.4 years; 30 males) to assess the actual duration of LMWH treatment and to identify predictors of a slow achievement of the INR range. Thirty patients (54.4%) reached the therapeutic INR range and stopped LMWH within 7 days, and 25 patients (45.6%) had to continue for an average of 10.5 days. The latter group was significantly younger than the former (57 and 65 years, respectively; P = 0.039). Patients younger than 60 years old had an odds ratio for an extended treatment of 4.92 (P = 0.0057). Algorithms with different loading doses of warfarin according to age should be proposed for outpatient treatment of DVT.

A randomised controlled trial of patient self management of oral anticoagulation treatment compared with primary care management

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...

Benefits of a Mobile, Point-of-Care Anticoagulation Therapy Management Program

Current guidelines recommend anticoagulation therapy for a number of medical conditions, but this therapy also has the potential for serious complications, particularly bleeding complications. Maintenance of anticoagulation within a narrow therapeutic window usually entails frequent monitoring with a blood test called the international normalized ratio (INR). Anticoagulation therapy management (ATM) clinics lead to improvements in quality of care, in terms of improved INR control and reduced complications. This study examined the impact of a mobile multisite, office-based ATM program that operated in seven cardiology offices in all three counties in Delaware. ATM PROGRAM: The ATM program was managed by a trained nurse who rotated among all seven offices. Patients made office visits to the nurse and received patient education, point-of-care INR testing, and medication adjustment based on a physician-approved algorithm. This retrospective cohort study compared INR levels in the year before (May 1998-Apr 1999) and the year after (Aug 1999-Jul 2000) the start of the ATM program. From the year before to the year after implementation of the ATM program, the percentage of in-range INRs increased from 40.7% to 58.5% (p < 0.001). The percentage in the modified target range also increased (50.0% to 62.9%, p < 0.001). This study demonstrates the positive impact of a statewide office-based ATM program. If similar programs could be implemented in other networks of specialty offices or primary care offices, they could have a significant benefit to quality of care for patients who require anticoagulation therapy.

Prospective Assessment of a Nomogram for the Initiation of Oral Anticoagulation Therapy for Outpatient Treatment of Venous Thromboembolism

Venous thromboembolism is a common medical problem. Recently, the emphasis has been on a switch to outpatient low molecular weight heparin therapy. Previous warfarin nomograms have been developed only for inpatients. We prospectively assessed a warfarin initiation nomogram in 105 consecutive outpatients; the nomogram requires International Normalized Ratio (INR) testing on only days 3, 5, and 8. Eighty-three percent had a therapeutic INR by day 5 and 98% by day 8. There were no major bleeds and only 6 instances of INR >4.5. This outpatient warfarin nomogram appears to be safe and efficacious in obtaining timely therapeutic levels of warfarin and deserves further study.

Warfarin Therapy for Atrial Fibrillation in the Elderly

OBJECTIVE:To evaluate a clinical practice model that addresses special needs for managing anticoagulation in a community-dwelling elderly population with atrial fibrillation and high risk of stroke.METHODS:Medical records of 18 patients (mean age 82 y) followed by the Geriatric Ambulatory Program over 2 years, with a target international normalized ratio (INR) of 2.0–3.0, were reviewed. Risk factors for stroke, number and results of INR tests, suspected reasons for suboptimal response, and adverse events were analyzed. Patients were defined as having cognitive impairment if they had a Folstein Mini-Mental State Exam score ≤26. Functional impairment was defined by ≥2 disabilities in activities of daily living.RESULTS:Eighty-three percent (15/18) had ≥2 additional stroke risk factors. Fifty-one percent (273/541) of INR responses were therapeutic. Female gender (p = 0.015) and cognitive (p = 0.019) and functional impairment (p = 0.001) were associated with supratherapeutic INR response. All patients with cognitive impairment and 85% of those with functional impairment received caregiver support for medication administration. There were 4 minor bleeding events and no thromboembolic events. The mean number of medications was 9.3 in those with bleeding versus 6.8 in those without bleeding (p = 0.052).CONCLUSIONS:Elderly patients with high stroke risk achieved therapeutic INR responses. However, those with significant cognitive or functional impairment require caregiver support and special consideration for anticoagulation management.

Warfarin therapy for atrial fibrillation in the elderly.

To evaluate a clinical practice model that addresses special needs for managing anticoagulation in a community-dwelling elderly population with atrial fibrillation and high risk of stroke. Medical records of 18 patients (mean age 82 y) followed by the Geriatric Ambulatory Program over 2 years, with a target international normalized ratio (INR) of 2.0-3.0, were reviewed. Risk factors for stroke, number and results of INR tests, suspected reasons for suboptimal response, and adverse events were analyzed. Patients were defined as having cognitive impairment if they had a Folstein Mini-Mental State Exam score < or = 26. Functional impairment was defined by > or = 2 disabilities in activities of daily living. Eighty-three percent (15/18) had > or = 2 additional stroke risk factors. Fifty-one percent (273/541) of INR responses were therapeutic. Female gender (p = 0.015) and cognitive (p = 0.019) and functional impairment (p = 0.001) were associated with supratherapeutic INR response. All patients with cognitive impairment and 85% of those with functional impairment received caregiver support for medication administration. There were 4 minor bleeding events and no thromboembolic events. The mean number of medications was 9.3 in those with bleeding versus 6.8 in those without bleeding (p = 0.052). Elderly patients with high stroke risk achieved therapeutic INR responses. However, those with significant cognitive or functional impairment require caregiver support and special consideration for anticoagulation management.

Home international normalized ratio monitoring: where evidence-based medicine is exemplified in the Medicare coverage process.

Nearly three years ago, the Centers for Medicare & Medicaid Services (CMS), formerly the Health Care Financing Administration, announced a new process for making national coverage determinations [1]. Prior to this time, the process had been criticized as inconsistent, closed, and based on a “blackbox” methodology. The new process is designed to be evidence-based, as well as open and inclusive, and relying upon scientific and clinical literature to make coverage determinations. One controversial issue that prompted the creation of the new process was the topic of home prothrombin international normalized ratio (INR) monitors. At that time, CMS was considering issuing a national noncoverage determination. Within the past year, a coalition of manufacturers, physicians, specialty societies, and patients successfully used the evidence-based process to obtain coverage of home prothrombin (INR) monitoring for patients with mechanical heart valves. This communication explains the reasoning behind this decision, particularly with respect to the coupling of testing and outcomes, and it also explores ways to possibly expand coverage, as additional information becomes available. A detailed explanation of this decision can be found on CMS’s website at www.hcfa.gov/coverage. The recent CMS Decision Memorandum on home INR monitoring embodies the use of a rigorous evidence-based approach to CMS policy decisionmaking. The construction of a desirable analytical framework for assessing the clinical effectiveness of any diagnostic test is predicated upon the notion that the results of such a test will influence patient outcomes. The ideal, randomized controlled trial for effectiveness occurs when results of the diagnostic test alter a treatment intervention, and the health outcomes associated with such treatment are included within the boundaries of that same study. However, there are possibilities where appropriate linkages of randomized controlled trials can demonstrate a similar, strong relationship between testing and health outcomes. In this latter instance, there is a coupling of surrogate (or intermediate outcomes) with eventual health outcomes. The presence of key clinical trials, particularly among patients with mechanical heart valves (MHVs) who require long-term anticoagulation, afforded CMS the opportunity to evaluate both types of analytical frameworks, which are described above. In the first case, the typical study design was comprised of a home INR test group vs. a “standard” care control group, and health outcomes are event rates (bleeding and thromboembolism). In the second analytical framework, a home INR test group was still compared against a standard care control group, but, in this instance, time-in-therapeutic range (TTR) was a more achievable surrogate outcome, given the much larger sample sizes needed to adequately compare event rates. However, since a separate body of literature has established a causal relationship between TTR and event rates, particularly as highlighted by Samsa and Matchar [2], CMS was able to rely upon such an indirect approach which is contingent upon the use of surrogate outcomes. It should be emphasized that CMS does not restrict its review of evidence to only include randomized controlled trials, but in this evaluation of home INR testing where several trials were available, it is reasonable to emphasize the strongest type of evidence that was considered. Studies involving diagnostic technologies are usually represented by crosssectional, two-by-two table analyses, which in spite of generating useful sensitivity and specificity values, do not often afford the opportunity to address outcomes, even those which are surrogate and usually more accessible. Although the Decision Memorandum contains further details, some representative supportive trials in the MHV setting (i.e., at least 50% MHV patients in both study arms) are summarized below. Horstkotte conducted one of the first randomized prospective trials related to home INR testing [3].

Quality assessment of oral anticoagulant treatment in the Beer-Sheba district.

To evaluate the adequacy of oral anticoagulation therapy in patients with either prosthetic heart valves or atrial fibrillation. Adequacy of anticoagulation therapy of patients treated with warfarin was determined before and after implementation of an improvement programme. The central haematology laboratory of the Soroka Medical Center, Beer-Sheba Israel. One hundred and ten patients treated with chronic anticoagulation therapy were evaluated by measuring the international normalized ratio of the prothrombin time before and after implementation of an improvement plan aimed at improving anticoagulation control. A programme that included physician and patient education and procedural changes covering all aspects of anticoagulation therapy was implemented. The percent of international normalized ratio tests below, within and above the therapeutic range was determined. Prior to implementation of an improvement plan, only 32% of the measured international normalized ratio values were within the therapeutic range. 16% were above and 52% were below therapeutic range. Improvement intervention led to an increase in the proportion of international normalized ratio tests that fell within the therapeutic range from 32% to 43.2%. Improvement in the control of anticoagulation therapy of patients receiving long-term warfarin treatment is possible. A combined effort involving the community, physician and patient is required.

Analysis of Warfarin Therapy in Pediatric Patients: A Prospective Cohort Study of 319 Patients

This study details warfarin use in a large pediatric population followed in a central anticoagulation clinic. A prospective, consecutive cohort of nonselected children were studied. Patients were divided into groups by age, target international normalized ratio (INR) range, disease, medications, and vitamin K supplemented enteral nutrition use. Groups were analyzed on multiple aspects of warfarin therapy using multivariate methods. A total of 319 patients received 352 warfarin courses representing 391 treatment years. Age independently influenced all aspects of therapy. When compared with all older children, the ≤1 year of age group required increased warfarin doses, longer overlap with heparin, longer time to achieve target INR ranges, more frequent INR testing and dose adjustments, and fewer INR values in the target range. Although significantly different than children ≤1 year, children 1 to 6 years of age showed the same findings when compared with 7- to 18-year-olds. Fontan patients required 25% decreased dosage as compared with other congenital heart disease patients. Children on corticosteroids had less INRs in the target range and children on phenobarbital/carbamazepine required increased maintenance dosages of warfarin. Also, patients receiving enteral nutrition required increased dosages of warfarin. Serious bleeding occurred in 2 children (0.5% per patient year). Recurrent thromboembolic events (TEs) occurred in 8 children. Two children had recurrences while receiving warfarin (1.3% per patient year). This study outlines the profound effect of age and relative complexity of clinical management of warfarin therapy in children.

Analysis of Warfarin Therapy in Pediatric Patients: A Prospective Cohort Study of 319 Patients

AbstractThis study details warfarin use in a large pediatric population followed in a central anticoagulation clinic. A prospective, consecutive cohort of nonselected children were studied. Patients were divided into groups by age, target international normalized ratio (INR) range, disease, medications, and vitamin K supplemented enteral nutrition use. Groups were analyzed on multiple aspects of warfarin therapy using multivariate methods. A total of 319 patients received 352 warfarin courses representing 391 treatment years. Age independently influenced all aspects of therapy. When compared with all older children, the ≤1 year of age group required increased warfarin doses, longer overlap with heparin, longer time to achieve target INR ranges, more frequent INR testing and dose adjustments, and fewer INR values in the target range. Although significantly different than children ≤1 year, children 1 to 6 years of age showed the same findings when compared with 7- to 18-year-olds. Fontan patients required 25% decreased dosage as compared with other congenital heart disease patients. Children on corticosteroids had less INRs in the target range and children on phenobarbital/carbamazepine required increased maintenance dosages of warfarin. Also, patients receiving enteral nutrition required increased dosages of warfarin. Serious bleeding occurred in 2 children (0.5% per patient year). Recurrent thromboembolic events (TEs) occurred in 8 children. Two children had recurrences while receiving warfarin (1.3% per patient year). This study outlines the profound effect of age and relative complexity of clinical management of warfarin therapy in children.

Is the international normalised ratio (INR) reliable? A trial of comparative measurements in hospital laboratory and primary care settings.

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...

Primary care anticoagulant clinic management using computerized decision support and near patient International Normalized Ratio (INR) testing: routine data from a practice nurse-led clinic.

Increasing indications for warfarin therapy has led to increased pressure on primary care to undertake therapeutic monitoring. This study evaluates a primary care model of oral anticoagulation monitoring which utilises computerized decision support (CDSS) and near patient testing (NPT) within a practice nurse-led clinic. Whilst this has been shown to be a successful model under trial conditions, this paper reports the first data from a long-standing clinic, outside a formal study. A prospective evaluation of therapeutic and clinical control of all patients taking warfarin within one inner city general practice. Data were collected via CDSS. 29 patients were seen in 208 appointments. The mean percentage of patients within therapeutic range was 72%. The costs to the practice were pound sterling 1751. The costs the practice would have incurred had these patients been seen at the hospital with the same frequency would have been pound sterling 2290. The use of CDSS and NPT for nurse-delivered oral anticoagulation monitoring could enable the safe transfer of the majority of patients from secondary to primary care. Funding mechanisms to support the transfer of costs will be essential for most practices, as will be the maintenance of adequate staff training and quality assurance.

Determinants of Compliance with Anticoagulation: A Case-Control Study

BACKGROUND: The number of patients for whom long-term anticoagulation is indicated has increased dramatically over the past decade. Good patient compliance is necessary to safely realize the benefits of anticoagulation, yet barriers to compliance with anticoagulation therapy have not been studied.METHODS: We conducted a case-control study in the Anticoagulation Therapy Unit (ATU) at Massachusetts General Hospital. Forty-three patients who had been discharged from the ATU for noncompliance (cases) and 89 randomly selected compliant ATU controls were interviewed. Noncompliant cases had self-discontinued warfarin or were taking warfarin with inadequate monitoring of international normalized ratio (INR) levels. Telephone interviews assessed sociodemographic features, indication for anticoagulation, patient satisfaction, and health beliefs.RESULTS: Noncompliant cases were more likely to be younger (mean 53.7 years versus 68.7 years, P <0.0001), male (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.5, 8.2), and non-white (OR 6.4, 95% CI 1.9, 21.9), and less likely to have had a stroke or transient ischemic attack (OR 0.2, 95% CI 0.1, 0.7). In open-ended questioning, cases were more likely to report that they did not know why warfarin had been prescribed (OR 4.4, 95% CI 1.4, 14.2). Noncompliant cases were more likely not to have a regular physician (OR 11.1, 95% CI 3.6, 50.0); among patients with a regular physician, noncompliant cases were more likely to feel dissatisfied. Examination of health beliefs revealed that noncompliant cases felt more burdened by taking warfarin, and perceived fewer health benefits.CONCLUSIONS: Patients who are noncompliant with warfarin share distinctive clinical characteristics. Notably, younger, male patients who have not experienced a thromboembolic event are more likely to forego INR testing or to stop anticoagulation therapy completely. Improved patient education, physician involvement, and ease of monitoring may improve compliance, particularly among younger male patients.

Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease

The hypothesis that the combination of low-dose aspirin and warfarin therapy is more effective than aspirin alone in secondary prophylaxis after myocardial infarction is to be examined in the Coumadin Aspirin Reinfarction Study. This pilot study addressed the safety and anticoagulation effect of a fixed, low-dose combination in 114 patients (aged 64 ± 8 years, 85% men) with stable coronary artery disease receiving 3 mg of warfarin plus 80 mg of aspirin daily for 8 weeks. The international normalized ratio (INR) was measured within 72 hours of initial therapy, and weekly. Of the 110 patients with evaluable INRs, 87 patients (79%) maintained the 3 + 80 mg combination, 19 (17%) had the dose reduced to 1 mg warfarin + 80 mg aspirin, and 4 (4%) discontinued therapy because of a confirmed INR of ≥4.5. At steady state, patients had INRs of 1.48 ± 0.41 (3 + 80 mg group) and 1.21 ± 0.23 (1 + 80 mg group), and inter- and intra-patient variability (estimated by the mean of the between- and within-patient SDs at steady state) was 0.49 ± 0.08 and 0.13 ± 0.14, respectively. There was no apparent effect of age on INR distribution. Microscopic hematuria was the most frequent (20%) adverse clinical event, but was unrelated to the INR. Three patients required discontinuation of therapy because of bleeding events (persistent hematuria and epistaxis). A fixed low-dose combination of warfarin and aspirin results in a predictable and stable increase in the INR in a large proportion of patients with coronary artery disease. Provided that early INR testing is undertaken in order to identify patients with significant sensitivity to low-dose warfarin and to establish steady-state dosing, the Coumadin Aspirin Reinfarction Pilot Study suggests that this treatment modality may be safe for long-term administration as secondary prophylaxis.