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The author explains the nature, reason and practical implications of determining the International Normalized Ratio (INR) for all clinicians and technical personnel, mainly those who work in laboratories. An exhaustive revision is made of the studies performed by the centres involved in thromboplastin calibration exercises to obtain the International Sensitivity Index (ISI) values.
OBJECTIVE: To assess the extent of incorporation of international normalized ratio (INR) reporting in US academic hospitals. DESIGN: Survey of academic hospital clinical laboratories in January 1995. SETTING/PARTICIPANTS: Fifty-eight academic hospital clinical laboratories at institutions that are members of the University Health System Consortium. MAIN OUTCOME MEASURES: The methods for monitoring oral anticoagulant therapy at the surveyed laboratories were determined. The extent of reporting of prothrombin time (PT), PT ratio, INR, and INR therapeutic range was determined. RESULTS: All 58 of the responding hospital clinical laboratories reported INR in patients receiving oral anticoagulation. The median length of time that hospitals had been reporting INR was 24 months (range 3-108). A majority of hospitals continued to report PT values (95%) and PT reference ranges (93%) in addition to INR. Therapeutic INR ranges were reported by only 25 of the laboratories (43%). Of those that report INR ranges, many follow the published recommendations by the American College of Chest Physicians and the Food and Drug Administration. A majority of the hospitals (79%) do not confirm the accuracy of the international sensitivity index (ISI) for their own analyzers. CONCLUSIONS: Contrary to previous reports, academic hospital clinical laboratories have now adopted the more accurate system of reporting INR values in addition to PT values in patients receiving oral anticoagulation. However, better reporting of INR ranges, use of more sensitive thromboplastins, and confirmation of the accuracy of the ISI for local analyses would further improve the monitoring of oral anticoagulation.
Recently, a change in anticoagulation therapy occurred that is still partially ignored by the healthcare community. Understanding the controversy over the use of the internal normalized ratio in monitoring patients receiving warfarin therapy is important for nurses who provide care to these patients. Five questions related to current monitoring of patients treated with anticoagulants are addressed. Nurses must recognize the importance to their practice of changes in laboratory methods and move toward using the most useful measures available to influence patients' outcomes. The international normalized ratio is the most appropriate way to evaluate the effects of warfarin therapy. All healthcare providers should use this ratio as the standard in evaluating the effects of anticoagulation therapy.
A 43-year-old African-American woman taking warfarin for prevention of ischemic stroke experienced fluctuating international normalized ratio (INR) values over 8.5 months; no cause could be identified. After reading a pharmacy information sheet that accompanied a warfarin refill, she reported that she had been refrigerating her warfarin because her other drugs had been "sticking together." She then was instructed to store her warfarin at room temperature. During the 8.5 months she had been refrigerating her warfarin, 80% of her INR values had been outside her goal range versus 37.5% during 9 months of storage at room temperature. A MEDLINE search and communication with the drug's manufacturer provided no information regarding storage of warfarin outside the temperature range of 59-86 degrees F and resultant changes in potency of the drug. Because of potential fluctuation in anticoagulation control, patients should be reminded to store their warfarin at room temperature.
OBJECTIVE: To determine the accuracy of 2 commercially available point-of-care devices relative to plasma international normalized ratio (INR) values. PATIENTS AND METHODS: Point-of-care INR testing was performed with the CoaguChek and ProTime 3 devices in consecutive patients attending an anticoagulation clinic between June 18, 2003, and August 6, 2003. Results were compared with plasma INRs using a sensitive thromboplastin (International Sensitivity Index, 1.0). RESULTS: Ninety-four patients agreed to participate in the study. Relative to the plasma INR, values were in agreement +/-0.4 INR unit 82% and 39% of the time for the CoaguChek and ProTime 3 devices, respectively. The mean +/- SD CoaguChek INRs were 0.2+/-0.31 unit lower, whereas ProTime 3 INRs were 0.8+/-0.68 unit higher than plasma INR values. Treatment decisions based on these data would have resulted in inappropriate dose adjustments 10% and 22% of the time for these 2 respective devices. Correlation with plasma was greater for the CoaguChek (r2=0.90) compared with the ProTime 3 device (r2=0.73). CONCLUSIONS: Optimal warfarin treatment requires accurate measurement of the INR. The choice of a point-of-care device for INR management depends on the reliability of INR data generated by the device.
STUDY OBJECTIVE: We determine the prevalence of nontherapeutic and coagulopathic international normalized ratios (INRs) among patients receiving warfarin and presenting to an emergency department (ED). As a secondary goal, we aim to determine whether a simple decision aid composed of physical examination and historical features could be predictive of INR greater than 5. METHODS: This was a prospective, observational study at 2 associated urban academic centers from February 2003 through May 2004, using a convenience sample of patients identified by direct questioning and contemporaneous medical record review in the ED as receiving long-term warfarin therapy. Inclusion criteria were warfarin therapy and self-reported compliance. Patients were enrolled by trained researchers. The primary outcome measure was the percentage of patients within appropriate therapeutic range for their condition according to accepted national guidelines. Descriptive statistics were used, and multivariate regression analysis was performed to identify associations. RESULTS: One thousand nineteen patients were enrolled. INR values were obtained in 77% (782/1019) of patients. Of these patients, 72% (95% confidence interval 67% to 76%) were outside the desired range. Values were less than 2 in 43% of patients and greater than 3 in 29% of patients. INR greater than 5 was present in 11% (86/782) of patients, and 40% (34/86) of these patients exhibited gross bleeding. Emergency therapy was administered in 12% (96/782) of patients: fresh frozen plasma in 7% of patients, heparin in 5% of patients. Intracranial hemorrhage was found in 12 patients, 5 with INR greater than 3. Ischemic stroke or venous thromboembolism occurred in 51 patients known to be receiving warfarin specifically for prevention of the event that occurred. Of these patients, 49% (25/51) had INR less than 2. Regression analysis indicated no sensitive or specific constellation of features, though 2 factors were associated with INR greater than 5: gross hemorrhage (P=.006) and increasing duration of therapy (P=.047). CONCLUSION: The prevalence of undesirable INR in the ED is higher than in warfarin populations previously studied, and a significant number of nontherapeutic levels were associated with thromboembolism, stroke, or hemorrhage. Given the prevalence and established danger of subtherapeutic and supratherapeutic levels, a low threshold should be maintained for testing and addressing INR levels in patients receiving warfarin in the ED.
The objective of our study was to determine the rates of bleeding complications and thromboembolic events in patients receiving oral anticoagulant therapy monitored with the prothrombin time (PT) ratio versus therapy monitored with the International Normalized Ratio (INR) using a retrospective time-series study design. Over 650 patients enrolled in a large anticoagulation clinic were studied during two time periods corresponding to the use of the PT ratio versus the INR to guide anticoagulant therapy, with over 400 patient-years of follow-up for each time period. The rate of bleeding complications using the PT ratio to guide therapy was 6.7% (1.2% major, 5.5% minor) per patient-year, compared with 2.9% (0% major, 2.9% minor) using the INR (p = 0.02). The rate of thromboembolic complications was 1.0% using the PT ratio, compared with 0.2% using the INR (p = NS). Therapy monitored with the INR required 19.8 visits per year, compared with 20.7 visits per year using the PT ratio. We conclude that the INR should be used to monitor oral anticoagulant therapy in an effort to reduce bleeding complications while maintaining an acceptable rate of thromboembolic events.
OBJECTIVE: To determine whether a 24-hour delay in testing affects international normalized ratio (INR) reproducibility as much as using alternative thromboplastin reagents. METHODS: Specimens from warfarin-treated patients were tested at 0 hours and again at 24 hours to determine the INR, each time using RecombiPlasTin, Innovin, and C-Plus thromboplastin reagents. RESULTS: There was no clinically significant difference in INRs when a specimen was tested with the same reagent at 0 and 24 hours. However, at 0 hours, the INRs were significantly higher when a specimen was tested using C-Plus and RecombiPlasTin as compared with the result with Innovin (both P < .0001). CONCLUSIONS: A specimen can be maintained at room temperature for 24 hours without a significant change in the INR. Changing the reagent, however, can result in statistically and clinically significant differences in the INR.
While monitoring coagulation testing in Yucatan miniature swine being given oral anticoagulants, we noticed instances of high international normalized ratios (INR) without clinical complications in our animal model. All pigs (n = 17) weighed approximately 35.2 kg and were dosed daily with 2 to 3 mg of coumadin. Plasma samples were obtained and assayed for prothrombin time (PT), calculated INR, and activated partial thromboplastin time (APTT) at baseline, and after 7 and 14 days of coumadin therapy. Results of initial testing indicated high INR values after anticoagulation and short APTT values at baseline, which led us to consider the activity of vitamin K-dependent coagulation factors in the pig. This information was not available in literature concerning this strain of swine, and was surprising given that pigs are frequently used cardiac research models. Using the same plasma samples, we repeated the PT, INR, and APTT determinations using different reagents and a different analyzer. We also determined activities of coagulation factors II, VII, IX, and X. Large PT and INR differences were seen between the two instrument/reagent combinations, possibly due to the differences in the thromboplastins used and differences in the photo-optic versus manual clot-detection method of the instruments. Vitamin K-dependent factors in all pigs responded to coumadin by decreasing to < 30.0% activity, except for factor IX. The high INR values were not as pronounced when the second instrument/reagent combination was used, and the results seemed more in line with the animals' clinical condition. With this instrument/reagent combination, the pig can be considered a good model for research requiring oral anticoagulant medication.
The recommended therapeutic range of International Normalized Ratio (INR) for oral anticoagulant treatment in patients with the antiphospholipid syndrome remains controversial. As a part of this controversy, it has been suggested that lupus anticoagulants (LA) could interfere with the determination of prothrombin time, thus questioning the validity of monitoring the treatment of these patients using INR. To clarify this point, we compared the values of INR obtained in the plasmas of two groups of patients, one without LA (n = 47), and the other with LA (n = 43). INR were determined using 8 different thromboplastin reagents on the same automated coagulation instrument. Chromogenic factor X, which is supposed to be insensitive to the presence of LA, was also measured. The results are the following: provided INR was calculated using calibrated reference plasmas, there was no significant difference between INR values obtained with the 8 reagents, both in the non-LA and in the LA groups (CV: 5.9 and 6.7%. respectively). Closer examination revealed that INR results obtained with one reagent (the recombinant thromboplastin Innovin) diverged from those of the 7 others, leading to an overestimation of INR, to a very large extent in some instances. However this effect was restricted to a subset of the patient population with LA (6 out of 43). Finally, the relationship between INR (average value obtained using the 8 reagents) and factor X was identical in non-LA and in LA patient groups. We conclude that, provided the reagents which display the LA interference are identified and excluded for this purpose, the INR system is valid for monitoring oral anticoagulant treatment in patients with LA.
The motivation behind the creation of the International Normalized Ratio (INR) was to improve interlaboratory comparison for patients on anticoagulation therapy. In principle, a laboratory that reports the prothrombin time (PT) as an INR can standardize its PT measurements to an international reference thromboplastin. Using probability theory, the authors derived the equation for the probability distribution of the INR based on the PT, the International Sensitivity Index (ISI), and the geometric mean PT of the reference population. With Monte Carlo and numeric integration techniques, the model is validated on data from three different laboratories. The model allows computation of confidence intervals for the INR as a function of PT, ISI, and reference mean. The probabilistic model illustrates that confidence in INR measurements degrades for higher INR values. This occurs primarily as a result of amplification of between-run measurement errors in the PT, which is inherent in the mathematical transformation from the PT to the INR. The probabilistic model can be used by any laboratory to study the reliability of its own INR for any measured PT. This framework provides better insight into the problems of monitoring oral anticoagulation.
Prothrombin time (PT) testing is used for monitoring oral anticoagulant therapy, its result being usually expressed as international normalized ratio (INR). This is done using the international sensitivity index (ISI) specific of thromboplastin employed to carry out the test. In this way a good PT standardization may be achieved although the instruments used to calibrate the thromboplastins might influence the ISI value.
BACKGROUND: Investigators commonly rely on unvalidated, mainly arithmetic criteria to predict if point-of-care fingerstick devices that assess International Normalized Ratio (INR) lead to the same warfarin dosing decisions as a standard measure. METHODS: Criteria that predict warfarin dosing agreement between 2 INR measurements were evaluated using clinicians' actual dosing decisions as the standard. Bayesian hierarchical modeling was used to rank the criteria by the proportion of correct dosing predictions and the magnitude of difference between actual and predicted dosing agreement. RESULTS: The prediction criteria misclassified dosing agreement for between 19% and 38% of paired INR values (x: 27%). The magnitude of misclassification varied inconsistently throughout the INR scale. CONCLUSION: The unvalidated criteria used to predict warfarin dosing agreement between 2 INR measurements are associated with large error. Warfarin dosing decisions should be measured directly in such assessments.
This retrospective pilot study determined whether a change in the daily International Normalized Ratio (INR) correlates with a decrease in Coumadin (DuPont Pharma, Wilmington, Del) dosage. Four hundred seventeen patients yielded 1167 pairs of INR values and Coumadin doses. An increase in INR > 0.4 units correlated 81% with a decrease in the Coumadin dose (P < .05). In patients aged > or = 70 years, the correlation fell to 70% compared to an 89% correlation in patients aged < 70 years (P < .05). The correlation fell to 78% in women, while men exhibited an increase to 87% (P < .05). Although this is a pilot study, when managing postoperative Coumadin anticoagulation for orthopedic patients, an increase in INR > 0.4 units correlates highly with the need to decrease the Coumadin dose. A prospective study is needed to test the usefulness of this parameter.
Some thromboplastin manufacturers are currently supplying the instrument-specific international sensitivity index (ISI) values of their reagents, allowing clinical laboratories to calculate instrument-specific international normalized ratio (INR) values on plasma samples from patients receiving coumarin therapy. However, the assumption that systematic interinstrument variability in the INR would be eliminated if manufacturer-determined ISI values were used remains unsubstantiated. This assumption was evaluated by comparing INR values obtained on one instrument that measures a mechanical endpoint (fibrometer) with one that measures a photo-optical endpoint (MLA-700). Three thromboplastin reagents with instrument-specific ISI values supplied by the manufacturer (ISI range, 1.23-2.79) were used. For two of three reagents, the fibrometer INR values were significantly higher than the MLA-700 INR values (P < .01). Analysis of log prothrombin time ratio plots showed that this systematic variability was caused by inaccurate manufacturer ISI values. Of clinical significance is that the inaccurate ISI values produced a high number of discordant INR values between these two instruments (> 47% of plasma samples had one INR value within and one out of the recommended therapeutic range). The implication of these findings for laboratory monitoring of oral anticoagulation is discussed.
With the increasing use of the international normalized ratio (INR) to monitor warfarin therapy, a number of problems with prothrombin time (PT) testing have been identified that have led some laboratory physicians to question the reliability of the INR. This is ironic, because it was the introduction of the INR system that brought to light some of the long-standing problems with the technique of PT monitoring. However, these problems are not insurmountable if a compromise can be reached between the expectations of laboratory physicians and of clinicians. Thus, the laboratory physician seeks a perfect assay system, which in the case of the INR is unattainable at present, because of differences in PT reagents and methods. In contrast, the clinician is satisfied with a system of monitoring that provides safe and effective warfarin dosing. This goal can be achieved provided that certain details of PT testing are observed. In this communication, which is directed to practicing clinicians, the potential problems with the INR system are discussed, their clinical relevance is critically reviewed, and solutions are offered.
We reviewed retrospectively the medical records of all patients (n = 77, mean age 74.2) on oral anticoagulants with an International normalized ratio (INR) of eight or above in a 12-month period in the Leicestershire District Health Authority (DHA). From a total of 55,625 INRs, 131 (0.24%) were > or = 8. A major cause of over-anticoagulation was unsatisfactory dose loading during in-hospital commencement of oral anticoagulation. The incidence of major bleeding was 12.9% of total episodes of INR > or = 8 with two haemorrhage-related fatalities. Therapy of major haemorrhage with fresh frozen plasma (FFP) and intravenous (i.v) vitamin K proved effective but was not given in a majority of such cases. In conclusion, improvements in initial dose loading of oral anticoagulation and in the management of major haemorrhage are required. Severely over-anticoagulated patients without obvious bleeding should nevertheless receive small dose vitamin K therapy to reduce the risk of haemorrhage related morbidity and mortality without compromising subsequent oral anti-coagulant control.
OBJECTIVE: Describe the course of patients with an elevated international normalized ratio (INR) in the emergency department (ED) and determine physicians' adherence with treatment recommendations. METHODS: One-year retrospective review of all ED patients with an INR >5.0. RESULTS: Ninety-four patients met the entry criteria. Bleeding was present in 28.7% patients. Two thirds of the major bleeding episodes were of gastrointestinal origin. Physicians' adherence decreased as bleeding and INR increased. At the lowest risk, adherence was 66.6%, whereas at the highest risk, it was 36.3%. Two thirds of patients were admitted to the hospital, one fourth were discharged, and 7.4% were observed in an observation unit. Average length of stay was 3.8 days. CONCLUSION: Adherence to the recommendations regarding managing elevated INR was suboptimal. There is a need for formal endorsement of recommendations by emergency medicine organizations and development of disposition criteria based on bleeding status and site of bleeding.