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INR: a better way to report prothrombin times.

Oral anticoagulants are among the most common medications taken on a long-term basis. Medical attention has recently focused on new indications for therapy with this family of drugs, such as nonvalvular atrial fibrillation. Interest has revived as well in older applications, such as postmyocardial infarct therapy. There is some suggestion that low doses of oral anticoagulants may also be prophylactic against atherosclerosis. [1] Whatever the indication, laboratories are likely to encounter a steady increase in the volume of prothrombin time (PT) tests, the assay used to monitor long-term therapy with these drugs.

It has been recognized for some time that standardizing the PT for monitoring oral anticoagulant therapy would be extremely helpful. Worldwide, laboratories determine the prothrombin time with various thromboplastins of differing reactivity while using numerous methods and analytical techniques. PT results are expressed in seconds, PT ratios, percent prothrombin activity, and other ways. The lack of a common standard has led to many discrepancies in the interpretation of results of clinical trials, especially regarding the optimal degree of anticoagulation.

*Standards. Until recently, human brain thromboplastins were used for PT testing in the United Kingdom and Europe. These are more sensitive to a reduction in vitamin K-dependent clotting factors than are the rabbit brain thromboplastins commonly used on this continent. Patients in North America have therefore tended to be overly anticoagulated.

One study found the average dose of oral anticoagulant taken by European phlebitis patients to be significantly less than that received by a comparable group in North America. [2] In another trial of patients with phlebitis anticoagulated to the two sets of standards, the groups had similarly low rates fo recurrent clots. Yet while hemorrhagic complications occurred in only 4% of the European patients, the rate was far higher--22%--among the North American ones, whose oral anticoagulation was more intense. [3]

* WHO steps in. The need for a generally accepted standard was clear. The World Health Organization (WHO), together with the International Commission on Standardization in Hematology and other groups, developed a simple monitoring method for PT: the International Normalized Ratio (INR). It permits better control for patients taking oral anticoagulants.

INR facilitates standardization of resultse derived from the use of different thromboplastins, instruments, and assay methodologies. It has three essential characteristics:

[paragraph]INR is the PT ratio that would have been obtained if a WHO international reference thromboplastin had been used for PT determination.

[paragraph]INR is figured for specific thromboplastins as derived on particular instruments using defined methodologies. Reagant manufacturers supply some of the values needed to make the calculation.

[paragraph]INR was devised for monitoring patients on longterm oral anticoagulant therapy. Typically, it is used in patients who have been stable on medication for at least six to eight weeks.

* Calculating INR. Two sets of information are needed to determine the INR. One, the prothrombin time ratio, is obtained by dividing the patient's PT value, given in seconds, by the mean of the normal PT range. The other, the International Sensitivity Index (ISI), is available from the manufacturer of the batch of thromboplstin used. (The figure is derived from a comparison of the reagent with an international reference thromboplastin.) These working reference reagents serve as calibrated thromboplastins, gold standards to which all other sources are compared. Since the ISI depends somewhat on the coagulation instrument used, the laboratory should identify its instrument when requesting the IS from the thromboplastin supplier.

The ISI of most thromboplastins currently used in North America ranges from 2.0 to 2.6. Many European reagents have ISIs below 2.0; some approach 1.0. A major advantage of using thromboplastins with a low ISI is having a considerably extended therapeutic range (in seconds), which allows more precision in anticoagulation control.

Here is the formula for calculating the INR: INR = [(Patient PT / Normal PT).sup.ISI]

This calcuation can be made easily with a hand-held calculator, nomogram, or simple computer program. The INR derived in this way represents the PT ratio that would have been obtained if the patient's PT had been determined with a WHO international reference thromboplastin. Using one of the published reference nomograms allows rapid determination of the INR for many PT ratios and ISIs. An example is shown in Figure 1.

* Simplified ranges. One major benefit of using the INR system for reporting PTs is that it simplifies therapeutic ranges. The INR therapeutic ranges for venous and arterial thrombosis recommended by a panel of experts include only two levels (Table 1).

Another major advantage offered by the system is the potential for standardized interlaboratory comparisons. As North American labs switch to European-type thromboplastins, lower ISIs will mean inreased variability in therapeutic ranges (reported in seconds) and in PT ratios derived by individual labs. By addressing much of the variability worldwide--caused by different instruments and by varying brands and batche of thromboplastin--universal INR reporting will make it easier for travelers taking oral anticoagulants to remain in good control.

* Benefits and limitations. Enabling clinicians to determine the optimum ranges for patient treatment more easily should help lower the incidence of adverse effects associated with oral anticoagulants, such as bleeding complications, thus in turn reducing health care costs and laboratory liability. The use of INR reporting should allow physicians to make better comparisons of clinical trial results involving different regimens of anticoagulants.

The INR system, devised for standardized reporting of PT in patients who have been stable on oral anticoagulants for several weeks, is not so useful during the induction phase of oral anticoagulant therapy. It is also less suitable for testing for hemostatic abormalities, such as those associated with liver disease, or for preoperative screening for bleeding disorders. That's one reason many facilities continue to report PT results both in seconds and as INRs.

* Imprecision. Three factors can contribute to an imprecise INR determination: imprecision of the ISI, interlaboratory variation of the measured PT ratio, and biological variation of an individual patient's INR. It seems possible by using thromboplastins with an ISI approaching 1.0 to limit the total variation in INR to approximately 11% to 14%. A wider variation of up to 26% has been observed when thromboplastins with an ISI of 2.0 to 2.5 were used. Since any imprecision in the PT ratio is magnified by a large ISI, using thromboplastins with a low index will produce less variability in the INR calculation--another reason to follow the European lead and move to thromboplastins with lower ISIs.

* Implementing INR. Many Canadian provinces are well on the way to reporting PTs in seconds and with the INR system. In some geographic areas, hospitals have been in the vanguard; in others, independent laboratories have taken the first step (see "The switch to INR on Vancouver Island," above).

Change is less rampant in the United States. While a number of medical centers use the INR for monitoring patients or as an investigative tool, the mainstream of U.S. medicine has little or no working knowledge of this important reporting method.

Laboratorians can take steps to increase awareness of INR and its potential benefits for improved patient care. Establishing educational programs is a good start. Eventually the question of reporting only INR values will arise. An impetus for change will be the marked variation in PT therapeutic ranges expressed in seconds that will occur among different institutions as they switch to various thromboplastins with different ISIs. Even within the same institution, if a lab switches to a new thromboplastin with a much lower ISI, the therapeutic ranges will be considerably greater than those obtained with the former reagent.

Clinicians who continue to rely on PT results reported in seconds may become confused and possibly undertreat patients. Most North American institutions that have embraced the International Normalized Ratio have adopted a conservative approach, reporting PT results both in seconds and as INR values.

[1] Meade, T.W. Low-dose warfarin and low-dose aspirin in the primary prevention of ischemic heart disease. Am. J. Cardiol. 65(6): 7C--11C, 1990.

[2] Hirsh, J. Is the dose of warfarin prescribed by American physicians unnecessarily high? J. Intern. Med. 147(4): 769-771, 1987.

[3] Hull, R.; Hirsh, J.; Jay, R.; et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N. Engl. J. Med. 307(27): 1676-1681, 1982.

[4] Poller, L., and Hirsh, J. Special report: A simple system for the derivation of International Normalized Ratios for the reporting of prothrombin time results with North American thromboplastin reagents. Am. J. Clin. Pathol. 92(1): 124-126, 1989.

General references:

Biemer, J.J. Control of oral anticoagulant therapy. Ann. Clin. Lab. Sci. 18(6): 421-428, 1988.

Hirsh, J.; Poller, L.; Deykin, D.; et al. Optimal therapeutic range for oral anticoagulants. Chest 95(2): 5S-11S, 1989.

Moriarty, H.T.; Lam-Po-Tang, P.R.; and Anastas, K. Comparison of thromboplastins using the ISI and INR system. J. Pathol. 22(2): 71-76, 1990.

Dr. Bridgen is director of hematology and Preece is chief technologist in the department of hematology at Island Medical Laboratories, Victoria, B.C., Canada.
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Title Annotation:includes related article; International Normalized Ratio
Author:Brigden, Malcolm L.; Preece, Ethel
Publication:Medical Laboratory Observer
Date:Dec 1, 1991
Words:1499
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