Address reprint requests to Dr. Malcolm L. Brigden, Island Medical .... Nichols WL, Bowie EJW: Standardization of the prothrombin time for monitoring ...
American Journal of Hematology 48:237-239 (1995)
INR Reporting in Canadian Medical Laboratories Thrombosis Interest Group of Canada: M. Andrew, M. Brigden, J. Bormanis, M. Cruickshank, W. Geerts, A. Giles, J. Hirsh, R. Hull, J. Johnson, M. Johnston, J. Leclerc, M. Mant, G. Pineo, S. Robinson, D. Robitaille, S. Rudledge Harding, M.F. Scully, A.G. Turpie, L. Vickars, and L. Whitman Hamilton, Ontario, Canada
A written survey of all licensed medical laboratories in Canada performing coagulation testing was performed to investigatethe level of knowledge and overall usage of the INR system for reporting prothrombin time results in medical laboratories. There was an overall response rate of 857 of 1,228 laboratories surveyed. Fifty-seven percent of responding laboratories utilized some format of INR reporting. The IS1 of the individual thromboplastin utilized was known by 89% of laboratories. The IS1 of the thromboplastin utilized was known to be specific for the particular reagenthstrument combination in 44% of cases. Fifty-five percent of client physicians preferred PT results to be reported in seconds while 42% desired an INR format. The situation in Canada is similar to the United States in that further education regarding the INR system for PT reporting is required by o 1995 Wiley-Liss, inc. both medical laboratoriesand physicians. Key words: INR, anticoagulation, oral anticoagulant monitoring, warfarin therapy
INTRODUCTION
Oral anticoagulant therapy has considerably improved the long-term treatment of patients with a variety of thrombotic disorders. However, the coumarin or warfarin drugs are potent anticoagulants associated with significant variations in patient response and a relatively narrow therapeutic window [ 1-31. The most common test used to monitor oral anticoagulant therapy is the prothrombin time (PT). In the 1960s commercial manufacturers of thromboplastins in North America began to provide rabbit brain-derived preparations. These had decreased sensitivity to the reduction in Vitamin K dependent coagulation factors induced by oral anticoagulant therapy as compared to the traditional responsive human brain thromboplastins which had been produced in individual laboratories in North America and Europe [4].Despite these changes, clinicians did not readjust their treatment protocols by changing therapeutic ranges. Clinical studies ultimately documented that as a result, patients in North America were receiving more Coumadin than their European counterparts and that this increased dosing was associated with a concomitant increase in bleeding risk with no improvement in therapeutic efficacy [5,6]. In the late 1970s, recognition of the variability in the sensitivity of thromboplastins and their effects on the PT determination led to increased efforts to standardize this 0 1995 Wiley-Liss, Inc.
procedure so that patients could be uniformly anticoagulated. The International Normalized Ratio (INR) was introduced as a means of “normalizing” the PT assay between laboratories by relating the sensitivity of individual thromboplastins to a universal standard with a known relationship to the antithrombotic effects of oral anticoagulants [7,8]. Although use of the INR by clinical laboratories has been advocated for more than a decade, recent studies elsewhere in North America have revealed that many laboratories and physicians remain unaware of the benefits of this method of reporting PT results [9,10]. To assess the frequency of reporting and general knowledge relating to INR in Canada, the Thrombosis Interest Group, a cohort of health care individuals with a major interest in thrombosis, undertook an interprovincial survey.
Received for publication July 12, 1994; accepted October 12, 1994. Address reprint requests to Dr. Malcolm L. Brigden, Island Medical Laboratories, Ltd., 4489 Viewmont Avenue, Victoria, BC, V8Z 5K8 Canada.
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Thrombosis Interest Group of Canada
TABLE I. Format Utilized by Canadian Medical Laboratories for PT Reporting No. of laboratories
%
INR INR and PT ratio INR and PT in seconds PT ratio only PT in seconds only
127 52 309 57 312
1s 6 36 7 36
Total INR reporting
488
57
Format
PT ~nSECS
METHODS
Registered clinical laboratories in Canada including hospitals and out-patient facilities were identified via the provincial licensing agencies. In the fall of 1992, a standard questionnaire was sent to the laboratory cohort. Laboratories were queried as to the type of thromboplastin and coagulation instrument utilized, the method used to derive the ISI, the format used for prothrombin time reporting, and local physician preferences for prothrombin time reporting. Non-responding institutions were followed up by telephone. Survey results were verified and tabulated in early 1993.
PT in SECS + INR
INR Only
PT Ratio
Fig. 1. Physician preference for format utilized for PT reporting.
Reported physician preferences for the format of PT reporting are illustrated in Figure 1. These included PT in seconds 55%, INR and PT in seconds 23%, INR only 19%, and PT ratio 3%. DISCUSSION
There have been major problems associated with traditional methods utilized for reporting PT results in North America [3,7,8]. Percent activity, which fortunately is no longer supplied by most North American laboratories, RESULTS relies on a dilution curve unique to each individual laboEight hundred fifty-seven responses were received ratory and renders interlaboratory comparisons impossifrom a possible 1,228 laboratories contacted giving an ble. The reporting of PT results only in seconds, fails to overall 70% response rate. Individual provincial response take into account both the mean of the reference interval rates vaned from a low of 42% to a high of 100%. The of PT values for the particular thromboplastin reagent frequency of the various formats for reporting PT results (which may vary from 10 to 15 sec) and the individual is outlined in Table I. Ninety percent of laboratories used sensitivity of the particular thromboplastin chosen. In an an automated method for PT determination while 10% attempt to surmount the former problem, many laboratostill relied on manual testing. Overall, 57% of the 857 ries switched to reporting PT ratios, that is, the radio laboratories utilized some format of INR reporting. The calculated by dividing the patient’s PT result in seconds frequency of INR reporting by type of laboratory ranged by the mean of the PT reference interval in seconds. from 63% in academic hospitals to 49% in community However, as Bussey and other authors have demonstrated, the introduction of thromboplastinswith different hospitals, and 46% in private laboratories. The IS1 value for the thromboplastin utilized was sensitivities has meant that utilizing only PT ratios may known by 89% of laboratories. The ISIs in this survey provide dangerously misleading results [7,9,11]. Indeed, ranged from 1.O to 2.98 with a mean IS1 of 2.07. Eighty- uncertainty about the true intensity of anticoagulation eight percent of the 857 responding institutions had taken may reduce the potential gain in life expectancy adjusted the IS1 from the package insert. In only 44% of the for quality of life by more than half and may increase the institutions was the IS1 known to be specific for the ratio of cost effectiveness of oral anticoagulation therapy particular reagenthnstrumentcombination utilized. Three to almost five times the optimal value [ 121. thromboplastin manufacturers, Organon Teknika, Dade Unfortunately, our survey illustrated that many CanaBaxter Diagnostics, and Ortho Diagnostic Systems ac- dian laboratories and clinicians remain unaware of the counted for more than 87% of the thromboplastins uti- advantages of utilizing the INR for reporting PT results. lized in the survey population. Fifty-nine percent of the It is disconcerting that only 57% of Canadian institutions 857 survey institutions provided some type of therapeutic had opted for some form of INR reporting while the rate ranges to their physicians. Of the 857 institutions 34% in community laboratories was even lower (47%). Simiused some method for highlighting non-therapeutic val- larly, only 42% of physicians expressed a desire for INR ues. reporting and the use of seconds only was still a favored
INR Reporting
format (55%). Some authorities have suggested that laboratories ultimately might utilize two PT order codes: a PT diagnostic expressed in seconds and a PT therapeutic expressed as an INR [14]. Such a routine may not be necessary once physicians have been conditioned to thinking in INR values because any increase in the PT in seconds will be reflected in the calculated INR since this is a mathematically derived value from the PT ratio [ 131. It is also of concern that 11% of laboratories surveyed did not know the IS1 of the thromboplastin being used for their coagulation testing. Obviously, if laboratory personnel cannot provide the IS1 of their thromboplastin, accurate interlaboratory comparison of PT results is impossible. Only 44% of laboratories utilized a reagent/ instrument specific ISI. This process is important since the actual IS1 of individual thromboplastin reagents is dependent on the particular reagent/instrument combination utilized [ 15-17]. Indeed, some authorities have recommended that each laboratory should establish its own instrument specific IS1 [ 14,171. It is interesting to note that the problems experienced in Canada are similar to those that have been described in the United States. For instance, a state wide study in Massachusetts found that only 5% of hospitals reported the INR [9]. A more recent investigation in the state of Utah was more encouraging revealing that 50% of laboratories used INR reporting [ 101. However, this study also demonstrated that many of the same laboratories were probably providing inaccurate INR values. The two commonest problems were that the laboratories in question were not using ISIs specific for the reagenuinstrument combination used and that the mean of the normal control value was utilized for the denominator of the INR calculation rather than the mean of the PT reference interval. Specifically, with regards to ISIs, another study found that 30% of surveyed institutions could not provide IS1 data and that unlabeled thromboplastin was being used in 24% of the laboratories investigated [ 111. What can be done to facilitate reporting in North America? A new requirement by journals to exclusively use the INR format when reporting clinical trial results will probably be of some value. However, the following recently made recommendations should be strongly endorsed [18]: 1) All laboratories should report INR’s for the monitoring of oral anticoagulation. 2) Manufacturers of thromboplastin reagents should be required by the appropriate branches of government regulatory agencies to provide accurate IS1 values for each lot of thromboplastin released commercially. The individual IS1 values supplied by the manufacturer should be appropriate for
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the reagent/instrumentation combination used by the particular laboratory. 3) Individual laboratories should be encouraged to use sensitive thromboplastins with lower IS1 values as this optimizes INR reporting. Further education of both laboratories and physicians regarding the INR system for PT reporting should lead to more effective oral anticoagulation therapy in North America. REFERENCES 1. Hirsh J, Dalen JE, Deykin D, Poller L: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 102:3128-3268, 1992. 2. Freedman MD: Oral anticoagulants; pharmacodynamics, clinical indications and adverse effects. J Clin Pharmacol2:196-209, 1992. 3 . Brigden ML: Oral anticoagulant therapy: newer indications and improved method of monitoring. Post Grad Med 1:285-296, 1992. 4. Hirsh J: Is the dose of warfarin prescribed by American physicians unnecessarily high? Ann Intern Med 147:769-771, 1987. 5. Poller L, Tabener DA: Dosage and control of oral anticoagulants: An international survey. Br J Hematol 1:479485, 1982. 6 . 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: 1676-1 68 1, 1982. 7. Hirsh J: Oral anticoagulant therapy: urgent need for standardization. Circulation 861332-1335 (editorial), 1992. 8. Hirsh J: Substandard monitoring of warfarin in North America: Time for change. Arch Intern Med 152:257-258 (editorial), 1992. 9. Ansell J: Imprecision of prothrombin time monitoring of oral anticoagulation: A survey of hospital laboratories. Am J Clin Pathol 98:237239, 1992. 10. Garr SB, Rodgers GM: Laboratory monitoring of warfarin therapy in Utah. Am J Hematol45:85-87, 1994. 11. Bussey HL, Force RW, Bianco TM, Leonard AD: Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy. Arch Intern Med 152:278-282, 1992. 12. Eckman MH, Herbert JL, Pauker SG: Effect of laboratory variation in the prothrombin-time ratio on the results of oral anticoagulant therapy. N Engl J Med 329596702, 1993. 13. Nichols WL, Bowie EJW: Standardization of the prothrombin time for monitoring orally-administered anticoagulant therapy with use of the International Normalized Ratio system. Mayo Clin Proc 68:897-898, 1993. 14. Triplett DA, Brandt J: International normalized ratios: Has their time come? Arch Pathol Lab Med 117:59&592, 1993. 15. Chantarangkul V, Tripodi A, Mannucci PM, Bunomi AB: The effect of instrumentation on thromboplastin calibration. Thromb Haemat 67: 588-589, 1992. 16. Ray MJ, Smith IR: The dependence of the International Sensitivity Index on the coagulometer used to perform the prothrombin time. Thromb Haemost 63:424429, 1990. 17. Swaim WR: Prothrombin time reporting and the International Normalized Ratio system: Improvements are needed. Am J. Clin Pathol 99: 653455, 1993. 18. Alhers GW: Laboratory monitoring of oral anticoagulant therapy: are we being misled? Neurology 43:468470, 1993.
