Normalization of INR
Abstracts & Commentary
Synopsis: The information from this study may prove helpful in deciding whom to give vitamin K, what dose to provide, and how soon to perform a follow-up INR.
Sources: Hylek EM, et al. Ann Intern Med. 2001;135:393-400; Bussey HI. Ann Intern Med. 2001;135:460-462.
Hylek and colleagues ask the question, what are the patient-specific factors that influence the rate of normalization of the international normalized ratio (INR) after interruption of warfarin therapy? Knowing which patients can be predicted to normalize rapidly might avoid the administration of vitamin K, which has the potential of overcorrection of INR, warfarin resistance, and increased risk of thromboembolism. On the other hand, it will be of help in identifying those patients who are at risk for prolonged exposure to excessive anticoagulation (and, therefore, hemorrhage) and require more aggressive intervention.
Hylek and colleagues performed a retrospective study of patients who had been taking warfarin for more than 60 days and whose index INR was greater than 6.0. During the period of August 1993 through September 1998, 633 patients were studied. Variables included: recently started medications, intercurrent illness, decrease in oral intake, confusion about dose or nonadherance, errors in warfarin prescription, hospitalization within 30 days, report of increased alcohol intake, decompensated heart failure within 14 days of the index INR, and active cancer (chemotherapy of evidence of metastatic disease). The mean age of patients was 69 years (range, 25-95 years) and 55% were female. Nearly 80% had taken warfarin for more than 1 year, and 90% had less than a 10% change in warfarin dose over the previous 2 INR measurements.
Hylek et al report that patients whose INR remained 4 or greater on day 2 after the last dose of warfarin were more likely to be older, to be taking a lower maintenance dose of warfarin, and to have had a higher index INR (INR of 8 or higher). Other parameters associated with an INR of 4 or greater on day 2 included decompensated congestive heart failure, active cancer, and recent use of a medication known to potentiate warfarin. Too few patients reported alcohol use to allow meaningful assessment.
Comment by Michael K. Rees, MD, MPH
The information in this paper can be used when faced with that thorny decision: "Can I wait it out or should I give the patient vitamin K?" Hylek et al found that the rate of decay of INR was a function of age: the odds of having an INR of 4 or greater increased by 18% for each decade of age. That the rate of decay of INR is slower in patients who require low doses of warfarin to maintain INR in therapeutic range seems logical, as does the finding that the higher the index INR, the more likely that it will not have fallen below 4 on day 2. The observation that recent onset of decompensated heart failure is a risk is important. It certainly means that we have to use warfarin with great care here, and the finding of a high INR in an otherwise stable cardiac patient might be a warning to look for onset of CHF. The patient with "active cancer" also requires close monitoring.
In an accompanying editorial, Bussey makes the following comments: "Because the study is retrospective, there was no opportunity to repeat the Index INR to ensure it was not in error, which is important because 10-20% of laboratory INR measurements are erroneous, and half are higher than 4.5. Nevertheless, until data from prospective studies are available, this information may prove helpful in deciding whom to give vitamin K, what dose to provide, and how soon to perform a follow-up INR." Bussey suggests the following: 1) do not give vitamin K subcutaneously because it is ineffective in some patients; 2) the oral route is reliable; 3) limit the oral dose of vitamin K to 2.5 mg if the INR is between 6 and 10 or 5 mg if the INR is greater than 10. If there is concern that correction of INR may overshoot, measure INR 24 hours (rather than 48 hours) after vitamin K, which will allow warfarin to be restarted—if appropriate. If vitamin K is given intravenously, usually 0.5 mg is effective, and infuse at a rate of less than 1 mg/min.
Dr. Rees, Senior Associate in Medicine, Beth Israel Deaconess Medical Center, and Instructor in Medicine, Harvard Medical School, Brookline, Mass., is Associate Editor of Internal Medicine Alert.
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