Follow-up International Normalized Ratio Research Articles

Low-dose Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage with INR Less Than 2.0.

Prothrombin complex concentrates (PCCs) have become the first-line therapy for warfarin reversal in the setting of central nervous system (CNS) hemorrhage. Randomized, controlled studies comparing agents for warfarin reversal excluded patients with international normalized ratio (INR) <2, yet INR values of 1.6-1.9 are also associated with poor outcomes. We retrospectively reviewed our use of a low-dose (15 units/kg) strategy of 4-factor PCC (4F-PCC) on warfarin reversal (INR 1.6-1.9) in the setting of both traumatic and spontaneous intracranial bleeding. A total of 21/134 (15.7%) patients with either spontaneous or traumatic intracranial hemorrhage presented with an INR value of 1.6-1.9. Nine patients (43%) presented with traumatic bleeding and 12 (57%) with spontaneous bleeding. The median (IQR) presenting INR was 1.8 (1.7, 1.9) which decreased to 1.3 (1.2, 1.3) following the administration of low-dose 4F-PCC (median dose=1062 units; 15.2 units/kg). A total of 19/20 (95%) patients achieved a goal INR value of ≤1.5 on the first check following dosing and 17/20 (85%) achieved an INR value ≤1.3. One patient did not have follow-up INR testing due to withdrawal of life support. No patient experienced hematoma expansion within 48h of 4F-PCC, and there were no thromboembolic events within 72h of administration. The administration of low dose (15 units/kg) of 4F-PCC for urgent warfarin reversal in the setting of CNS hemorrhage was effective in correcting the INR in patients presenting with INR values of 1.6-1.9. Further assessment of low-dose PCC for urgent reversal of modest INR elevation is warranted.

Prothrombin Complex Concentrate Accelerates International Normalized Ratio Reversal and Diminishes the Extension of Intracranial Hemorrhage in Geriatric Trauma Patients

Warfarin therapy increases the incidence intracranial hemorrhage (ICH), especially in the geriatric population. Timely reversal of international normalized ratio (INR) is integral in the management of these patients for whom fresh frozen plasma (FFP) with vitamin K is the standard of treatment. We hypothesized that implementing a protocol that used prothrombin complex concentrate (PCC) would reverse INR values more swiftly and decrease the amount of FFP administered. In November 2011, a protocol was implemented for administering PCC to the geriatric population on warfarin admitted for life-threatening bleeds. These patients received 25 IU/kg ideal body weight of a three-factor PCC (Profilnine SD) if their INR was over 1.5 or greater. FFP was given if follow-up INR revealed an INR of 1.5 or greater. Retrospectively the data from 29 patients who received PCC were compared with a historical control group of 34 patients. Protocol use resulted in a significantly faster INR reversal (PCC: 151.6 ± 84.3 minutes vs control: 485.0 ± 321 minutes; P < 0.001), time to achieve an INR less than 1.5 (PCC: 484 ± 242 minutes vs control: 971 ± 1208 minutes; P = 0.036), and less FFP administered (PCC: 1.3 ± 1.0 vs control:3.3 ± 1.5; P < 0.001). PCC patients had a decreased incidence of progression of their ICH (PCC: 17.2% vs control: 44.2%; P = 0.031). Rapid reversal of coagulopathy in geriatric patients on warfarin is vital to limit the extent of ICH. PCC allows a much more rapid reversal than standard treatment with only FFP and vitamin K. Adopting such a protocol is associated not only with a more rapid reversal and less FFP use, but also less patients went on to extend their head bleeds.

Warfarin Interactions With Antibiotics in the Ambulatory Care Setting

The effect of antibiotic coadministration on the international normalized ratio (INR) in a relatively stable, real-world warfarin population has not been adequately described. Case reports and studies of healthy volunteers do not account for the potential contribution of acute illness to INR variability. To compare the risk of excessive anticoagulation among patients with stable warfarin therapy purchasing an antibiotic (antibiotic group) with the risk in patients purchasing a warfarin refill (stable controls) and patients with upper respiratory tract infection but not receiving an antibiotic (sick controls). A retrospective, longitudinal cohort study evaluated patients receiving warfarin between January 1, 2005, and March 31, 2011, at Kaiser Permanente Colorado, an integrated health care delivery system. Continuous data were expressed as mean (SD) or median (interquartile range). Multivariable logistic regression analysis was used to identify factors independently associated with a follow-up INR of 5.0 or more. A total of 5857 (48.8%), 5579 (46.5%), and 570 (4.7%) patients were included in the antibiotic, stable control, and sick control groups, respectively. Mean age was 68.3 years, and atrial fibrillation was the most common (44.4%) indication for anticoagulation. Warfarin therapy with a medical visit for upper respiratory tract infection or coadministration of antibiotics. Primary outcomes were the proportion of patients experiencing a follow-up INR of 5.0 or more and change between the last INR measured before the index date and the follow-up INR. The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more. Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.

Analysis Of Warfarin Drug-Drug Interactions With Antibiotics In The Ambulatory Care Setting

▪ BackgroundThe typical effect of antibiotic initiation on the international normalized ratio (INR) in a real-world, stable warfarin population has not been adequately described. In addition, the influence of acute illness on the risk of excessive anticoagulation is not known. MethodsThis retrospective, longitudinal cohort study evaluated patients who received stable warfarin therapy between January 1, 2005 and March 31, 2011. The protocol for patients receiving warfarin and initiating antibiotic therapy during the study time-frame was to continue the warfarin dose unchanged and measure an INR within 3 to 7 days. Patients who purchased an antibiotic (antibiotic group) were compared to those purchasing a warfarin refill (stable controls) and patients with upper respiratory infection who did not purchase an antibiotic (sick controls). Primary outcomes included the mean INR change between the last INR prior to study inclusion (pre-index INR) and the first follow-up INR as well as the percentage of patients with a follow-up INR ≥ 5.0. The influence of interaction mechanism on the risk of a follow-up INR ≥ 5.0 was evaluated and predictors of a follow-up INR ≥ 5.0 were identified. ResultsA total of 5905 (49.0%), 5579 (46.2%), and 570 (4.8%) patients were included in the antibiotic, stable control, and sick control groups, respectively. The mean age was 68.3 years and the median pre-index INR was 2.5 (IQR 2.2-2.9). The mean change in INR was greater in the antibiotic group compared to the stable and sick control groups (both p< 0.05) but the increase was not clinically relevant (i.e., mean increase was less than 0.1 INR units). There were 3.2%, 2.6%, and 1.2% of patients with a follow-up INR ≥ 5.0 in the antibiotic, sick, and stable groups respectively (antibiotics v. stable and sick v. stable p<0.001; antibiotics v. sick p=0.434). Antibiotics interfering with warfarin metabolism were more likely to result in a follow-up INR ≥ 5.0 (9.6%) than those disrupting Vitamin K synthesis (3.1%) and those without a known interaction with warfarin (2.1%) (p<0.01) (Table). Antibiotic use, acute illness, cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR ≥ 5.0. ConclusionIn the absence of antibiotics, acute illness alone increases the risk of excessive anticoagulation in previously stable warfarin patients. The risk of an INR ≥ 5.0 was greatest among antibiotics interfering with warfarin metabolism. In addition to antibiotics and acute illness, patients with cancer, elevated baseline INR, and females were most susceptible to excessive anticoagulation. Disclosures:Hylek:Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy. Garcia:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Roche Diagnostics: Consultancy; CSL Behring: Consultancy. Crowther:Asahi Kasai: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity's Board of Directors or advisory committees.

A Randomized Controlled Trial of Empiric Warfarin Dose Reduction with the Initiation of Doxycycline Therapy

BackgroundWhen interacting medications, such as doxycycline, are initiated during warfarin therapy, one method to correct for non-therapeutic international normalized ratio (INR) is adjusting the warfarin dose, if necessary. Another approach is preemptive warfarin dose adjustment. This study's objective was to evaluate the utility of preemptive warfarin dose adjustment for preventing non-therapeutic INR following doxycycline-warfarin co-administration. MethodsPatients were randomized to either a 10% to 20% preemptive warfarin dose reduction (intervention) or reactive warfarin dose adjustment (control) within 72hours of warfarin-doxycycline co-administration. Subjects received a follow-up INR within 7days (index INR). Primary outcome was the occurrence of index INR≥1 point over the INR goal range upper limit. Secondary outcomes included INR control, purchases of prescription vitamin K, and warfarin-associated adverse events in the 30days after doxycycline initiation. ResultsTwenty and 17 patients comprised the intervention and control groups. The intervention group's warfarin dose was reduced by a median of 11%. More control patients (n=2) experienced an INR≥1 point over the INR goal range upper limit compared to intervention (n=0); however, the difference (12% vs. 0%) was not statistically significant (p=0.20). A higher percentage of intervention patients had subtherapeutic index INRs compared to control (35% vs. 6%, p<0.05). One patient from each group experienced warfarin-associated bleeding. No thromboembolic complications or vitamin K use were observed. ConclusionsFor warfarin patients initiating doxycycline therapy, preemptive warfarin dose reduction did not result in supratherapeutic INRs but increased the likelihood of subtherapeutic INRs compared to INR monitoring with reactive warfarin dose adjustment.

Long-Term Oral Anticoagulant Management Associated with Routine Medical Care (RMC) In Patients with Non-Valvular Atrial Fibrillation (NVAF) In Canada,

Abstract 4192 Introduction:There are no prospective, long-term studies describing the process and quality of care, resource utilization (RU), and quality of life (QoL) associated with being on oral anticoagulant therapy for non-valvular atrial fibrillation (NVAF) patients managed through routine medical care (RMC) in Canada. Methods:Resource utilization associated with Oral Anticoagulant Management (ROAM) is a prospective cohort study being conducted across 9 Canadian provinces whose objective is to describe the process and quality of care, RU, clinical events and health utility scores associated with long-term oral anticoagulant (warfarin) therapy in patients with new onset or chronic NVAF. Eligible, consenting patients are followed for 48 weeks and complete a weekly study diary providing data on international normalized ratio (INR) test dates and values, RU associated with warfarin monitoring, and all physician visits, procedures and hospitalizations. Health utility scores, representing the patient's health state, measured using the EuroQol-5D (EQ-5D) standardized QoL instrument are collected every 4 weeks. INR test values and dates and source documentation around patient reported clinical events are also collected from the participating physicians. Results:497 out of a planned enrolment of 600 patients have been recruited. 180 patients with completed 48 week follow-up and physician-provided INR values are included in this analysis, 98% from primary care physicians and specialists (RMC) and 2% from anticoagulant clinics. Median age [range] was 75 [39, 90] years with 67% males. Common co-morbidities were hypertension (60%) and ischemic heart disease (27%). Estimated median [range] time since NVAF diagnosis was 4 [0, 32] years. Physicians reported a total of 2484 INR tests over the study duration (a mean of 13.8 tests per patient) while patients recorded 2711 tests being completed in their diaries over the same time period (a mean of 15.06 tests per patient). Of the 2711 patient reported tests only 1914 INR results (71%) were communicated back to patients via telephone (70%) or in person (15%). Median [quartile] time between the INR test and the patient acquiring the results was 1.4 [1.0, 2.5] days. The INR test dates provided by physicians matched the dates recorded by patients in the diary 67% of the time. 51 (28%) of patients recorded no INR values. Of the 129 patients with at least one recorded INR value, physician and patient INR values matched completely for only 8 (4%) patients and matched on average 62% of the time (range 30% to 98%) for the rest. Mean [95% CI] time in therapeutic range (TTR) by the Rosendaal method was 67% [64%, 71%] using physician reported values and 67% [62%, 72%] based on patient reported values. Mean INR testing frequency was 30 days following an INR in the therapeutic range, 25 days following an INR of less than 2 and 22 days following an INR greater than 3. Three strokes and 3 bleeds were self-reported in 5 patients (9%) that are being adjudicated. The initial mean [95% CI] health utility score was 0.85 [0.83, 0.88]. A decrease in health utility score was observed in 133 (74%) of the patients based on a random effects regression model. Fixed effect estimate of the mean [95% CI] change in health utility scores per 6 months was −0.01 [0, −0.02]. Covariates (age, gender and time since diagnosis) were investigated but had limited effect on the health utility score. Conclusions:This is the first prospective cohort study of NVAF patients on long-term warfarin therapy being monitored primarily through RMC in Canada. The majority of patients are monitored via telephone with frequent miscommunication between health care providers and patients about INR results and delays in getting results to patients. TTR is higher than previously reported for RMC, which may suggest a self-selection bias for better quality physician-patient combinations. Although frequency of testing was appropriate for in-range INRs, the times to testing after out-of-range results appear delayed. Analysis of health utility scores showed a small decrease in health status over time in this cohort of patients with generally high health utility scores. Relationship between TTR and clinical events will be presented. Disclosures:Selby:Boehringer Ingelheim: Honoraria, Research Funding. Mittmann:Boehringer Ingelheim: Research Funding. Isogai:Boehringer Ingelheim: Research Funding. Kaus:Boehringer Ingelheim: Research Funding. Koo:Boehringer Ingelheim: Research Funding. Sealey:Boehringer Ingelheim: Research Funding.

Randomized Trial of a Warfarin Communication Protocol for Nursing Homes: an SBAR-based Approach

Background More than 1.6 million Americans currently reside in nursing homes. As many as 12% of them receive long-term anticoagulant therapy with warfarin. Prior research has demonstrated compelling evidence of safety problems with warfarin therapy in this setting, often associated with suboptimal communication between nursing home staff and prescribing physicians. Methods We conducted a randomized trial of a warfarin management protocol using facilitated telephone communication between nurses and physicians in 26 nursing homes in Connecticut in 2007-2008. Intervention facilities received a warfarin management communication protocol using the approach “Situation, Background, Assessment, and Recommendation” (SBAR). The protocol included an SBAR template to standardize telephone communication about residents on warfarin by requiring information about the situation triggering the call, the background, the nurse's assessment, and recommendations. Results There were 435 residents who received warfarin therapy during the study period for 55,167 resident days in the intervention homes and 53,601 in control homes. In intervention homes, residents' international normalized ratio (INR) values were in the therapeutic range a statistically significant 4.50% more time than in control homes (95% confidence interval [CI], 0.31%-8.69%). There was no difference in obtaining a follow-up INR within 3 days after an INR value ≥4.5 (odds ratio 1.02; 95% CI, 0.44-2.4). Rates of preventable adverse warfarin-related events were lower in intervention homes, although this result was not statistically significant: the incident rate ratio for any preventable adverse warfarin-related event was .87 (95% CI, .54-1.4). Conclusion Facilitated telephone communication between nurses and physicians using the SBAR approach modestly improves the quality of warfarin management for nursing home residents. (Registered on ClinicalTrials. gov; URL: http://clinicaltrials.gov/. Registration number: NCT00682773).

Empiric warfarin dose adjustment with prednisone therapy. A randomized, controlled trial

Typically, the international normalized ratio (INR) is monitored and warfarin dose adjusted, if necessary, to correct non-therapeutic INR after interacting medications, like prednisone, are initiated during warfarin therapy. Preemptively adjusting the warfarin dose is another approach. To evaluate the utility of preemptive warfarin dosage adjustment for preventing non-therapeutic INR following prednisone-warfarin co-administration. Patients were randomized to either a preemptive warfarin dose reduction between 10 and 20% (intervention) or reactive warfarin dose adjustment (control) within 72 h of warfarin-prednisone co-administration. Subjects received a follow-up INR within 7 days. Primary outcome was the occurrence of follow-up INR ≥ 1 point over the INR goal range upper limit. Secondary outcomes included INR control, purchases of prescription vitamin K, and warfarin-associated adverse events in the 30 days after prednisone initiation. Twenty and 17 patients comprised the intervention and control groups. The intervention group's warfarin dose was reduced by a median of 11.8%. More control patients (n = 5) experienced an INR ≥ 1 point over the INR goal range upper limit compared to intervention (n = 2); however, the actual difference (29.4 vs.10.0%) was not statistically significant (P = 0.21). A higher percentage of intervention patients had a subtherapeutic follow-up INR compared to control (40 vs. 5.9%, P = 0.02). One patient from each group experienced warfarin-associated bleeding. No thromboembolic complications or vitamin K purchases were observed. For patients initiating prednisone therapy, preemptive warfarin dose reduction resulted in a non-significant reduction in supratherapeutic INR but increased the likelihood of subtherapeutic INR compared to INR monitoring with reactive warfarin dose adjustment.

Pharmacy Students Provide Care Comparable to Pharmacists in an Outpatient Anticoagulation Setting

To evaluate whether student participation in ambulatory clinics influenced the percentage of therapeutic international normalized ratio (INR) results among patients on chronic warfarin therapy. Medical records in outpatient anticoagulation clinics managed by pharmacists under physician protocol were reviewed retrospectively in 2 university-affiliated clinics in Amarillo and Lubbock, TX. Pharmacy student activities included patient interviews, vital sign measurements, fingersticks, counseling, and documentation. Patient visits were conducted by a precepted pharmacy student or a pharmacist without a student, and the INR was measured at the subsequent patient visit. Records of 1,958 anticoagulation patient visits were reviewed; 865 patients were treated by pharmacists, and 1093 were treated by precepted students. The follow-up INR was therapeutic for 48.5% of third-year (P3) students' patients, 45.6% of fourth-year (P4) students' patients, 51.2% of residents' patients, and 44.7% of pharmacists's patients (p = 0.23). Eight variables were associated with the follow-up INR (baseline INR, warfarin noncompliance, held warfarin doses, a warfarin dosage adjustment, diet change, alcohol use, tobacco use, and any medication changes). Student participation in the patient-care process did not compromise patient care and no significant difference in patient outcomes was found between patients in an anticoagulation clinic cared for by precepted students and those cared for by pharmacists.

Black licorice ingestion: Yet another confounding agent in patients with melena

We describe an 80-year-old woman with atrial fibrillation, anti-coagulated with warfarin, who on two separate occasions developed black tarry stools and an elevated international normalized ratio (INR) after eating a pound of Black Licorice. During her most recent episode, her hematocrit was 14 (baseline 34) and her INR was 5.5 (baseline 2.1). She was advised to restrict licorice consumption, and a follow-up INR two weeks later was 1.2. Black Licorice is derived from the root of the plant, Glycyrrhiza glabra. The components of its extract inhibit the P450 system enzymes that metabolize Warfarin, inhibit thrombin, and prolong fibrinogen clotting times. Hence, the anti-thrombotic activity and inhibition of warfarin metabolism might synergistically amplify anti-coagulation. The presence of Black Licorice in the stool can also mimic melena and confound its clinical presentation. Health care providers should caution patients who are at risk for bleeding or on warfarin to avoid black licorice due to an elevated risk of gastrointestinal bleeding.

Single-dose adjustment versus no adjustment of warfarin in stably anticoagulated patients with an occasional international normalized ratio (INR) out of range

Background Well-controlled patients on warfarin may still have occasional International Normalized Ratios (INRs) outside the therapeutic range. It is unclear whether there is any benefit of a single-dose correction in this situation. Aim To evaluate whether patients with very stable INR results should continue with the maintenance dose of warfarin without a single-dose correction, even when the result unexpectedly is moderately below or above the therapeutic range. Methods A) We reviewed retrospectively 364 patients with unchanged maintenance dose for at least 6 months and an occasional INR outside the therapeutic range regarding decision on dosing and the effect on the next INR. B) We randomized 160 patients with at least 3 months of unchanged maintenance dose, an occasional INR deviating to a minimum of 1.5 or a maximum of 4.4 and unexplained or temporary, removable cause to a single-dose Change or No change. Follow-up INRs and telephone interviews were obtained after 2 weeks. Results A) Retrospectively, the proportion of follow-up INRs outside the therapeutic range was 29.9% after No change, 27.1% after Increased dose and 25.7% after Skipped/reduced dose. However, the decision on No change was mainly taken in case of minimal INR deviations. B) Forty-eight (60%) of the patients randomized to Change were within the therapeutic range at follow-up versus 45 (56%) of those with No change, odds ratio 1.17 (95% confidence interval 0.59-2.30). For baseline INRs deviating down to 1.6 or up to 3.6 (therapeutic range, INR 2.0-3.0) the 2-week INRs did not differ between the groups. Conclusion Our results suggest only a small or no difference between the two managements of an occasional INR out of range in terms of the 2-week follow-up INR. In stable patients on warfarin with an occasional INR outside the therapeutic range it seems reasonable to continue with the same dose without a single-dose change and perform a repeat test in about 2 weeks. (ClinicalTrials.gov number, NCT00814177.)

Vigilant Monitoring Avoids Adverse Reactions

Vigilant Monitoring Avoids Adverse Reactions

Systemic Anticoagulation and Prevention of Hemodialysis Catheter Malfunction

Although chronic anticoagulation is commonly prescribed to prevent thrombosis and malfunction of hemodialysis tunneled cuffed catheters (TCC), there are only limited data regarding its efficacy. The aim of this prospective study was to evaluate whether anticoagulation with adjusted-dose warfarin targeting an international normalized ratio (INR) of 1.5-2.0 is associated with improved catheter outcome in long-term patients at high risk of TCC malfunction. Among the 65 patients included in the study, 35 were considered at high risk (i.e., patients with a history of previous TCC thrombosis requiring catheter replacement and/or with TCC malfunction occurring within 2 weeks after catheter insertion in the absence of mechanical problems) and were prescribed warfarin, whereas 30 low-risk patients did not receive anticoagulation. During follow-up, TCC malfunction, defined as the need for inversion of catheter lines and/or recombinant tissue-type plasminogen activator infusion, was observed in 61.5% of patients. Among patients receiving warfarin, 19 (54.3%) achieved adequate anticoagulation (i.e., > 80% of follow-up INR values and INR value at the time of malfunction within target range). Anticoagulation was considered inadequate in 16 patients (45.7%). Malfunction-free catheter survival at 9 months was 47.1% in patients with adequate anticoagulation compared with 8.1% in patients with inadequate anticoagulation (p = 0.01). This difference remained statistically significant after adjustment for aspirin intake. These results suggest that achieving adequate anticoagulation with target INR 1.5-2.0 may prevent TCC malfunction and improve catheter outcome.

Warfarin Dose Reduction vs Watchful Waiting for Mild Elevations in the International Normalized Ratio

Whether clinicians should decrease the warfarin dose in response to a mild, asymptomatic elevation in the international normalized ratio (INR) is unknown. The study objectives were as follows: (1) to evaluate the safety of an anticoagulation service (ACS) policy advocating that the warfarin dose not be changed for isolated, asymptomatic INRs of < or = 3.4; (2) to compare the dosing strategies of an ACS and primary care providers (PCPs); and (3) to quantify the relationship between reduction of the warfarin dose and the subsequent fall in the INR. Randomized controlled study of health maintenance organization outpatients who were receiving warfarin. We identified 231 patients with a target INR of 2.5 and an isolated, asymptomatic INR between 3.2 and 3.4. Our ACS monitored 103 of the patients; PCPs monitored the remaining 128 patients. From all 231 patients, we obtained INRs and warfarin dosing history. From the 103 ACS enrollees, we also recorded adverse events. One ACS patient had epistaxis in the 30 days after the elevated INR. Twenty-three percent of ACS enrollees and 47% of PCP patients reduced their warfarin dose (p < 0.001). The median follow-up INRs were similar in both cohorts: 2.7 in the ACS enrollees and 2.6 in the PCP patients. However, in a subgroup analysis of 190 patients who presented with an INR of 3.2 or 3.3, ACS enrollees were more likely to have a follow-up INR in the range of 2 to 3 (p = 0.03). The median follow-up INR was 2.7 in 148 patients who maintained their warfarin dose, 2.5 in 77 patients who decreased their dose by 1 to 20%, and 1.7 in 6 patients who decreased their dose by 21 to 43% (p < 0.001). These findings support maintaining the same warfarin dose in asymptomatic patients with an INR of < or = 3.3, and reducing the dose for patients who have a greater INR or an increased risk of hemorrhage. Warfarin dose reductions > 20% should be avoided for mildly elevated INRs.

Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin.

An elevated international normalized ratio (INR) increases the risk for major hemorrhage during warfarin therapy. Optimal management of patients with asymptomatic elevations in INR is hampered by the lack of understanding of the time course of INR decay after cessation of warfarin therapy. To identify predictors of the rate of INR normalization after excessive anticoagulation. Retrospective cohort study. Outpatient anticoagulant therapy unit. Outpatients with an INR greater than 6.0 were identified from August 1993 to September 1998. Patients in whom two doses of warfarin were withheld and a follow-up INR was obtained on the second calendar day were enrolled. No patient received vitamin K(1). The INR was measured 2 days after an INR greater than 6.0 was recorded. Of 633 study patients with an initial INR greater than 6.0, 232 (37%) still had an INR of 4.0 or greater after two doses of warfarin were withheld. Patients who required larger weekly maintenance doses of warfarin were less likely to have an INR of 4.0 or greater on day 2 (adjusted odds ratio per 10 mg of warfarin, 0.87 [95% CI, 0.79 to 0.97]). Other risk factors for having an INR of 4.0 or greater on day 2 included age (odds ratio per decade of life, 1.18 [CI, 1.01 to 1.38]), index INR (odds ratio per unit, 1.25 [CI, 1.14 to 1.37]), decompensated congestive heart failure (odds ratio, 2.79 [CI, 1.30 to 5.98]), and active cancer (odds ratio, 2.48 [CI, 1.11 to 5.57]). Steady-state warfarin dose, advanced age, and extreme elevation in INR are risk factors for prolonged delay in return of the INR to within the therapeutic range. Decompensated congestive heart failure and active cancer greatly increase this risk.