A comparison of anticoagulation results of patients managed with narrow vs. standard international normalized ratio target ranges.

Abstract

While most patients anticoagulated with warfarin have a therapeutic range that is 1.0 international normalized ratio (INR) unit wide, it is not uncommon for physicians to select narrower INR target ranges in an attempt to more tightly control anticoagulation and minimize complications. For example, a physician may select an INR target range of 2.0–2.5 for a patient with atrial fibrillation who is at high risk of bleeding, or an INR range of 3.0–3.5 for a patient with a prosthetic mitral valve who is considered at high risk of thrombosis. However, the outcomes associated with narrow‐ vs. standard‐range INR management strategies have never been compared. Furthermore, it has never been determined whether aiming for tighter anticoagulation control by selecting narrower INR ranges actually achieves reduced variation in INR results. We compared the INR outcomes of a cohort of patients managed with a narrow INR range (i.e. 0.5 INR unit wide) and a standard INR range (i.e. 1.0 INR unit wide) at separate times during their course of anticoagulation. We retrospectively evaluated all patients followed by the University of Michigan Health System Anticoagulation Management Service (AMS), a nurse‐staffed, outpatient service that utilizes standardized treatment algorithms to manage patients whose INR ranges are set by the referring attending physician. We identified 57 patients managed at different times by the AMS with a narrow INR range (2.0–2.5, 2.5–3.0, 3.0–3.5, or 3.5–4.0) and a standard INR range (2.0–3.0, 2.5–3.5, or 3.0–4.0), each for at least 90 days. Forty‐two patients were converted from a narrow to a standard range by their attending physician after being asked to do so by the AMS Medical Director, who made this request simultaneously to all attending physicians of patients with INR ranges less than 1.0 INR unit wide, without any review of INR results of individual patients, in an attempt to increase adherence to published anticoagulation guidelines. Fifteen patients were converted by their attending physicians from a standard to a narrow INR range in an attempt to achieve tighter anticoagulation control. Sixteen patients were managed with the narrow range 2.0–2.5 and the standard range 2.0–3.0 (Group 1), and 16 patients were managed with the narrow range 3.0–3.5 and the standard range 2.5–3.5 (Group 2). The remaining 25 patients were managed with other combinations of narrow and standard INR ranges. We excluded from analysis INR results obtained within 30 days of initiating warfarin or within 14 days after changing the INR target range or transiently interrupting warfarin for an invasive procedure. The study population included 35 men and 22 women with mean age 57.0 ± 18.5 years. Commonest indications for anticoagulation were prosthetic cardiac valve (53%), atrial fibrillation (30%), stroke/transient ischemic attack (28%), and venous thromboembolism (14%), with some patients having multiple indications. As expected, for all 57 patients, narrow‐range management resulted in a lower % of INRs in‐range than standard‐range management (row E of Table 1). A narrow‐range strategy was associated with a higher frequency of blood draws (row K). Interestingly, the coefficient of variation of INR results (i.e. standard deviation of INR results divided by the mean INR [1Nozawa T. Asanoi H. Inoue H. Instability of anticoagulation intensity contributes to occurrence of ischemic stroke in patients with non‐rheumatic atrial fibrillation.Jpn Circ J. 2001; 65: 404-8Crossref PubMed Scopus (18) Google Scholar]) did not differ significantly between narrow‐ vs. standard‐range management strategies (row L). There were five thromboembolic events, four during standard‐range management (three deep venous thromboses and one stroke) and one during narrow‐range management (stroke). There was one major bleed (gastrointestinal) during standard‐range management and none during narrow‐range management.Table 1Summary of international normalized ratio (INR) dataAll patients (n= 57)Group 1 (n= 16)Group 2 (n= 16)NarrowStandard2.0–2.52.0–3.03.0–3.52.5–3.5ANumber INRs422215829994281159444BPt‐yrs174.979.846.422.446.622.9CMean FU/pt (yrs)3.0 ± 1.51.4 ± 1.0†2.9 ± 1.51.4 ± 0.9*2.9 ± 1.41.4 ± 1.3*DMean INR––2.4 ± 0.12.6 ± 0.2*3.4 ± 0.13.1 ± 0.2†E% INRs in range31.3 ± 12.953.2 ± 14.7†40.0 ± 12.963.8 ± 15.6†25.2 ± 9.348.5 ± 12.7†F% time in range––40.0 ± 11.770.1 ± 11.4†30.4 ± 11.758.3 ± 13.4†G% INRs < 2.0––23.6 ± 9.617.2 ± 10.6†4.6 ± 3.67.7 ± 8.5‡H% time INR < 2.0––20.6 ± 10.813.9 ± 9.5*2.0 ± 2.23.3 ± 4.5‡I% INRs > 4.0––2.2 ± 3.64.0 ± 6.3§21.2 ± 5.513.0 ± 9.1*J% time INR > 4.0––1.0 ± 2.01.7 ± 3.5‡16.0 ± 7.89.4 ± 8.7*KMean blood draws/90 days6.1 ± 2.45.3 ± 2.1*5.2 ± 1.45.4 ± 2.7‡7.0 ± 2.84.7 ± 0.1*LMean CV0.29 ± 0.110.29± 0.10‡0.28 ± 0.020.26 ± 0.10‡0.30 ± 0.070.29 ± 0.10‡pt, patient; FU, follow‐up; CV, coefficient of variation. For intra‐group comparisons: *P < 0.05; †P< 0.001; ‡P ≥ 0.2; §P > 0.1. Open table in a new tab pt, patient; FU, follow‐up; CV, coefficient of variation. For intra‐group comparisons: *P < 0.05; †P< 0.001; ‡P ≥ 0.2; §P > 0.1. For Group 1, a narrow‐ vs. standard‐range strategy was associated with a lower mean INR, % of INR results in range, and % of time in range (determined as described [2Rosendaal F.R. Cannegieter S.C. Van Der Meer F.J. Briet E. A method to determine the optimal intensity of oral anticoagulant therapy.Thromb Haemost. 1993; 69: 236-9Crossref PubMed Scopus (1661) Google Scholar]) (rows D–F, respectively). There was a significantly higher % of INR results < 2.0 during narrow‐ vs. standard‐range management, and a significant increase in the % of time that the INR was < 2.0 (rows G, H). However, there was no significant difference in the % of INR results > 4.0 during narrow‐ vs. standard‐range management, or in the % of time that the INR was > 4.0 (rows I, J). There was no significant difference in the frequency of blood draws between management strategies (row K). For Group 1 patients, narrow‐range management was not associated with tighter anticoagulation control (row L). For Group 2, a narrow‐ vs. standard‐range strategy was associated with a higher mean INR (row D). As anticipated, narrow‐range management was associated with a lower % of INRs in range and a lower % of time in range than standard‐range management (rows E, F). There was a higher % of INR results > 4.0 during narrow‐ than standard‐range management, and a higher % of time that the INR was > 4.0 (rows I, J). However, the incidence of INR results < 2.0 did not differ significantly between narrow‐ vs. standard‐range management (rows G, H). For Group 2, the frequency of blood draws was significantly higher for patients managed with a narrow‐range strategy (row K). Narrow‐ and standard‐range strategies resulted in nearly identical INR variability (row L). Our data demonstrate that a narrow‐range strategy is associated with more frequent INR testing, which has significant cost and patient convenience implications. Interestingly, our data suggest that aiming at a narrower INR range does not result in tighter anticoagulation control. Our analyses of Group 1 (INR 2.0–2.5 vs. 2.0–3.0) and Group 2 (INR 3.0–3.5 vs. 2.5–3.5) suggest that aiming at a narrower range shifts the mean INR in the intended direction. However, these desirable results were obtained at some cost. For Group 1, there was a significant increase in the incidence of INR results that were < 2.0 during narrow‐range management. INR values < 2.0 are strongly associated with an increased risk of thrombosis [3Hylek E.M. Skates S.J. Sheehan M.A. Singer D.E. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation.N Engl J Med. 1996; 335: 540-6Crossref PubMed Scopus (760) Google Scholar, 4Hylek E.M. Go A.S. Chang Y. Jensvold N.G. Henault L.E. Selby J.V. Singer D.E. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.N Engl J Med. 2003; 349: 1019-26Crossref PubMed Scopus (1113) Google Scholar]. Similarly, the Group 2 data suggest that while it is possible to shift the INR higher with a narrow‐range management strategy, such an approach increases the frequency of INR testing and significantly increases the incidence of INR results that are associated with increased hemorrhagic risk [5Hylek E.M. Singer D.E. Risk factors for intracranial hemorrhage in outpatients taking warfarin.Ann Intern Med. 1994; 120: 897-902Crossref PubMed Scopus (869) Google Scholar]. Importantly, narrow‐range management strategies in Groups 1 and 2 did not yield tighter anticoagulation control than standard‐range management. Each patient in our study was managed with both narrow‐ and standard‐range INR management strategies, which controlled for multiple patient‐specific variables that affect anticoagulation. While the number of patients was modest, the total number of INRs and duration of follow‐up was substantial (rows A–C). Limitations of our study were its retrospective design, the inability to determine the impact of narrow vs. standard INR range on bleeding and thrombotic complications and the frequency of warfarin dose adjustments, and the fact that conversions between narrow and standard INR ranges were left to the discretion of the managing physician, which potentially introduced bias. As a whole, our data suggest that a narrow‐range INR strategy does not offer significant advantages over a standard‐range INR strategy. While a narrow‐range strategy can shift the level of anticoagulation in the intended direction, the net change in mean INR is relatively minor. In addition, a narrow INR management strategy results in a significantly increased incidence of out‐of‐range INR results and blood draws. The incidence of INR results in ranges associated with increased risk of thrombosis and bleeding risk also appears to be increased during narrow‐range INR management. Furthermore, our data suggest that aiming at a narrower INR range does not actually achieve tighter anticoagulation control. Therefore, we recommend that physicians generally avoid narrow‐range INR management strategies, realizing that there may be situations in which a narrow‐range target may be reasonable, provided that the potential limitations of such a strategy are considered. A prospective, randomized study comparing the effects of narrow‐ vs. standard‐range INR management on INR results, clinical events, and costs is indicated. The authors state that they have no conflict of interest. We are grateful for the kind assistance of the University of Michigan Anticoagulation Management Service and especially J. Merz, RN, MSN for her help with this project. We are also thankful for the data analysis contributions of D. Montgomery.