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Journal of Thrombosis and Haemostasis, 8: 744–749
DOI: 10.1111/j.1538-7836.2010.03756.x
ORIGINAL ARTICLE
Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users D. M. WITT,* à T. DELATE, à N. P. CLARK,* C. MARTELL, T. TRAN, M. A. CROWTHER,§ D . A . G A R C I A , – W . A G E N O * * and E . M . H Y L E K O N B E H A L F O F T H E W A R P E D C O N S O R T I U M 1 *Kaiser Permanente Colorado Clinical Pharmacy Anticoagulation Service, Lafayette, CO; University of Colorado School of Pharmacy, Denver, CO; àKaiser Permanente Colorado Clinical Pharmacy Research Team, Aurora, CO, USA; §McMaster University, Hamilton, Canada; –University of New Mexico School of Medicine, Albuquerque, NM, USA; **University of Insubria, Varese, Italy; and Boston University School of Medicine, Boston, MA, USA
To cite this article: Witt DM, Delate T, Clark NP, Martell C, Tran T, Crowther MA, Garcia DA, Ageno W, Hylek EM, on behalf of the WARPED Consortium. Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users. J Thromb Haemost 2010; 8: 744–9.
Summary. Background: For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible. Objective: To identify patients with stable INRs (INR values exclusively within the INR range) and comparator patients (at least one INR outside the INR range), compare occurrences of thromboembolism, bleeding and death between groups, and identify independent predictors of stable INR control. Methods: The study was a retrospective, longitudinal cohort study using data extracted from electronic databases. Patient characteristics and risk factors were entered into multivariate logistic regression models to identify variables that independently predict stable INR status. Results: There were 533 stable and 2555 comparator patients. Bleeding and thromboembolic complications were significantly lower in stable vs. comparator patients (2.1% vs. 4.1% and 0.2% vs. 1.3%, respectively; P < 0.05). Independent predictors of stable INR control were age >70 years, male gender and the absence of heart failure. Stable patients were significantly less likely to have target INR ‡3.0 or chronic diseases. Conclusion: A group of patients with exclusively therapeutic INR values over 12 months is identifiable. In general, these patients are older, have a target INR 4 weeks. Keywords: clinical outcomes, international normalized ratio, monitoring, warfarin. Introduction Warfarin is effective for the prevention and treatment of arterial and venous thromboembolic disorders. Intra- and interpatient variability in dose response, susceptibility to drug– drug and drug–food interactions and a narrow therapeutic index necessitate periodic monitoring of physiologic response to warfarin using the international normalized ratio (INR) [1]. In addition, to provide the best combination of thrombosis reduction and bleeding avoidance, target INR ranges are varied by therapeutic indication (e.g. an INR target range of 2.0–3.0 for atrial fibrillation or venous thrombosis and 2.5–3.5 for patients with mechanical heart valves) [1]. While the INR is used to monitor the impact of warfarin therapy, few studies have addressed the optimization of INR measurement frequency or INR recall interval. Current guidelines suggest an INR recall interval not exceeding 4 weeks between measurements [1,2]. However, this suggestion is not evidence-based, having evolved instead from regional differences in routine clinical practise and expert opinion [3]. Frequent INR testing, perhaps as often as weekly, has been suggested for patients who self-monitor warfarin using pointof-care technology [1,4,5]. High frequency INR testing raises the likelihood of measuring slightly out-of-range INR values (which often leads to unnecessary warfarin dose changes) [6], increases the costs associated with warfarin therapy, and is probably unnecessary in those patients who demonstrate longterm INR stability (i.e. minimal INR deviation and longitudinal warfarin dose stability). Less frequent INR monitoring should be possible for patients with a stable warfarin dose, as 2010 International Society on Thrombosis and Haemostasis
Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users 745
suggested by routine clinical practise in the United Kingdom where INR recall intervals of up to 90 days are employed in such patients [7]. Recent evidence suggests that longer INR recall intervals may also be associated with improved INR control [8,9], which has in turn been associated with reduced risk for anticoagulation therapy-related adverse events [10,11]. Moreover, anticoagulated patients with 6-month stable INR control have been identified [12]. Patients with such stable INR control experienced significantly fewer anticoagulation therapy-related complications compared with anticoagulated patients who did not have 6 months of stable INR control. The objective of this investigation was to expand on previous research by identifying anticoagulated patients with very stable (i.e. all INR values in the therapeutic range during a 12-month time interval) INR control. In addition to identifying patient characteristics associated with very stable INR values, we compared the rates of anticoagulation therapy-related adverse events with those from a group of comparator patients whose INR control was less stable. Patients and methods Study design and setting
The study was a retrospective, longitudinal cohort study conducted at Kaiser Permanente Colorado (KPCO), an integrated health care delivery system that provides services to over 450 000 members in the Denver–Boulder metropolitan area. Anticoagulation services at KPCO are provided by a centralized Clinical Pharmacy Anticoagulation Service (CPAS) [11]. Working collaboratively with the referring physician and using standardized dosing algorithms [13], CPAS clinical pharmacists initiate, adjust and refill anticoagulant medications and order relevant laboratory tests. Dosing algorithms utilized during this study at KPCO specified a maximum INR recall interval of 6 weeks. Integrated, electronic medical, pharmacy and laboratory records systems and the CPAS database (Dawn-AC; 4S Systems, Ltd., Milnthorpe, UK) were utilized to identify patients, treatments and outcomes for this study. Approval to conduct this study was obtained from the KPCO Institutional Review Board. Patients
Patients with a duration of warfarin therapy in excess of 90 days during the study timeframe (January 2000 through to December 2005), an age of greater than 18 years and warfarin therapy continuing throughout at least one 12-month observation period were included in the study. Stable patients were defined as having all INR values within each patientÕs strictly defined therapeutic INR range for the first identifiable continuous 12-month period (i.e. 100% INR control) during the study timeframe. Comparator patients were those who did not have any continuous 12-month period where all INR values were within the therapeutic range. In order to ensure a minimal standard for compliance with ongoing INR monitoring, both 2010 International Society on Thrombosis and Haemostasis
stable and comparator patients had to have at least one INR determination every 8 weeks during the 12-month observation period. For example, a patient who had an INR target range of 2.0–3.0, at least one INR measurement every 2 months for a minimum of six measurements, and all INR values recorded during the 12-month observation period between 2.0 and 3.0, would be assigned to the stable group. Data collection
Variables collected for analysis included the primary warfarin indication, age at start of the 12-month observation period, gender, INR target, duration of warfarin therapy, and INR values. Patient-specific factors that could influence the risk for anticoagulant-related complications also were recorded, including a history of diabetes, hypertension, heart failure, venous thrombosis, hemorrhage, stroke, cancer, and/or use of estrogen therapy. Risk factors were considered present when a coded assessment for a given factor during a KPCO healthcare visit was identified in the 180 days prior to the start of the observation period. Estrogen therapy was defined as a prescription for a systemic estrogen-containing product sold within 90 days prior to the start of the observation period. A validated measure of patient acuity, the chronic disease score (CDS), was calculated for each patient by using ambulatory prescription drug data from the observation period [14]. Chronic disease scores can range from 0 to 35, with increasing scores indicating an increasing burden of chronic diseases under treatment. Use of the CDS allows for the accounting of each patientÕs risk of mortality and future health care utilization [14,15]. The first occurrence of anticoagulant-related complications (thromboembolism, bleeding and death) requiring admission to the hospital or emergency department were sought using ICD-9 discharge diagnostic codes (available upon request) within KPCO electronic administrative databases. All events were subsequently confirmed through independent review of the patientÕs electronic medical record by two investigators. Events were scored using a modified Naranjo Scale to quantify the relationship of the adverse event with warfarin therapy [16]. A third reviewer was employed to resolve disagreements. Thromboembolic complications were defined as any deep vein thrombosis, pulmonary embolism, cerebral vascular accident, transient ischemic attack, systemic embolism, or heart valve thrombosis. Bleeding complications included episodes such as intracranial bleeding, gastrointestinal hemorrhage, hematoma, hemoptysis, epistaxis and hematuria. All bleeding episodes resulting in admission to the emergency department or hospital were included regardless of severity. Fatal events were assessed for direct relationship to bleeding or thromboembolism using the medical record and/or a death certificate. Statistical analysis
Data analyses were performed utilizing SAS 9.1.3 (SAS, Cary, NC, USA) statistical software. Patient characteristics were
746 D. M. Witt et al
reported as means and standard deviations for interval-level variables (e.g. age, warfarin dose, length of warfarin therapy, etc.) and percentages for categorical variables (e.g. gender, target INR, occurrence of anticoagulation therapy-related complications, etc.). Group associations between categorical variables were assessed using the chi-square test and continuous variables were compared between groups using the independent samples t-test or Wilcoxon rank sum test (depending on the distribution of the data). Patient characteristics and risk factors with an overall incidence of ‡1% were entered into a multivariate logistic regression model to identify variables that independently predicted INR stability. The alpha was set at 0.05. Results Records from 4701 patients were screened; of these, 3088 patients had a period where at least one INR was measured every 8 weeks for 12 months. The stable group comprised 533 patients with INR values within the desired reference interval on all determinations and the comparator group comprised 2555 patients with at least one INR outside the desired reference interval. Baseline characteristics of stable and comparator patients are presented in Table 1. Stable patients were older and more likely to have had a target INR 70 years [odds ratio (OR) = 1.93, 95% confidence interval (CI) 1.56– 2.38], male sex (OR = 1.44, 95% CI 1.16–1.78), target INR of 2.0 (OR = 2.80, 95% CI 1.83–4.28), and the absence of comorbid heart failure (OR = 2.08, 95% CI 1.36–3.17) (Table 3). Conversely, an increasing burden of chronic illness (i.e. higher CDS) (OR = 0.92, 95% CI 0.88–0.95) and a target
Table 1 Baseline characteristics
Characteristic
Stable group (n = 533)
Comparator group (n = 2555)
Mean age* (SD) 72.9 (9.5) 67.9 (13.5) Age >70 years (%) 65.5 48.7 Male (%) 58.7 50.0 INR target (%) 2.0 7.5 2.5 2.5 86.1 77.2 ‡3.0 6.4 20.3 Primary indication for anticoagulation therapy (%) Atrial fibrillation 51.0 41.4 Venous 23.3 26.0 thromboembolism Heart valve 6.4 14.9 replacement Other 19.3 17.8 risk factors (%) Diabetes mellitus 2.4 4.2 22.3 23.1 Hypertension Heart failure 5.1 10.6 Prior venous 2.4 4.3 thrombosis Prior hemmorhage 0.8 1.7 Prior stroke 0.0 0.1 Cancer 0.2 0.7 8.4 11.5 Estrogen therapyà Mean chronic disease 6.2 (2.1) 6.7 (2.7) score (SD) Median duration of 1220 (615, 1940) 790 (726, 1782) warfarin therapy (days)§ (IQR)
P-value
