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Original Research: ANTITHROMBOTIC THERAPY |

Reexamining the Recommended Follow-up Interval After Obtaining an In-Range International Normalized Ratio ValueFollow-up Interval for Patients With Good Control: Results from the Veterans Affairs Study to Improve Anticoagulation FREE TO VIEW

Adam J. Rose, MD; Al Ozonoff, PhD; Dan R. Berlowitz, MD, MPH; Arlene S. Ash, PhD; Joel I. Reisman, AB; Elaine M. Hylek, MD, MPH
Author and Funding Information

From the Center for Health Quality, Outcomes, and Economic Research (Drs Rose, Ozonoff, and Berlowitz and Mr Reisman), Bedford VA Medical Center, Bedford; the Department of Medicine, Section of General Internal Medicine (Drs Rose, Berlowitz, Ash, and Hylek), and the Department of Health Policy and Management (Dr Berlowitz), Boston University School of Public Health; the Biostatistics Section (Dr Ozonoff), Boston Children’s Hospital, Boston; and the Department of Quantitative Health Sciences, Division of Biostatistics and Health Services Research (Dr Ash), University of Massachusetts School of Medicine, Worcester, MA.

Correspondence to: Adam J. Rose, MD, Center for Health Quality, Outcomes, and Economic Research, Bedford VA Medical Center, 200 Springs Rd, Bldg 70, Bedford, MA 01730; e-mail: adamrose@bu.edu


Funding/Support: This study was funded by a Career Development Award [CDA2-08-017] to Dr Rose from the Health Services Research and Development Service of the US Department of Veterans Affairs.

For editorial comment see page 281

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(2):359-365. doi:10.1378/chest.10-2738
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Background:  Patients receiving oral anticoagulation therapy should be tested often enough to optimize control, but excessive testing increases burden and cost. We examined the relationship between follow-up intervals after obtaining an in-range (2.0-3.0) international normalized ratio (INR) and anticoagulation control.

Methods:  We studied 104,451 patients who were receiving anticoagulation therapy from 100 anticoagulation clinics in the US Veterans Health Administration. Most patients (98,877) had at least one in-range INR followed by another INR within 56 days. For each such patient, we selected the last in-range INR and characterized the interval between this index value and the next INR. The independent variable was the site mean follow-up interval after obtaining an in-range INR. The dependent variable was the site mean risk-adjusted percentage of time in the therapeutic range (TTR).

Results:  The site mean follow-up interval varied from 25 to 38 days. As the site mean follow-up interval became longer, the risk-adjusted TTR was worse (−0.51% per day, P = .004). This relationship persisted when the index value was the first consecutive in-range INR (−0.63%, P < .001) or the second (−0.58%, P < .001), but not the third or greater (−0.12%, P = .46).

Conclusions:  Sites varied widely regarding follow-up intervals after obtaining an in-range INR (25-38 days). Shorter intervals were generally associated with better anticoagulation control, but after obtaining a third consecutive in-range value, this relationship was greatly attenuated and no longer statistically significant. Our results suggest that a maximum interval of 28 days after obtaining the first or second in-range value and consideration of a longer interval after obtaining the third or greater consecutive in-range value may be appropriate.

Figures in this Article

Oral anticoagulation therapy (OAT) is used to treat or prevent thromboembolic disease for millions of patients.1-6 Although OAT has been used for decades,7 many aspects of this therapy are governed by tradition rather than evidence, including the maximum allowable follow-up interval. It is important to follow patients often enough to achieve good control, because better control is associated with improved outcomes.8-12 However, we should not follow patients more often than necessary, because extra testing is costly and burdensome for patients and the medical system. In the absence of evidence, guideline committees have recommended different maximum follow-up intervals. The American College of Chest Physicians recommends a maximum interval of 28 days for all patients.1 The American College of Cardiology/American Heart Association/European Society of Cardiology guideline allows up to 42 days when good control has been achieved for the patient.2 The British Society of Haematology allows up to 90 days when good control has been achieved.13 Underlying these divergent recommendations is a disagreement about whether frequent testing will capture important changes in the international normalized ratio (INR) or merely capture random noise and allow more possibilities for unwise and excessive dose adjustments.14

If more frequent testing were found to be unnecessary for a subset of patients with stable control, then increasing the follow-up interval for these patients would save money and reduce patient burden. We, therefore, set out to examine the impact of follow-up intervals after obtaining an in-range INR value (2.0-3.0) upon anticoagulation control for patients. Because patient-level follow-up intervals can be endogenously related to anticoagulation control (that is, these variables can exert a mutual influence on each other),15,16 we studied follow-up intervals at the level of the site of care. We will show that this approach successfully addressed the problem of endogeneity. Our objective was to find empirical support for one or more of the existing guideline recommendations for the maximum follow-up interval.

Data

The database for this study has been described in detail.17,18 The Veterans Affairs Study to Improve Anticoagulation (VARIA) included all patients who were deemed to be receiving OAT from the Veterans Health Administration (VA) between October 1, 2006, and September 30, 2008, according to the criteria described in the next sections. The study was approved by the institutional review board of the Bedford VA Medical Center.

Sites of Care

We studied 100 VA sites of care, each of which has a specialized anticoagulation clinic run by clinical pharmacists under the supervision of a medical director.19 For this study, we excluded INR values from the first 6 months of therapy with warfarin (the inception period). We have previously shown that the percentage of time in the therapeutic range (TTR) is lower during the inception period,16-18 and follow-up intervals are justifiably shorter during this period.

Dependent Variable: Site Risk-Adjusted TTR

Our dependent variable was mean site risk-adjusted for the TTR, a measure of anticoagulation control over time. We calculated the TTR using the Rosendaal method, which uses linear interpolation to assign an INR value to each day between successive observed INR values.20 Gaps of > 56 days between INR values are not interpolated. After interpolation, the percentage of time during which the interpolated INR values are between 2.0 and 3.0 is calculated.20 We calculated the risk-adjusted TTR for all patients, including the small subset that did not record an in-range INR value.

We included INR values obtained when patients were given warfarin, that is, when a patient was either in possession of warfarin or having INR tests at least every 42 days. We defined the period of warfarin possession as the duration of the most recent VA prescription for warfarin plus 30 days. We excluded INR tests measured while the patient was hospitalized within the VA system. We also excluded patients whose primary indication to receive warfarin was valvular heart disease or the use of a prosthetic heart valve. Many such patients have a target INR range of 2.5 to 3.5 rather than the more standard 2.0 to 3.0, but it is not possible to determine with certainty which patients have the higher target range. Without specific knowledge of the target range, we cannot calculate the TTR.

Our risk adjustment model for the TTR, which controls for patient-level risk factors for poor TTR, has been described previously.17,18 Site risk-adjusted TTR was calculated using the following procedure. First, for each patient, we calculated the observed TTR (O) and applied the risk-adjustment model to calculate the expected TTR (E). Then, an observed minus expected (O − E) score was calculated for each patient. The mean O − E score for each site constituted its risk-adjusted TTR.

Independent Variables: Site Mean Follow-up Intervals

We located all patients who had at least one in-range INR value (2.0-3.0) followed by a second INR value 14 to 56 days later, without an intervening hospitalization. We judged that obtaining a follow-up INR value within < 2 weeks was unlikely to represent usual treatment and was more likely related to an event such as an emergency visit or an outpatient procedure. We excluded intervals > 56 days because they could not be interpolated for the calculation of the TTR.20 To examine the impact of these decisions, we also reran our main analyses using different qualifying intervals, including 1 to 56 days, 14 to 90 days, and 1 to 90 days; our main results did not change.

When a patient had multiple qualifying episodes, we arbitrarily selected the last such episode, so that each patient was sampled no more than once. We examined the number of days between the index INR (ie, the in-range value) and the following INR. We averaged values from individual patients to calculate a mean value for each site. We also looked backward from each index INR value to see whether the INR immediately before it was also in range, and, if so, also looked at the INR before that. Thus, we divided patients into three mutually exclusive groups based on whether the index INR value was the first, second, or third consecutive in-range value. We stratified the sample on these three categories and calculated the mean follow-up interval within each stratum. Thus, for each site, we calculated the mean follow-up interval after obtaining a single in-range INR value, two consecutive INR values, and three consecutive INR values.

Statistical Analyses

We examined the baseline characteristics of the patients in our source population (all patients who received OAT) and our study sample (patients with at least one in-range value). We examined the relationship between follow-up intervals and risk-adjusted TTR at the level of the individual patient. We then examined this relationship at the site level, using both simple correlation and linear regression. Finally, we examined the differential effect on anticoagulation control of the mean site follow-up interval after obtaining one, two, or three consecutive in-range INR values. All analyses were conducted using SAS, version 9.1 (SAS Institute Inc; Cary, North Carolina).

Patient Population and Anticoagulation Control

Baseline characteristics for the study patients are described in Table 1, and they were similar between the source population (104,451 patients who received OAT) and the study sample (98,877 patients with at least one in-range INR). The sample patients were mostly men (98%) and had a median age of 73 years. Patients had a substantial burden of comorbidity. For example, 40% had diabetes, 32% had heart failure, and 14% had chronic kidney disease. The burden of mental illness and substance abuse was considerable: 21% had major depression, 9% abused alcohol, and 5% had dementia. The mean TTR for the study sample was 63%.

Table Graphic Jump Location
Table 1 —Baseline Sample Characteristics for Source Population and Study Sample

Data on the source population were used to calculate site performance (ie, risk-adjusted TTR), and data on the study sample were used to characterize the follow-up interval after obtaining an in-range (2.0-3.0) INR value. Data are presented as % unless otherwise indicated. INR = international normalized ratio; IQR = interquartile range; TTR = percentage of time in the therapeutic range; VA = Veterans Health Administration.

a 

Patients whose main indication for anticoagulation was valvular heart disease or the use of a prosthetic heart valve were excluded from this study.

There were 100 sites of care. The site mean TTR (O) ranged from 41% to 72%. The site expected TTR (E) ranged from 58% to 65%. The site risk-adjusted TTR (O − E) score ranged from 19% below to 12% above expected.

Follow-up Intervals

We characterized the follow-up intervals after stratifying by the index INR (ie, the INR value that preceded the interval). As would be expected, the follow-up intervals were longest when the index value was in range (Fig 1) and were uniform throughout that range. This confirmed our decision to treat all INR values within the target range (2.0-3.0) equally.

Figure Jump LinkFigure 1. The interval (in days) between INR tests stratified by the index INR value (N = 104,451). Each patient contributes one interval (the patient’s last in the database). All INR values ≥ 5.0 are combined into a single data point. f/u = follow-up; INR = international normalized ratio.Grahic Jump Location
Patient-Level Analysis

The mean interval after obtaining an in-range INR was 29.8 days, and the mean TTR was 63%. For each additional day of the follow-up interval, the patient experienced a 0.35% higher TTR (P < .001) and a 0.25% higher TTR after adjustment for covariates (P < .001). The effect was therefore in the expected direction (ie, longer follow-up intervals were associated with improved control on the patient level).

Site-Level Analysis

There were 100 sites, with a median of 888 patients per site (interquartile range [IQR], 576-1,341). The mean site follow-up interval after obtaining an in-range INR varied from 25 to 38 days (Fig 2). A longer mean follow-up interval after obtaining any in-range INR value was associated with worse performance, the opposite effect of that seen at the patient level (Fig 2; r = −0.28, P = .004). For each day of follow-up interval after obtaining an in-range INR, the site O−E score was 0.51% lower (P = .004) (Table 2).

Figure Jump LinkFigure 2. The correlation between the mean site-level follow-up interval after obtaining an in-range INR value (2.0-3.0) and the site-level performance as measured by the risk-adjusted percentage of time in the therapeutic range (TTR) (No. = 100 sites). For the regression line, r = −0.28 (P = .004), indicating that shorter follow-up intervals are associated with better site-level performance. O − E = observed TTR minus expected TTR. See Figure 1 legend for expansion of the other abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 2 —Relationship Between Site Mean Follow-up Interval After Obtaining an In-Range INR (2.0-3.0) and Site Performance

Data were measured by risk-adjusted TTR. The index (in-range) INR value was stratified by whether it was the first, second, or third or greater consecutive in-range value. Analyses were performed first using the entire dataset, followed by selected subsets (ie, patients aged > 75 years, patients with atrial fibrillation). The effect on site performance was determined in units of TTR per additional day of follow-up interval. For example, an effect size of −1.0 signifies a 1% decrease in the site mean TTR per additional day of follow-up interval. See Table 1 legend for expansion of abbreviations.

We subdivided the index INR values into the first, second, or third consecutive in-range values. We found that 47% of the index values were preceded by an out-of-range value, while 23% were preceded by a single in-range value, and 31% were preceded by at least two consecutive in-range values (Table 2). The relationship between longer intervals and poorer site-level performance held for the interval after obtaining the first consecutive in-range value (−0.63%, P < .001) and the second consecutive in-range value (−0.58%, P < .001), but was greatly attenuated and no longer statistically significant after obtaining the third or greater consecutive in-range value (−0.12%, P = .46). Similar results were seen among patients aged > 75 years and patients who received anticoagulation treatment for atrial fibrillation.

In our study, 100 sites in an integrated health system varied considerably regarding the follow-up interval after obtaining an in-range (2.0-3.0) INR value. This variation likely reflects a lack of evidence and divergent practice guidelines.1,2,13 We took advantage of these variations in practice to examine the relationship between follow-up intervals and anticoagulation control. We found that longer follow-up intervals predicted better anticoagulation control at the level of the individual patient but worse anticoagulation control at the level of site of care. This apparent paradox, which is what we expected to find, can be explained as follows.

Each site of care is managed by a group of clinicians who, whether by official policy or unofficial tradition, have arrived at a usual follow-up interval after obtaining an in-range INR. However, this usual interval may be lengthened or shortened depending on the clinician’s suspicion that a particular patient will be in range at the next visit. Because these clinical impressions have some validity, longer follow-up intervals at the patient level predict better anticoagulation control.16 However, by examining the mean follow-up intervals at the site level, we showed that when the site had a pattern of longer follow-up intervals, the intervals were actually associated with worse anticoagulation control.

In a previous study,18 we showed that patients who receive anticoagulation treatment at VA facilities have a mean TTR of 58%; our goal is to improve this to approximately 70%. An improvement of this magnitude would be expected to improve patient outcomes considerably.8-12 In the present study, the site mean follow-up intervals varied from 25 to 38 days. Because each additional day in the follow-up interval reduces the site-level TTR by 0.51%, this variation would be expected to account for a 6.6% difference in the TTR across the range of practice we observed. These results suggest that optimizing the follow-up intervals after obtaining in-range INR values could help achieve our goal of improving the TTR to 70%. Our main finding (that longer follow-up intervals were associated with poorer control) persisted when we limited our analysis to patients aged > 75 years and those who received anticoagulation treatment for atrial fibrillation. Given the particular importance of excellent control for improving outcomes in these groups,2,5,8,12 they may benefit most from efforts to improve TTR by optimizing the follow-up interval.

In addition, we examined follow-up intervals after obtaining the first, second, or third or greater consecutive in-range INR value. The association between longer follow-up intervals and poorer performance was seen only after obtaining a first or second consecutive in-range value, but after obtaining a third or greater consecutive in-range value, it was greatly attenuated and no longer statistically significant. This provides an opportunity to explain our main findings in the context of divergent guideline recommendations. In general, this study lends support to the American College of Chest Physicians recommendation to limit follow-up intervals for many patients to 28 days,1 because sites of care that pursued this strategy in our study had the best anticoagulation control (Fig 2). However, our results also suggest that for patients with extremely stable control, extending the follow-up interval beyond 28 days might be considered. Several previous studies have also supported the idea that some patients can safely extend their follow-up interval beyond 28 days.16,21 Most notably, Witt et al21 showed that patients with all of their INR values in range had lower rates of complications than the comparator patients, despite the fact that they also had fewer INR tests. Indeed, an ongoing randomized trial is comparing a 1-month follow-up interval with a 3-month follow-up interval for patients whose warfarin dose has been stable for at least 6 months,22 a group likely to overlap considerably with patients who record three consecutive in-range values. If a longer follow-up interval is confirmed to be safe for such patients, this could save time and money for patients and the health-care system.

This study has important strengths. The database comprised over 100,000 patients and was rich in clinical detail. Our outcome measure (risk-adjusted TTR) is the product of extensive development17,18 and represents the state of the art in quality measurement in OAT. We used innovative methods to avoid the problem of endogeneity in observational studies of follow-up intervals. However, our study also has limitations. As with any observational study, inferences about cause and effect must be interpreted with caution. A second limitation is that we measured the follow-up interval that was achieved, not necessarily the interval that the clinician requested. It is possible that some patients were followed up later than the clinician wanted and that this negatively impacted anticoagulation control. We addressed this by risk adjusting the risk for patient characteristics that impact anticoagulation control,17 thereby equalizing this effect between sites. Furthermore, our finding that longer follow-up intervals are associated with better control on the patient level would also argue against this being an issue. A third limitation is that this study was limited to patients with a target INR of 2.0 to 3.0 and at least 6 months of experience with warfarin; our results may not apply to patients with different target ranges or those new to warfarin. Finally, our sample population was predominantly male and had a high degree of comorbidity. However, it is unclear how this would alter the basic relationships we demonstrated between follow-up intervals and anticoagulation control.

In summary, we found that 100 sites of care within an integrated health system (the VA) pursued widely divergent follow-up intervals after obtaining an in-range INR value. Longer follow-up intervals are associated with poorer anticoagulation control at the site level, except when three or more consecutive in-range values have been recorded for the patient. Our results support a 28-day maximum follow-up interval after obtaining one or two consecutive in-range values and consideration of a longer interval after obtaining a third or greater in-range value. Our study also suggests that reducing practice variation could contribute both to improved anticoagulation control and enhanced efficiency.

Author contributions: Dr. Rose had full access to the data and will vouch for the integrity of the data analysis.

Dr Rose: contributed to the development of the study idea, obtaining of funds, data collection, analysis and interpretation of the data, drafting of the manuscript, revision of the manuscript for important intellectual content, and study supervision.

Dr Ozonoff: contributed to the statistical supervision of the data, analysis and interpretation of the data, and revision of the manuscript for important intellectual content.

Dr Berlowitz: contributed to the obtaining of funds, analysis and interpretation of the data, revision of the manuscript for important intellectual content, and study supervision.

Dr Ash: contributed to the analysis and interpretation of the data and revision of the manuscript for important intellectual content.

Mr Reisman: contributed to data collection, statistical programming, analysis and interpretation of the data, and revision of the manuscript for important intellectual content.

Dr Hylek: contributed to the analysis and interpretation of the data, revision of the manuscript for important intellectual content, and study supervision.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rose is supported by a Career Development Award from the Health Services Research and Development Service of the US Department of Veterans Affairs. Dr Hylek has received honoraria from Bayer and Bristol-Myers Squibb and has served on advisory boards for Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Drs Ozonoff, Berlowitz, and Ash and Mr Reisman have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The US Department of Veterans Affairs had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, and approval of the manuscript. The opinions expressed in this manuscript do not necessarily represent the official views of the US Department of Veterans Affairs.

E

expected percentage of time in the therapeutic range

INR

international normalized ratio

IQR

interquartile range

O

observed percentage of time in the therapeutic range

OAT

oral anticoagulation therapy

TTR

percentage of time in the therapeutic range

VA

Veterans Health Administration

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. American College of Chest Physicians American College of Chest Physicians Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:160S-198S. [CrossRef] [PubMed]
 
Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines American College of Cardiology/American Heart Association Task Force on Practice Guidelines European Society of Cardiology Committee for Practice Guidelines European Society of Cardiology Committee for Practice Guidelines European Heart Rhythm Association European Heart Rhythm Association Heart Rhythm Society Heart Rhythm Society ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;1147:e257-e354. [CrossRef] [PubMed]
 
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. American College of Chest Physicians American College of Chest Physicians Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:454S-545S. [CrossRef] [PubMed]
 
Salem DN, O’Gara PT, Madias C, Pauker SG. American College of Chest Physicians American College of Chest Physicians Valvular and structural heart disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:593S-629S. [CrossRef] [PubMed]
 
Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians American College of Chest Physicians Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:546S-592S. [CrossRef] [PubMed]
 
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;16713:1414-1419. [CrossRef] [PubMed]
 
Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med. 2001;1345:409-417. [PubMed]
 
Connolly SJ, Pogue J, Eikelboom J, et al; ACTIVE W Investigators ACTIVE W Investigators Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;11820:2029-2037. [CrossRef] [PubMed]
 
van Leeuwen Y, Rosendaal FR, Cannegieter SC. Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants. J Thromb Haemost. 2008;63:451-456. [CrossRef] [PubMed]
 
van Walraven C, Oake N, Wells PS, Forster AJ. Burden of potentially avoidable anticoagulant-associated hemorrhagic and thromboembolic events in the elderly. Chest. 2007;1315:1508-1515. [CrossRef] [PubMed]
 
Veeger NJ, Piersma-Wichers M, Tijssen JG, Hillege HL, van der Meer J. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol. 2005;1284:513-519. [CrossRef] [PubMed]
 
White HD, Gruber M, Feyzi J, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med. 2007;1673:239-245. [CrossRef] [PubMed]
 
Baglin TP, Keeling DM, Watson HG. British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition-2005 update. Br J Haematol. 2006;1323:277-285. [CrossRef] [PubMed]
 
Rose AJ, Ozonoff A, Berlowitz DR, Henault LE, Hylek EM. Warfarin dose management affects INR control. J Thromb Haemost. 2009;71:94-101. [CrossRef] [PubMed]
 
Fitzmaurice DA. Oral anticoagulation should be managed in the community with treatment aimed at standard therapeutic targets and increased recall intervals. J Thromb Haemost. 2008;610:1645-1646. [CrossRef] [PubMed]
 
Rose AJ, Ozonoff A, Henault LE, Hylek EM. Warfarin for atrial fibrillation in community-based practise. J Thromb Haemost. 2008;610:1647-1654. [CrossRef] [PubMed]
 
Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA). J Thromb Haemost. 2010;810:2182-2191. [CrossRef] [PubMed]
 
Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans AffaiRs study to Improve Anticoagulation (VARIA). Circ Cardiovasc Qual Outcomes. 2011;41:22-29. [CrossRef] [PubMed]
 
Department of Veterans AffairsDepartment of Veterans Affairs Veterans Health Administration. Anticoagulation therapy management. 2009; Washington, DC US Department of Veterans Affairs VHA Directive 2009-003.
 
Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;693:236-239. [PubMed]
 
Witt DM, Delate T, Clark NP, et al; Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood. 2009;1145:952-956. [CrossRef] [PubMed]
 
National Institutes of Health Clinical CenterNational Institutes of Health Clinical Center Prolongation of the interval between monitoring of warfarin in stable patients. NCT00356759. ClinicalTrials.gov. 2010; Bethesda, MD National Institutes of Health http://www.clinicaltrials.gov.
 

Figures

Figure Jump LinkFigure 1. The interval (in days) between INR tests stratified by the index INR value (N = 104,451). Each patient contributes one interval (the patient’s last in the database). All INR values ≥ 5.0 are combined into a single data point. f/u = follow-up; INR = international normalized ratio.Grahic Jump Location
Figure Jump LinkFigure 2. The correlation between the mean site-level follow-up interval after obtaining an in-range INR value (2.0-3.0) and the site-level performance as measured by the risk-adjusted percentage of time in the therapeutic range (TTR) (No. = 100 sites). For the regression line, r = −0.28 (P = .004), indicating that shorter follow-up intervals are associated with better site-level performance. O − E = observed TTR minus expected TTR. See Figure 1 legend for expansion of the other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Sample Characteristics for Source Population and Study Sample

Data on the source population were used to calculate site performance (ie, risk-adjusted TTR), and data on the study sample were used to characterize the follow-up interval after obtaining an in-range (2.0-3.0) INR value. Data are presented as % unless otherwise indicated. INR = international normalized ratio; IQR = interquartile range; TTR = percentage of time in the therapeutic range; VA = Veterans Health Administration.

a 

Patients whose main indication for anticoagulation was valvular heart disease or the use of a prosthetic heart valve were excluded from this study.

Table Graphic Jump Location
Table 2 —Relationship Between Site Mean Follow-up Interval After Obtaining an In-Range INR (2.0-3.0) and Site Performance

Data were measured by risk-adjusted TTR. The index (in-range) INR value was stratified by whether it was the first, second, or third or greater consecutive in-range value. Analyses were performed first using the entire dataset, followed by selected subsets (ie, patients aged > 75 years, patients with atrial fibrillation). The effect on site performance was determined in units of TTR per additional day of follow-up interval. For example, an effect size of −1.0 signifies a 1% decrease in the site mean TTR per additional day of follow-up interval. See Table 1 legend for expansion of abbreviations.

References

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. American College of Chest Physicians American College of Chest Physicians Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:160S-198S. [CrossRef] [PubMed]
 
Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines American College of Cardiology/American Heart Association Task Force on Practice Guidelines European Society of Cardiology Committee for Practice Guidelines European Society of Cardiology Committee for Practice Guidelines European Heart Rhythm Association European Heart Rhythm Association Heart Rhythm Society Heart Rhythm Society ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;1147:e257-e354. [CrossRef] [PubMed]
 
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. American College of Chest Physicians American College of Chest Physicians Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:454S-545S. [CrossRef] [PubMed]
 
Salem DN, O’Gara PT, Madias C, Pauker SG. American College of Chest Physicians American College of Chest Physicians Valvular and structural heart disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:593S-629S. [CrossRef] [PubMed]
 
Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians American College of Chest Physicians Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133suppl 6:546S-592S. [CrossRef] [PubMed]
 
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;16713:1414-1419. [CrossRef] [PubMed]
 
Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med. 2001;1345:409-417. [PubMed]
 
Connolly SJ, Pogue J, Eikelboom J, et al; ACTIVE W Investigators ACTIVE W Investigators Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;11820:2029-2037. [CrossRef] [PubMed]
 
van Leeuwen Y, Rosendaal FR, Cannegieter SC. Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants. J Thromb Haemost. 2008;63:451-456. [CrossRef] [PubMed]
 
van Walraven C, Oake N, Wells PS, Forster AJ. Burden of potentially avoidable anticoagulant-associated hemorrhagic and thromboembolic events in the elderly. Chest. 2007;1315:1508-1515. [CrossRef] [PubMed]
 
Veeger NJ, Piersma-Wichers M, Tijssen JG, Hillege HL, van der Meer J. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol. 2005;1284:513-519. [CrossRef] [PubMed]
 
White HD, Gruber M, Feyzi J, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med. 2007;1673:239-245. [CrossRef] [PubMed]
 
Baglin TP, Keeling DM, Watson HG. British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition-2005 update. Br J Haematol. 2006;1323:277-285. [CrossRef] [PubMed]
 
Rose AJ, Ozonoff A, Berlowitz DR, Henault LE, Hylek EM. Warfarin dose management affects INR control. J Thromb Haemost. 2009;71:94-101. [CrossRef] [PubMed]
 
Fitzmaurice DA. Oral anticoagulation should be managed in the community with treatment aimed at standard therapeutic targets and increased recall intervals. J Thromb Haemost. 2008;610:1645-1646. [CrossRef] [PubMed]
 
Rose AJ, Ozonoff A, Henault LE, Hylek EM. Warfarin for atrial fibrillation in community-based practise. J Thromb Haemost. 2008;610:1647-1654. [CrossRef] [PubMed]
 
Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA). J Thromb Haemost. 2010;810:2182-2191. [CrossRef] [PubMed]
 
Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans AffaiRs study to Improve Anticoagulation (VARIA). Circ Cardiovasc Qual Outcomes. 2011;41:22-29. [CrossRef] [PubMed]
 
Department of Veterans AffairsDepartment of Veterans Affairs Veterans Health Administration. Anticoagulation therapy management. 2009; Washington, DC US Department of Veterans Affairs VHA Directive 2009-003.
 
Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;693:236-239. [PubMed]
 
Witt DM, Delate T, Clark NP, et al; Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood. 2009;1145:952-956. [CrossRef] [PubMed]
 
National Institutes of Health Clinical CenterNational Institutes of Health Clinical Center Prolongation of the interval between monitoring of warfarin in stable patients. NCT00356759. ClinicalTrials.gov. 2010; Bethesda, MD National Institutes of Health http://www.clinicaltrials.gov.
 
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CHEST Journal Articles
Pharmacology and Management of the Vitamin K Antagonists*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Antithrombotic Therapy in Atrial Fibrillation*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543