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Original Research: ANTICOAGULATION |

Effect of Study Setting on Anticoagulation Control*: A Systematic Review and Metaregression FREE TO VIEW

Carl van Walraven, MD; Alison Jennings, MA; Natalie Oake, BA; Dean Fergusson, PhD; Alan J. Forster, MD
Author and Funding Information

*From the Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, ON, Canada.

Correspondence to: Carl van Walraven, MD, Clinical Epidemiology Program, Ottawa Health Research Institute, C405, Ottawa Hospital, Civic Campus, 1053 Carling Ave, Ottawa, ON, K1Y 4E9 Canada; e-mail: carlv@ohri.ca



Chest. 2006;129(5):1155-1166. doi:10.1378/chest.129.5.1155
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Background: For patients receiving therapy with oral anticoagulants (OACs), the proportion of time spent in the therapeutic range (ie, anticoagulation control) is strongly associated with bleeding and thromboembolic risk. The effect of study-level factors, especially study setting, on anticoagulation control is unknown.

Objectives: Describe anticoagulation control achieved in the published literature. We also used metaregressive techniques to determine which study-level factors significantly influenced anticoagulation control.

Studies: All published randomized or cohort studies that measured international normalized ratios (INRs) serially in anticoagulated patients and reported the proportion of time between INRs ranging from 1.8 to 2.0 and 3.0 to 3.5.

Results: We identified 67 studies with 123 patient groups having 50,208 patients followed for a total of 57,154.7 patient-years. A total of 68.3% of groups were from anticoagulation clinics, 7.3% were from clinical trials, and 24.4% were from community practices. Overall, patients were therapeutic 63.6% of time (95% confidence interval [CI], 61.6 to 65.6). In the metaregression model, study setting had the greatest effect on anticoagulation control with studies in community practices having significantly lower control than either anticoagulation clinics or clinical trials (−12.2%; 95% CI, −19.5 to −4.8; p < 0.0001). Self-management was associated with a significant improvement of time spent in the therapeutic range (+7.0%; 95% CI, 0.7 to 13.3; p = 0.03).

Conclusions: Patients who have received anticoagulation therapy spend a significant proportion of their time with an INR out of the therapeutic range. Patients from community practices showed significantly worse anticoagulation control than those from anticoagulation clinics or clinical trials. This should be considered when interpreting the results of, and generalizing from, studies involving OACs.

Figures in this Article

Oral anticoagulants (OACs) are commonly used and potentially dangerous. They are prescribed to approximately 7.2% of the elderly.1Treatment failures and bleeding events occur frequently during OAC therapy.2Insufficient or excessive anticoagulation therapy, respectively, significantly increases the risk of thrombotic and bleeding events.35

Because of the strong association between international normalized ratio (INR) levels and adverse outcomes, maximal time spent in the therapeutic range (ie, anticoagulation control) is crucial during OAC therapy. However, achieving high-quality anticoagulation control can be difficult. Without point-of-care devices, OAC monitoring requires frequent venous blood sampling, which requires patients to travel to laboratories. The discomfort and inconvenience of frequent venipunctures could decrease patient compliance and the frequency of INR testing. Decreased INR testing can decrease anticoagulation control.5In addition, anticoagulation control may be influenced by many factors including patient age,68 particular medications and foods,810 malignancy,7,10acute diarrheal illness,1112 congestive heart failure,1314 and variant alleles of the CYP2c9 gene.1516 The commonness and interactions of these factors may interfere with INR control.

Given the large number of factors that influence INR control, one would expect a large variation in anticoagulation quality. A systematic review involving all studies of anticoagulation control would summarize anticoagulation control in a large variety of populations and would be especially helpful in four circumstances. First, a systematic description of anticoagulation control could be used by individual physicians, practices, and health-service organizations to gauge the adequacy of anticoagulation in their organization. Such an evaluation is necessary because interventions including increased patient education17 and anticoagulation services4,1822 improve anticoagulation quality. Second, OACs are the control arm for randomized trials of new OACs such as ximelagatran.23 Outcome rates in the OAC arm will be influenced by the anticoagulation control achieved.35 Therefore, one needs to know the quality of anticoagulation control in a particular trial to interpret the results of the study. A reliable comparator requires a systematic review of the literature. Third, we need to know what anticoagulation control is achieved in regular practice to generalize the results from randomized trials. If anticoagulation control in randomized trials differs significantly from that of the community, the outcome rates for OAC patients will also be different. If the event rates in the comparator group of a trial do not vary by setting, an interaction between study setting and the absolute difference between OAC therapy and the comparator treatment will exist. This will influence how the results are generalized from randomized trials to the community. Finally, a systematic review could permit the use of metaregression techniques to be used to identify factors that may significantly influence anticoagulation control. The results of such an analysis could allow physicians to modify their practice and improve quality of care. In particular, such an analysis could determine the importance of study setting, independent of other study factors, on anticoagulation control. A previous article24 has suggested that study setting could heavily influence anticoagulation control.

Nonsystematic reviews have examined some components of the anticoagulation control literature.5,25 The objective of this study was to identify and describe all published randomized trials or cohort studies that measured anticoagulation control. A secondary objective was to determine which study-level factors significantly influenced anticoagulation control using metaregressive techniques. In particular, we determined the effect of study setting on anticoagulation control.

Search Strategy and Study Inclusion Criteria

We searched the MEDLINE database using the search strategy shown in Appendix 1. The rest of our search strategy, along with its outcome, is illustrated in Figure 1 . Studies were included if they contained original data measuring anticoagulation control in at least one patient group over time. This required the calculation of serial INRs on each person and an interpolation of the values between actual measures so that anticoagulation status could be determined on each day of observation. We required this patient-time approach for inclusion in our study because it measures anticoagulation control more accurately than simple averages of measured INRs.26Simple averages result in biased measures due to the excessive influence of extreme values.27 We limited our search to studies published in the English language. Finally, we were primarily interested in the proportion of time spent in traditional therapeutic ranges. Therefore, study groups needed a lower limit INR between 1.8 and 2.0 and an upper limit INR between 3.0 and 3.5 to be included.

Several studies have reported results on the total population as well as subgroups. In these situations, we reported the overall results unless subgroups were defined by a study-level variable the status of which could be determined for all studies. For example, patient self-monitoring was considered to be absent if a study did not mention its presence. If study subgroups were defined by such variables, we reported the subgroup results rather than the overall results. Some studies28 reported INR control for the same patient group using several interpolation methods. In such cases, we only reported results that used linear interpolation methods because this is the most commonly used interpolation method. Also, some studies28 reported INR control on the same patient group at different time periods of their therapy. In such cases, we only reported results for the time period of the longest duration.

Four other exclusion criteria were used. Studies were excluded if they had followed up patients for < 3 weeks, contained a total of < 25 patients, measured serial INRs after the administration of vitamin K, or reported unconventional control statistics including the proportion of people above a particular control threshold.29

Abstraction Criteria

We abstracted study-level data, including study year, indication for anticoagulation, study design, and the method used to interpolate between INRs. This was classified as linear interpolation,30 in which INR values are assumed to change linearly between successive measures, halving,26 in which the first half of the time between successive INRs is assigned the previous INR value and the second half of the time is assigned the next INR value, or other.

We abstracted group-level data, including the type of anticoagulant used, whether or not patients were self-managed, and the study group setting (classified as anticoagulation clinic, randomized trial, or community practice). Studies were classified as being based in an anticoagulation clinic if the authors stated that the study was set in an anticoagulation or thrombosis clinic, or if the methods stated that the role of the study physicians in patient care was limited to controlling the INR levels of patients. Randomized trials comparing OAC therapy to other therapies were classified as randomized trials. All others were classified as community practice-based. Patients who were self-monitored were classified as clinic-based if they had been followed up by the clinic. All data were abstracted by two reviewers (A.J. and N.O.) with discrepancies resolved by a third (C.vW.).

Analysis

For each study group, we abstracted the number of enrolled patients. Since a person-time approach was used for all study groups, we expressed the proportion of time at each INR range as an incidence density. The denominator for the incidence density was the total observation time for the group. If this was not provided for each group within the study, we used the total observation time multiplied by the proportion of patients in each group. The numerator for the incidence density was the proportion of time that the group spent within the INR range multiplied by the observation time. The 95% confidence intervals (CIs) were calculated for each incidence density.31

We determined how group-level factors influenced INR control with multiple linear models using mixed methods with random and fixed effects. Mixed models allowed us to account for the potential lack of independence of INR control within studies. Thus, patient groups were treated as dependent within studies, but as independent across studies. The use of mixed models helped to avoid the biased estimation of SEs that can arise due to the potential lack of independence among multiple groups within the same study. To account for interstudy variation in patient number and follow-up time, we weighted the analysis by the inverse variance of the proportion of time in the therapeutic range, which was the outcome of the mixed model.

The MEDLINE search retrieved 1,835 citations (Appendix 1), of which 190 appeared to study anticoagulation monitoring (Fig 1). A total of 79 of these articles studied anticoagulation control using a patient-time approach. We identified a further 39 articles from alternative sources including Embase (n = 8), Web of Science (n = 13), and hand searching (n = 18). Of the resulting 118 articles, we excluded 51 because the INR measures were not used to assess anticoagulation (n = 7), a target INR range of 1.8 to 2 to 3 to 3.5 was not reported (n = 41), or the target INR was not given (n = 3).

Our final analysis included 67 studies (Table 1 ). Studies were published between 1987 and 2005 with the majority being more recent. Patients had varied indications for anticoagulation therapy with the most common being atrial fibrillation (69% of studies). Most studies used prospective data collection (62% of studies) and interpolated between INR measures using linear methods (81% of studies). Warfarin was the most commonly used anticoagulant (73% of studies).

The 67 studies reported on 123 distinct patient groups (Table 1). These groups contained a median of 128 patients (25th to 75th percentile range, 44 to 330 patient; total, 50,208 patients) and were followed up for a median of 122.9 patient-years (range, 22.7 to 509.6 patient-years; total, 57,154.7 patient-years). Most patient groups were from anticoagulation clinics (68.3%) with the remainder from community practices (24.4%) and randomized trials (7.3%). Seven patient groups used self-management. Only two studies3233 were truly population-based and included all people who had received anticoagulation therapy in a defined population. Also, only two studies32,34 included all INR measures that patients had undergone and not just those conducted for OAC monitoring at a particular laboratory. Appendix 217,2223,28,3236,4097 describes the studies and patient groups in greater detail.

Across all patient groups, the percentage of time spent in the therapeutic range was 63.6% (95% CI, 61.6 to 65.6%). Several study factors appeared to have important effects on the mean percentage of time spent in the therapeutic range (Table 2[ column 3]). Study setting seemed to have a large effect with the unadjusted mean percentage of days spent in range varying from 66.4% for randomized trials to 56.7% for studies from community practices. The type of OAC used in the study appeared to influence results with study groups using acenocoumarol having a higher percentage in range (68.1%) compared to warfarin (60.6%). Patient groups using self-management also appeared to have better control than those using traditional methods (71.5% vs 63.1%, respectively). Study year, interpolation method, and study design appeared to have less effect.

The metaregression model confirmed these impressions (Table 2). After accounting for the clustering of groups within studies and controlling for the other group factors, study setting, drug, and self-management remained significantly associated with the proportion of time spent in the therapeutic range. Compared to randomized trials, the absolute percentage of time spent in the therapeutic range in studies from community practices was decreased by 12.2% (95% CI, −19.5 to −4.8). The difference between community practice and anticoagulation clinics was also significant (−8.3%; 95% CI, −4.4 to −12.1), but there was no significant difference between anticoagulation clinics and randomized trials. The difference in control between study groups using warfarin and those using acenocoumarol was not significant, but that between groups using warfarin and the other group was significant. Self-management groups had a significantly higher percentage of time spent in the therapeutic range (7.0%; 95% CI, 0.7 to 13.3). Patient groups from community practices using warfarin without self-management had a mean percentage of time spent in the therapeutic range of 50.0% (95% CI, 45.1 to 55.0%). The other study factors were not significant.

To our knowledge, this is the first systematic review and metaregression of studies measuring anticoagulation control. We found a large number of studies that used a patient-time approach to measure the percentage of time in a typical therapeutic target range. The overall percentage of time spent in the therapeutic range was 63.5% (95% CI, 61.6 to 65.6%). However, anticoagulation control varied extensively among study groups, with study setting, drug type, and self-monitoring being the most important study-level factors influencing anticoagulation control. Studies set in the community, those using warfarin, and those that did not use self-monitoring had the lowest percentage of time spent in the therapeutic range.

It is striking how often patients taking OACs are not in the therapeutic range. We found that, on average, patients spent more than a third of their time outside of the therapeutic range. In the worst subgroup, namely, patient groups treated with warfarin by community physicians without self-monitoring, patients spent half of their time outside of the therapeutic range. Unfortunately, it is likely that this is the most common subgroup in North America since self-management is relatively uncommon, warfarin is used almost exclusively, and anticoagulation monitoring is most commonly followed by community physicians. Given the strong association between time spent in the therapeutic range and outcomes,35 these findings have important implications for patients requiring long-term anticoagulation therapy.

The most important finding of our analysis is the influence that study setting had on anticoagulation control. After adjusting for all other factors, we found an absolute decrease in the percentage of time spent in the therapeutic range of 12.2% (95% CI, 4.8 to 19.5%) in studies in which patients were monitored by their community physician compared to randomized trials. We think that this difference is clinically important since it exceeds the minimal important difference used for sample size calculations in randomized trials that have the percentage of time spent in the therapeutic range as its primary outcome.22 This result has important implications for generalizing the results of randomized trials having an OAC arm. Assuming that the efficacy of a comparator therapy does not decrease in the community, significantly worse anticoagulation control in the community could have large implications. This is contingent on an association between INR control and the risk of thrombosis and bleeding, which has been shown in many studies.35 However, it should be remembered that INR levels are surrogate outcomes and that the translation of changes in anticoagulation control to differences in true outcome rates requires further study.

Our finding that anticoagulation control is significantly worse in the community helps to explain some inconsistent results in the literature comparing OAC efficacy in randomized trials to that in the real world.24,3538 An anticoagulation clinic-based study by Kalra et al35achieved therapeutic INRs 61% of the time, and rates of stroke and hemorrhage similar to those from randomized trials. The majority of patients in a study by Go et al36had anticoagulation therapy managed in a clinic. They found an OAC efficacy for stroke and peripheral embolism prevention that was similar to that in randomized trials. However, in a large community-based study, Frost et al37 found that the adjusted relative risk of stroke during OAC treatment was not significant in 2,425 women (relative risk, 1.0; 95% CI, 0.7 to 1.6). Gottlieb and Salem-Schatz24 studied 238 community-based patients with atrial fibrillation and found that OAC therapy was as efficacious as that in randomized trials but that patients had a significantly higher rate of minor bleeding. Caro et al38 included community-based patients and found a benefit of OAC therapy that was similar to that in randomized trials. However, the interpretation of their data is problematic because patients who switched to or from OAC therapy during the study were analyzed in a “blended therapy” group. This group had a very high event rate of 5.3 strokes per 100 patient-years of observation. It is possible that the event rate in the OAC group (1.8% per year) was artificially decreased because OAC-associated events in patients switching to or from OAC therapy were attributed to the blended-therapy group.

Our study identified two other factors that were significantly associated with anticoagulation control. Our model found that anticoagulation control in self-management groups was significantly better, with the adjusted percentage of time spent in the therapeutic range increasing by 7.0% (95% CI, 0.7 to 13.3%). Self-management has been associated with improved control in several studies.3941 The results of our model regarding anticoagulant type are less useful since many studies in the “other” group included warfarin4247 or did not specify the drug used.32,41,4851

Anticoagulation control in the studies included could potentially be biased. First, only two studies3233 were truly population-based. Second, only two studies32,34 included all INR measurements that patients had and not just those performed for OAC monitoring at a particular laboratory. The INR values of patients who are acutely ill, that is, those calculated for reasons other than OAC monitoring, are arguably less likely to be therapeutic. Third, the practices that participated in these studies could have better anticoagulation control than nonparticipating practices. This selection bias could influence results in community practices in all but the population-based studies.3233 Therefore, anticoagulation control in most of the studies included in this review may be biased because of patient selection and the incomplete capture of INR measures. We think that a true population-based study of anticoagulation control that avoids such potential biases is required for a truly unbiased assessment of anticoagulation control.

Several limitations of our study should be noted. Despite an exhaustive search strategy, it is possible that we missed eligible studies. However, given the large number of studies in the analysis and the precision of the estimates performed with the model, we consider it unlikely that our conclusions would deviate significantly with the omission of some studies. Second, our analysis was limited to examining the influence of study-level variables on anticoagulation control. It is possible that our study results would change if we also considered patient-level factors that influence anticoagulation control including age,68 comorbidities,7,1014 genetics,1516 and ingestions (ie, medications and food).,810 Finally, our definition of therapeutic range varied slightly between the studies with the lower limits ranging between 1.8 and 2 and the upper limits ranging between 3.0 and 3.5. However, these differences are very small and are unlikely to be clinically significant.

Our study shows that anticoagulated patients spend much of their time outside of the therapeutic range. We also showed that study setting is the most influential study-level factor, with time spent outside the therapeutic range being more common in patients from community-based studies than in those from anticoagulation clinics or randomized trials. This should be considered when interpreting the results of, and generalizing from, randomized studies involving OAC therapy. Further work is necessary to determine how to transplant the processes of care used in anticoagulation clinics and randomized to improve anticoagulation control into the community.

appendix 1: medline research strategy for study

  1. acenocoumarol.mp. or ACENOCOUMAROL/ (825)

  2. dicumarol.mp. or DICUMAROL/ (1310)

  3. ethyl biscoumacetate.mp. or Ethyl Biscoumacetate/ (163)

  4. phenprocoumon.mp. or PHENPROCOUMON/ (705)

  5. Warfarin.mp. or WARFARIN/ (11151)

  6. ADMINISTRATION, ORAL/or oral.mp. (301044)

  7. 1 or 2 or 3 or 4 or 5 or 6 (312429)

  8. *ANTICOAGULANTS/ (15843)

  9. INR.mp. or International Normalized Ratio/ (2675)

  10. international normalized ratio.mp. (2104)

  11. 9 or 10 (3108)

  12. prothrombin time.mp. or Prothrombin Time/ (9487)

  13. PT.mp. (12621)

  14. PTR.mp. (340)

  15. 12 or 13 or 14 (21096)

  16. 11 or 15 (23421)

  17. 7 and 8 and 16 (1835)

Abbreviations: CI = confidence interval; INR = international normalized ratio; OAC = oral anticoagulant

This study was supported in part by Institute for Safe Medication Practices Canada. Dr. Forster was an Ontario Ministry of Health Career Scientist when this study was conducted. No authors have conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Summary of 67 Studies and 123 Study Groups*
* 

Values given as No. (%), unless otherwise indicated. AF = atrial fibrillation.

 

Values are given as mean No. (SD).

Table Graphic Jump Location
Table 2. Results of Metaregression Analysis*
* 

RCT = randomized controlled trial.

 

Represents the significance of the entire group variable in the model.

Table Graphic Jump Location
Table A1. Appendix 2: Detailed Description of all Studies and Groups
Table Graphic Jump Location
Table A2. Appendix 2 Continued
Table Graphic Jump Location
Table A3. Appendix 2 Continued
* 

V = venous thromboembolic disease; AF = atrial fibrillation; C = cerebrovascular disease; PVD = peripheral vascular disease; VD = valvular disease; PD = prospective design; RD = retrospective design; W = warfarin; A = acenocoumarol; P = phenprocoumon; NA = not available; AC = anticoagulation; RCT = randomized controlled trial; SM = self-management; N = no; Y = yes; DSS = decision support system.

We thank Steve Doucette for his help with the analyses and Dr. Phillip Wells for reviewing previous drafts of this study.

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Baggio, D, Madore, F, Lalonde, G, et al Oral anticoagulant therapy for heart disease: results in actual cardiology practice.Can J Cardiol2000;16,153-161. [PubMed]
 
Barcellona, D, Contu, P, Marongiu, F, et al Patient education and oral anticoagulant therapy.Haematologica2002;87,1081-1086. [PubMed]
 
Taylor, FC, Gaminara, E, Cohen, H, et al Evaluation of a nurse specialist anticoagulant service.Clin Lab Haematol1997;19,267-272. [CrossRef] [PubMed]
 
van Dongen, CJ, Prandoni, P, Frulla, M, et al Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome.J Thromb Haemost2005;3,939-942. [CrossRef] [PubMed]
 
Veeger, NJ, Piersma-Wichers, M, Tijssen, JG, et al 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 Haematol2005;128,513-519. [CrossRef] [PubMed]
 
Hutten, BA, Prins, MH, Redekop, WK, et al Comparison of three methods to assess therapeutic quality control of treatment with vitamin K antagonists.Thromb Haemost1999;82,1260-1263. [PubMed]
 
Gullov, AL, Koefoed, BG, Petersen, P Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study; Atrial Fibrillation Aspirin and Anticoagulation.Arch Intern Med1999;159,1322-1328. [CrossRef] [PubMed]
 
Kearon, C, Gent, M, Hirsh, J, et al A Comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.N Engl J Med1999;340,901-907. [CrossRef] [PubMed]
 
Chiquette, E, Amato, MG, Bussey, HI Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs.Arch Intern Med1998;158,1641-1647. [CrossRef] [PubMed]
 
Abdelhafiz, AH, Wheeldon, NM Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic.Clin Ther2004;26,1470-1478. [CrossRef] [PubMed]
 
Pengo, V, Legnani, C, Noventa, F, et al Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding: a multicenter inception cohort study.Thromb Haemost2001;85,418-422. [PubMed]
 
Taube, J, Halsall, D, Baglin, T Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment.Blood2000;96,1816-1819. [PubMed]
 
Poli, D, Antonucci, E, Lombardi, A, et al Low rate of bleeding and thrombotic complications of oral anticoagulant therapy independent of age in the real-practice of an anticoagulation clinic.Blood Coagul Fibrinolysis2003;14,269-275. [PubMed]
 
Samsa, GP, Matchar, DB, Goldstein, LB, et al Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.Arch Intern Med2000;160,967-973. [CrossRef] [PubMed]
 
Menendez-Jandula, B, Souto, JC, Oliver, A, et al Comparing self-management of oral anticoagulant therapy with clinic management: a randomized trial.Ann Intern Med2005;142,1-10. [PubMed]
 
Kearon, C, Ginsberg, JS, Kovacs, MJ, et al Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.N Engl J Med2003;349,631-639. [CrossRef] [PubMed]
 
Fitzmaurice, DA, Murray, ET, Gee, KM, et al Does the Birmingham model of oral anticoagulation management in primary care work outside trial conditions?Br J Gen Pract2001;51,828-829. [PubMed]
 
Lackie, CL, Garbarino, KA, Pruetz, JA Warfarin therapy for atrial fibrillation in the elderly.Ann Pharmacother2002;36,200-204. [CrossRef] [PubMed]
 
Milligan, PE, Banet, GA, Waterman, AD, et al Substitution of generic warfarin for Coumadin in an HMO setting.Ann Pharmacother2002;36,764-768. [CrossRef] [PubMed]
 
Willey, VJ, Bullano, MF, Hauch, O, et al Management patterns and outcomes of patients with venous thromboembolism in the usual community practice setting.Clin Ther2004;26,1149-1159. [CrossRef] [PubMed]
 
Poli, D, Chiarugi, L, Capanni, M, et al Need of more frequent international normalized ratio monitoring in elderly patients on long-term anticoagulant therapy after influenza vaccination.Blood Coagul Fibrinolysis2002;13,297-300. [CrossRef] [PubMed]
 
Waterman, AD, Milligan, PE, Bayer, L, et al Effect of warfarin nonadherence on control of the international normalized ratio.Am J Health Syst Pharm2004;61,1258-1264. [PubMed]
 
Bull, K, Spiegelhalter, DJ Survival analysis in observational studies.Stat Med1997;16,1041-1074. [CrossRef] [PubMed]
 
Mitra, R, Marciello, MA, Brain, C, et al Efficacy of computer-aided dosing of warfarin among patients in a rehabilitation hospital.Am J Phys Med Rehabil2005;84,423-427. [CrossRef] [PubMed]
 
Witt, DM, Sadler, MA, Shanahan, RL, et al Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy.Chest2005;127,1515-1522. [CrossRef] [PubMed]
 
Menzin, J, Boulanger, L, Hauch, O, et al Quality of anticoagulation control and costs of monitoring warfarin therapy among patients with atrial fibrillation in clinic settings: a multi-site managed-care study.Ann Pharmacother2005;39,446-451. [CrossRef] [PubMed]
 
Albers, GW, Diener, HC, Frison, L, et al Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.JAMA2005;293,690-698. [CrossRef] [PubMed]
 
Sunderji, R, Gin, K, Shalansky, K, et al A randomized trial of patient self-managed versus physician-managed oral anticoagulation.Can J Cardiol2004;20,1117-1123. [PubMed]
 
Khan, TI, Kamali, F, Kesteven, P, et al The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation.Br J Haematol2004;126,557-564. [CrossRef] [PubMed]
 
Chan, TY, Miu, KY, Chan, TY, et al Hemorrhagic complications of anticoagulant therapy in Chinese patients.J Chin Med Assoc2004;67,55-62. [PubMed]
 
Matchar, DB Do anticoagulation management services improve care? Implications of the Managing Anticoagulation Services Trial.Card Electrophysiol Rev2003;7,379-381. [CrossRef] [PubMed]
 
van Geest-Daalderop, JH, Hutten, BA, Sturk, A, et al Age and first INR after initiation of oral anticoagulant therapy with acenocoumarol predict the maintenance dosage.J Thromb Thrombolysis2003;15,197-203. [CrossRef] [PubMed]
 
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Tassies, D, Freire, C, Pijoan, J, et al Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation.Haematologica2002;87,1185-1191. [PubMed]
 
Fitzmaurice, DA, Murray, ET, Gee, KM, et al A randomised controlled trial of patient self management of oral anticoagulation treatment compared with primary care management.J Clin Pathol2002;55,845-849. [CrossRef] [PubMed]
 
Evans, A, Perez, I, Yu, G, et al Should stroke subtype influence anticoagulation decisions to prevent recurrence in stroke patients with atrial fibrillation?Stroke2001;32,2828-2832. [CrossRef] [PubMed]
 
McCormick, D, Gurwitz, JH, Goldberg, RJ, et al Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting.Arch Intern Med2001;161,2458-2463. [CrossRef] [PubMed]
 
Evans, A, Perez, I, Yu, G, et al Secondary stroke prevention in atrial fibrillation: lessons from clinical practice.Stroke2000;31,2106-2111. [CrossRef] [PubMed]
 
Casais, P, Luceros, AS, Meschengieser, S, et al Bleeding risk factors in chronic oral anticoagulation with acenocoumarol.Am J Hematol2000;63,192-196. [CrossRef] [PubMed]
 
Gullov, AL, Koefoed, BG, Petersen, P, et al Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.Arch Intern Med1998;158,1513-1521. [CrossRef] [PubMed]
 
Gurwitz, JH, Monette, J, Rochon, PA, et al Atrial fibrillation and stroke prevention with warfarin in the long-term care setting.Arch Intern Med1997;157,978-984. [CrossRef] [PubMed]
 
Bona, RD, Sivjee, KY, Hickey, AD, et al The efficacy and safety of oral anticoagulation in patients with cancer.Thromb Haemost1995;74,1055-1058. [PubMed]
 
Van Deelen, BAJ, van den Bemt, PMLA, Egberts, TCG, et al Cognitive impairment as determinant for sub-optimal control of oral anticoagulation treatment in elderly patients with atrial fibrillation.Drugs Aging2005;22,353-360. [CrossRef] [PubMed]
 
Goldberg, Y, Meytes, D, Shabtai, E, et al Monitoring oral anticoagulant therapy by telephone communication.Blood Coagul Fibrinolysis2005;16,227-230. [CrossRef] [PubMed]
 
Marco, F, Sedano, C, Bermudez, A, et al A prospective controlled study of a computer-assisted acenocoumarol dosage program.Pathophysiol Haemost Thromb2003;33,59-63
 
Witt, DM, Tillman, DJ, Evans, CM, et al Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program.Pharmacotherapy2003;23,360-368. [CrossRef] [PubMed]
 
Vadher, BD, Patterson, DL, Leaning, M, et al Comparison of oral anticoagulant control by a nurse-practitioner using a computer decision-support system with that by clinicians.Clin Lab Haematol1997;19,203-207. [CrossRef] [PubMed]
 
Vadher, B, Patterson, DL, Leaning, M, et al Evaluation of a decision support system for initiation and control of oral anticoagulation in a randomised trial.BMJ1997;314,1252-1256. [CrossRef] [PubMed]
 
Johnson, SG, Witt, DM, Delate, T, et al An examination of the association between therapeutic anticoagulation control and glycemic control for patients with diabetes on oral anticoagulation therapy.J Thromb Thrombolysis2005;19,209-212. [CrossRef] [PubMed]
 
You, JHS, Chan, FWH, Wong, RSM, et al Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation?Br J Clin Pharmacol2005;59,582-587. [CrossRef] [PubMed]
 
Connolly, SJ, Laupacis, A, Gent, M, et al Canadian Atrial Fibrillation Anticoagulation (CAFA) study.J Am Coll Cardiol1991;18,349-355. [CrossRef] [PubMed]
 
Goudie, BM, Danskin, KL, Al-Agilly, SS, et al Near patient monitoring of anticoagulant therapy in general practice [letter]. Scot Med J. 2004;;49 ,.:70
 

Figures

Tables

Table Graphic Jump Location
Table 1. Summary of 67 Studies and 123 Study Groups*
* 

Values given as No. (%), unless otherwise indicated. AF = atrial fibrillation.

 

Values are given as mean No. (SD).

Table Graphic Jump Location
Table 2. Results of Metaregression Analysis*
* 

RCT = randomized controlled trial.

 

Represents the significance of the entire group variable in the model.

Table Graphic Jump Location
Table A1. Appendix 2: Detailed Description of all Studies and Groups
Table Graphic Jump Location
Table A2. Appendix 2 Continued
Table Graphic Jump Location
Table A3. Appendix 2 Continued
* 

V = venous thromboembolic disease; AF = atrial fibrillation; C = cerebrovascular disease; PVD = peripheral vascular disease; VD = valvular disease; PD = prospective design; RD = retrospective design; W = warfarin; A = acenocoumarol; P = phenprocoumon; NA = not available; AC = anticoagulation; RCT = randomized controlled trial; SM = self-management; N = no; Y = yes; DSS = decision support system.

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van Dongen, CJ, Prandoni, P, Frulla, M, et al Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome.J Thromb Haemost2005;3,939-942. [CrossRef] [PubMed]
 
Veeger, NJ, Piersma-Wichers, M, Tijssen, JG, et al 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 Haematol2005;128,513-519. [CrossRef] [PubMed]
 
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Gullov, AL, Koefoed, BG, Petersen, P Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study; Atrial Fibrillation Aspirin and Anticoagulation.Arch Intern Med1999;159,1322-1328. [CrossRef] [PubMed]
 
Kearon, C, Gent, M, Hirsh, J, et al A Comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.N Engl J Med1999;340,901-907. [CrossRef] [PubMed]
 
Chiquette, E, Amato, MG, Bussey, HI Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs.Arch Intern Med1998;158,1641-1647. [CrossRef] [PubMed]
 
Abdelhafiz, AH, Wheeldon, NM Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic.Clin Ther2004;26,1470-1478. [CrossRef] [PubMed]
 
Pengo, V, Legnani, C, Noventa, F, et al Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding: a multicenter inception cohort study.Thromb Haemost2001;85,418-422. [PubMed]
 
Taube, J, Halsall, D, Baglin, T Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment.Blood2000;96,1816-1819. [PubMed]
 
Poli, D, Antonucci, E, Lombardi, A, et al Low rate of bleeding and thrombotic complications of oral anticoagulant therapy independent of age in the real-practice of an anticoagulation clinic.Blood Coagul Fibrinolysis2003;14,269-275. [PubMed]
 
Samsa, GP, Matchar, DB, Goldstein, LB, et al Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.Arch Intern Med2000;160,967-973. [CrossRef] [PubMed]
 
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Fitzmaurice, DA, Murray, ET, Gee, KM, et al Does the Birmingham model of oral anticoagulation management in primary care work outside trial conditions?Br J Gen Pract2001;51,828-829. [PubMed]
 
Lackie, CL, Garbarino, KA, Pruetz, JA Warfarin therapy for atrial fibrillation in the elderly.Ann Pharmacother2002;36,200-204. [CrossRef] [PubMed]
 
Milligan, PE, Banet, GA, Waterman, AD, et al Substitution of generic warfarin for Coumadin in an HMO setting.Ann Pharmacother2002;36,764-768. [CrossRef] [PubMed]
 
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Witt, DM, Sadler, MA, Shanahan, RL, et al Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy.Chest2005;127,1515-1522. [CrossRef] [PubMed]
 
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