Skip main navigation
Close Drawer MenuOpen Drawer Menu
×

Anticoagulation Control and Prediction of Adverse Events in Patients With Atrial Fibrillation

A Systematic Review
Originally published1 Nov 2008https://doi.org/10.1161/CIRCOUTCOMES.108.796185Circulation: Cardiovascular Quality and Outcomes. 2008;1:84–91

Abstract

Background— To date, there has been no systematic examination of the relationship between international normalized ratio (INR) control measurements and the prediction of adverse events in patients with atrial fibrillation on oral anticoagulation.

Methods and Results— We searched MEDLINE, EMBASE, and Cochrane through January 2008 for studies of atrial fibrillation patients receiving vitamin-K antagonists that reported INR control measures (percentage of time in therapeutic range [TTR] and percentage of INRs in range) and major hemorrhage and thromboembolic events. In total, 47 studies were included from 38 published articles. TTR ranged from 29% to 75%; percentage of INRs ranged from 34% to 84%. From studies reporting both measures, TTR significantly correlated with percentage of INRs in range (P<0.001). Randomized controlled trials had better INR control than retrospective studies (64.9% versus 56.4%; P=0.01). TTR negatively correlated with major hemorrhage (r=−0.59; P=0.002) and thromboembolic rates (r=−0.59; P=0.01). This effect was significant in retrospective studies (major hemorrhage, r=−0.78; P=0.006 and thromboembolic rate, r=−0.88; P=0.03) but not in randomized controlled trials (major hemorrhage, r=0.18; P=0.33 and thromboembolic rate, r=−0.61; P=0.07). For retrospective studies, a 6.9% improvement in the TTR significantly reduced major hemorrhage by 1 event per 100 patient-years of treatment (95% CI, 0.29 to 1.71 events).

Conclusions— In atrial fibrillation patients receiving orally administered anticoagulation treatment, TTR and percentage of INRs in range effectively predict INR control. Data from retrospective studies support the use of TTR to accurately predict reductions in adverse events.

Atrial fibrillation (AF) is a common condition affecting 1 in 10 adults aged >75 years1 and is a strong independent risk factor for thromboembolism and ischemic stroke.2 Adjusted-dose oral anticoagulation is highly efficacious for prevention of all stroke (both ischemic and hemorrhagic), with a risk reduction of 62% (95% CI, 48% to 72%) when compared with placebo.3 Moreover, anticoagulation has recently been shown to be effective in elderly patients aged >75 years.4 However, the incidence of bleeding events increases with the intensity of anticoagulation, especially in the elderly population.5

Editorial see p 72

Clinical Perspective see p 84

The therapeutic range of anticoagulation is narrow and is measured via the international normalized ratio (INR). The range is normally 2.0 to 3.0 for AF,6 and an INR <2.0 increases the risk of thromboembolism,7 whereas an INR >4.0 increases the risk of major bleeding.8,9 Maintaining the INR in the reference range requires regular monitoring and appropriate modification of treatment. Therefore, interest has focused on appropriate measures to determine the therapeutic effectiveness of oral anticoagulation.

A systematic review recommended that ≥2 outcome measures should be reported and measures should be selected so that INR determinations and quality of dosing advice can be monitored.10 These measures include clinical event rates, proportion of INR values in therapeutic range, time in therapeutic range (TTR), and proportion of patients in range. Each of these measures has limitations11 and to date, no study has determined whether either of these correlates with measures of clinical effectiveness or adverse clinical outcome. And yet, important differences in the observed level of INR control depend on the chosen measure. This difference can be as high as 10% in terms of INR control.12

Therefore, this study aims to systematically examine the relationship between outcome measures and adverse clinical events (major hemorrhage and thromboembolic events) in patients with AF receiving oral anticoagulation.

Methods

Eligibility and Search Strategy

We searched the Ovid version of MEDLINE and EMBASE as well as the Cochrane Library through Wiley InterScience for the period from January 1990 to January 2008 using a maximally sensitive strategy. Medical subject headings and synonyms were used for these terms: atrial fibrillation, international normalized ratio, warfarin, anticoagulants, and vitamin-K antagonists (VKAs). No language restriction was applied. We also searched the reference lists of identified articles and reviews.

Studies were included if they satisfied the following criteria:

  • The study group was a broadly unselected group of adult patients (≥18 years of age) receiving outpatient VKA therapy with the specific indication for treatment being AF

  • Retrospective study design, prospective cohort study design, or randomized controlled trials (RCTs)

  • INR control reported as percentage of TTR, percentage of INRs in range, or similar measures

  • At least 25 patients enrolled in study

  • Duration of study or mean follow-up period of ≥3 months

Data Abstraction and Analysis

We reviewed the titles and abstracts of all identified articles and selected full-text articles containing data on INR. Only articles clearly not meeting the criteria were excluded at this stage. The remaining articles were then reviewed in detail for inclusion. We extracted data on reported control measures and outcomes, including TTR, percentage of INRs in range, and clinical outcomes of major hemorrhage and thromboembolic events. Reasons for study exclusion were different indication (eg, patients with deep-vein thrombosis), use of prophylactic agents other than VKAs, studies with <25 patients, duration of study <3 months, selected INR range (eg, patients with reference range INR >5 only), and no data on INR. Studies that included participants with postoperative AF or valvular disease were also excluded.

We reported subgroup analyses from the relevant studies that provided adequate data on target INR range (range, 2.0 to 3.0) and study type. Two reviewers extracted data independently, and disagreements were resolved by discussion. The reviewers were not masked to any aspects of the studies (eg, journal types, author names, or institutions).

Major hemorrhage and thromboembolic events were converted to rates (percent per patient-year) to allow for comparison across studies. Overall, major hemorrhage was defined as bleeding requiring hospitalization, transfusion required, or hemorrhage involving critical anatomic sites. Thromboembolic events were defined as the occurrence of a new stroke, myocardial infarction, peripheral embolism, or systemic emboli.

We used SPSS 15.0 for Windows (SPSS, Inc, Chicago, Ill) for the statistical analysis and calculated mean�SD and median with interquartile (or range) as summary statistics. Descriptive analysis was performed using ANOVA or Kruskal-Wallis H test. Correlation and regression analysis was performed between INR control measures (TTR or percentage of INRs in range) and adverse outcomes (major hemorrhage or thromboembolic events) with or without weighting by sample size. We excluded studies with missing data from the analysis (19 studies for major bleeding rate, 27 studies for thromboembolic rate, and 19 studies for both). There was no statistical difference between the eliminated and retained studies for TTR, mean age, sample size, duration of study, and mean INR tests per patient-year. However, for percentage of INRs in range, the studies with missing data reported significantly lower values (51.5% versus 66.7% [P=0.01] for major bleeding rate and 52.8% versus 66.5% [P=0.02] for thromboembolic rate).

We examined publication bias by constructing a funnel plot of precision (SE of log TTR or SE of log percentage of INRs in range) against log TTR (or log percentage of INRs in range). In addition, we used Begg rank correlation and Egger linear regression tests to assess funnel plot asymmetry with Stata 10 for Windows (Stata Corp, College Station, Tex).13

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Results

We identified 1571 citations (Figure 1). Of these, 2 authors screened 1078 abstracts (493 duplicate records were excluded) and independently reviewed 87 full-text articles for inclusion and data extraction. A total of 38 articles met the eligibility criteria, reporting 47 study groups (we use “studies” to refer to different groups if reported in the same article). Only 3 articles reported on cohorts including subjects receiving different VKAs (including warfarin),14–16 and the VKA used was not reported in 1 article.17 Thirty-two articles used a target range of 2.0 to 3.0, and 6 articles18–23 reported slight variations on this range (ie, 2.0 to 3.5).

Figure 1. Flowchart of search results.

Of the identified studies, 27 were retrospective, 5 were prospective cohorts, and 15 were RCTs, with a total of 33 976 participants (Table 1). Data were from the United States (18 studies, including 1 from the United States and Canada), the United Kingdom (10 studies), Italy (4 studies), Canada (3 studies), Spain (3 studies), France (1 study), Germany (1 study), Denmark (1 study), Belgium (1 study), Norway (1 study), The Netherlands (1 study) and Israel (1 study); 2 studies were multinational, from 13 and 23 countries, respectively. The mean age in studies ranged from 64 to 87 years (median, 72 years); duration of studies ranged from 4 to 42 months (median, 15 months); and mean INR tests number per patient-year ranged from 11 to 37 (median, 18). No statistically significant differences were found between different study designs for mean age (F=0.003; P=0.99), duration of studies (F=0.88; P=0.42), and mean INRs test interval (F=0.33; P=0.73).

Table 1. Characteristics of 47 Studies (38 Articles) Reporting INR Control and Outcomes

StudyDuration of Study, MonthsMean Age, YearsSample SizeMean INR Tests per Patient-YearTTR, %INRs, %Events Rate (% per Patient-Year)
In RangeBelowAboveIn RangeBelowAboveMajor BleedingThromboembolic
Anderson (2004) US24*12—8713———602514——
Menzin et al (2005) US25*117260019622513———3.61.0
Nichol et al (anticoagulation clinic) (2008) US26*31—35125682111———2.3—
Nichol et al (routine care) (2008) US26*19—7561942499———6.3—
Gaughan et al (2000) US18*8——————54————
Sarawate et al (2006) US27*—74614—294922—————
Bratland (2006) Norwegian28*1672427—571825———2.4—
Currie et al (stable) (2005) UK29*35727841175—————0.40.8
Currie et al (unstable) (2005) UK29*35747292656—————1.22.3
Jones et al (2005) UK30*—73222323681715—————
Neree (2006) Belgium14*4743953253939———4.42.9
Malik and Taylor (2000) US31*2468247—592714—————
Yousef et al (2004) UK32*127373937622314———3.81.8
Samsa et al (triangle practices) (2000) US33*969——365212345115——
Samsa et al (no anticoagulation clinic) (2000) US33*969——473419443423——
McCormick et al (2001) US34*128717435†513613—————
Espuny et al (primary care) (2004) Spain35*38762515———44————
Espuny et al (hospital) (2004) Spain35*42758712———51————
Copland et al (2001) UK19*1770328————6810222.8—
Ansell et al (2007) Italy15*127217717†702010602614——
Ansell et al (2007) Spain15*127221811†651817592318——
Ansell et al (2007) US15*127568617†582814513217——
Ansell et al (2007) Canada15*127415218†632512582814——
Ansell et al (2007) France15*127327817†591427512029——
Burton et al (2006) UK16*3777601—68—————2.6—
Boulanger et al (2006) US36*12696454—483814—————
Shalev et al (2007) Israel37*——440819†483517—————
Abdelhafiz and Wheeldon (2004) UK38‡197240216662014———1.7—
Hylek et al (2007) US5‡97747228582913———7.2—
McBride et al (2007) Germany17‡671324—561430—————
Kalra et al (2000) UK39‡1777167612613———1.73.8
Pengo et al (2001) Italy40‡176843318632116———1.81.6
Matchar et al (2002) US41�976680—543215———2.05.0
CAFA (1991) Canada42�1568187—444017———2.13.4
EAFT (1993) 13 countries20�2871225————593292.63.7
SPAF II (<75) (1994) US22�3764358————752051.72.8
SPAF II (>75) (1994) US22�2480197————722264.25.6
SPAF III (1996) US7�1371523————6125142.15.3
SIFA (1997) Italian21�1272454————841421.32.2
Pengo et al (1998) Italy43�147415314701812———2.71.1
AFASAK II (1998) Denmark44�2573170—73189———1.12.8
PATAF (stratum 1) (1999) Netherlands23�3770131————4828240.51.3
(Continued)

Table 1. Continued

StudyDuration of Study, MonthsMean Age, YearsSample SizeMean INR Tests per Patient-YearTTR, %INRs, %Events Rate (% per Patient-Year)
In RangeBelowAboveIn RangeBelowAboveMajor BleedingThromboembolic
— indicates data not reported.
*Retrospective study.
†Median value.
‡Prospective cohort study.
�Randomized controlled trial.
ACTIVE W (2006) Canada45�15†703371—642115———2.21.6
WASPO (2007) UK46�1284†36—70———————
BAFTA (2007) UK4�3282488—671914———1.9—
SPORTIF III (2003) 23 countries47�16701703—66—————1.72.9
SPORTIF V (2005) US and Canada48�20721962—682012———2.81.9

No funnel plot asymmetry was noted for TTR (Begg, P=0.13; Egger, P=0.15) or percentage of INRs in range (Begg, P=0.60; Egger, P=0.22).

TTR was used in 36 of 47 (77%) studies and percentage of INRs in range in 18 of 47 (38%), with 7 (15%) studies reporting both measures (Table 2). In these 7 studies, TTR (56.9�11.7%) significantly correlated with percentage of INRs in range (51.0�9.4%; r=0.99; P<0.001). A composite measure of INR control was calculated using TTR when provided or percentage of INRs in range.

Table 2. Median (Range) INR Control in Different Study Designs

Study DesignTime, %INRs, %
No.In RangeNo.Below RangeAbove RangeNo.In RangeNo.Below RangeAbove Range
INR indicates international normalized ratio.
Retrospective studies2259 (29–75)1925 (9–52)14 (9–39)1253 (34–68)926 (10–51)17 (14–29)
Prospective cohort studies561 (56–66)521 (14–29)14 (13–30)0————
Randomized control trials967 (44–73)720 (18–40)14 (9–17)667 (48–84)624 (14–32)8 (2–24)

Compared with RCTs, retrospective studies had a significantly lower percentage of INRs in range (52.8�9.1% versus 66.5�12.9%; P=0.02), and a significantly lower composite of TTR and percentage of INRs in range (56.4�10.9% versus 64.9�10.5%; P=0.01). No significant difference was found between prospective cohort and RCTs (P=0.44) or retrospective studies (P=0.38; Figure 2).

Figure 2. Distribution of TTR and INRs in range in different study designs. Probability values are reported for significant interactions between study designs. Error bar indicates mean�SD.

Major hemorrhage was reported in 28 (60%) studies and thromboembolic events in 20 (43%) studies (Table 1). In all studies, the median rate of major hemorrhage was 2.2 (interquartile, 1.7 to 2.8) per 100 patient-years, and the median rate of thromboembolic was 2.5 (interquartile, 1.6 to 3.6) per 100 patient-years. There was no significant relationship between percentage of time above range and major hemorrhage (r=−0.05; P=0.42) or between percentage of time below range and thromboembolic rates (r=0.48; P=0.07). As for percentage of INRs in range, no significant relationship with adverse outcome rates was found in all study designs or in different study designs (P>0.05).

TTR negatively correlated with major hemorrhage and thromboembolic rates (r=−0.59; P=0.002 and r=−0.59; P=0.01). A linear regression occurred after weighting by sample size between TTR and major hemorrhage (Y [major hemorrhage rate]=10.104−0.120X[TTR], R2=0.35; P=0.004) and between TTR and thromboembolic rate (Y [thromboembolic rate]=8.313−0.098X[TTR], R2=0.35; P=0.03). Thus, an 8.3% increase in TTR significantly reduced major hemorrhage by 1 event per 100 patient-years (95% CI, 0.35 to 1.64 events), and a 10.2% increase in TTR reduced thromboembolic events by 1 event per 100 patient-years (95% CI, 0.14 to 1.85 events; Figure 3). The unweighted regression analysis produced similar results for major hemorrhage rate (Y [major hemorrhage rate]=8.367−0.092X[TTR], R2=0.23; P=0.028) and thromboembolic rate (Y [thromboembolic rate]=7.323−0.080X[TTR], R2=0.32; P=0.034).

Figure 3. TTR versus adverse events (weighted by sample size) for all studies. TTR versus major hemorrhage rate (n=21), correlation: r=−0.59; P=0.002; linear regression: Y (major hemorrhage rate)=10.104−0.120X(TTR), R2=0.35; P=0.004. TTR versus thromboembolic rate (n=14), correlation: r=−0.59; P=0.01; linear regression: Y (thromboembolic rate)=8.313−0.098X(TTR), R2=0.35; P=0.03.

In retrospective studies alone, a significant correlation occurred between TTR and major hemorrhage (r=−0.78; P=0.006) and thromboembolic rate (r=−0.88; P=0.03). A linear relationship occurred between TTR and major hemorrhage (Y [major hemorrhage rate]=11.716−0.145X[TTR], R2=0.61; P=0.01) and between TTR and thromboembolic rate (Y [thromboembolic rate]=6.943−0.084X[TTR], R2=0.77; P=0.05). Studies were not affected by selection of a weighted or unweighted model. Thus, in retrospective studies, a 6.9% increase in TTR significantly reduced major hemorrhage by 1 event per 100 patient-years (95% CI, 0.29 to 1.71 events), and an 11.9% increase in TTR reduced thromboembolic events by 1 event per 100 patient-years (95% CI, −0.01 to 2.02 events; Figure 4). However, this linear relationship does not exist in RCTs (r=0.18; P=0.33 for major hemorrhage and r=−0.61; P=0.07 for thromboembolic event; Figure 5).

Figure 4. TTR versus adverse events (weighted by sample size) for retrospective studies. TTR versus major hemorrhage rate (n=9), correlation: r=−0.78; P=0.006; linear regression: Y (major hemorrhage rate)=11.716–0.145X(TTR), R2=0.61; P=0.01. TTR versus thromboembolic rate (n=5), correlation: r=−0.88; P=0.026; linear regression: Y (thromboembolic rate)=6.943− 0.084X(TTR), R2=0.77; P=0.05.

Figure 5. TTR versus adverse events (weighted by sample size) for randomized controlled trials. TTR versus major hemorrhage rate (n=8), correlation: r=0.18, P=0.33. TTR versus thromboembolic rate (n=7), correlation: r=−0.61, P=0.07.

Discussion

We determined that TTR and percentage of INRs in range were the most reported measures in studies of patients with AF who were receiving orally administered anticoagulation treatment. Most of those also reported percentage of INRs above and below target values. However, only a small proportion of studies (15%) reported both TTR and percentage of INRs in range.

We found that TTR had a significant relationship with adverse outcomes in all studies, including major hemorrhage and thromboembolic rates, supporting the reporting of TTR as the optimal measure of INR control. In retrospective studies, a strong negative correlation existed between TTR and adverse clinical outcomes. As a consequence, a 7% improvement in TTR would lead to a reduction of 1 major hemorrhage per 100 patient-years, and a 12% improvement in TTR would lead to a reduction of 1 thromboembolic event per 100 patient-years. The reason for the lack of relationship in RCTs is likely to be the relatively tight control of INR in the studies, which reduces the power of the linear relationship.

Our review has some potential limitations. First, although our search was comprehensive, the potential exists for missing both published studies (although this was minimized, because we looked at all references in identified articles) and unpublished studies. Second, variability in the details of studies can affect the results in different study designs. It is clear that a great number of factors can affect patients’ risk of clinical events (eg, patient characteristics, indication for anticoagulation, and risk factors).49 The level of details provided by studies was not similar, and problems with completeness of information existed. In addition, it is difficult to determine to what extent the reporting of both control measures impinges on study quality. To standardize as far as possible the INR ranges and clinical characteristics of the population, we restricted our review to 1 condition (AF). It was impossible to analyze the effects of extreme values of range and effects on outcomes because of incomplete information. Third, in some studies, the outcome measures were not blindly assessed or independently verified, which could have inflated the apparent results.50 However, analysis of blinding revealed there was no difference between studies with or without outcome blinding. Fourth, from our current analysis, the extent to which these results are linear across all ranges of INR control is unknown, particularly at the high and low ends of INR control, because these results were obtained for TTR range between 30% and 75%. Finally, although correlation existed between the 2 measures in the 7 studies reporting both TTR and percentage INRs in range, there was still a mean difference of 6% between them (P=0.001). To address this issue, we recommend that all future studies report both measures.

Conclusion

The key findings from our investigation are as follows:

  • Most studies of anticoagulation control in AF report TTR or percentage of INRs in range, with low INR control and relatively high adverse events;

  • TTR and percentage of INRs in range can be used to predict adverse events in anticoagulated AF patients;

  • As little as a 7% improvement in TTR reduced major hemorrhage by 1 event per 100 patient years;

  • A reduction in thromboembolic rate by 1 event per 100 patient years can be achieved by a 12% increase in TTR;

  • TTR and percentage of INRs in range should both be reported and used as predictors in studies of oral anticoagulation; and

  • Anticoagulation services should aim for a TTR between 70% and 80% to optimize benefits and reduce harm for patients.

Clinically, we have set a benchmark by which anticoagulation services can evaluate the impact of improving the percentage of TTR in their patient cohort. A small improvement in percentage of TTR may have a large impact on clinical care. However, when TTR cannot be calculated, percentage of INRs in range could be used as a proxy, given the strong correlation between the 2 measures.

Sources of Funding

Dr Wan received funding from the National Natural Science Foundation of China (grant 90612012) and sponsorship from Prof Thomas Stapleton to take part in this research project. Dr Bankhead has received funding from a National Institute of Health Research program grant in monitoring to undertake this work. Dr Heneghan is funded by a Department of Health, National Institute of Health Research training fellowship. The University Department of Primary Health Care is part of the National Institute of Health Research School of Primary Care Research, which provides financial support for senior investigators who contributed to this article. The opinions are those of the authors and not of the Department of Health.

Disclosures

None.

Footnotes

Correspondence to Yi Wan, Department of Primary Health Care, University of Oxford, Rosemary Rue Building, Old Road Campus, Headington, Oxford OX3 7LF, United Kingdom. E-mail

References

  • 1 Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol. 2001; 37: 371–378.CrossrefMedlineGoogle Scholar
  • 2 Prystowsky EN, Benson DW Jr, Fuster V, Hart RG, Kay GN, Myerburg RJ, Naccarelli GV, Wyse DG. Management of patients with atrial fibrillation. A Statement for Healthcare Professionals. From the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation. 1996; 93: 1262–1277.CrossrefMedlineGoogle Scholar
  • 3 Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL. 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. Circulation. 2006; 114: e257–e354.LinkGoogle Scholar
  • 4 Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, Murray E. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007; 370: 493–503.CrossrefMedlineGoogle Scholar
  • 5 Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007; 115: 2689–2696.LinkGoogle Scholar
  • 6 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126: 204S–233S.CrossrefMedlineGoogle Scholar
  • 7 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: stroke prevention in atrial fibrillation III randomised clinical trial. Lancet. 1996; 348: 633–638.CrossrefMedlineGoogle Scholar
  • 8 Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet. 1994; 343: 499–503.MedlineGoogle Scholar
  • 9 Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP Jr, Jackson CM, Pullicino P. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001; 345: 1444–1451.CrossrefMedlineGoogle Scholar
  • 10 Fitzmaurice DA, Kesteven P, Gee KM, Murray ET, McManus R. A systematic review of outcome measures reported for the therapeutic effectiveness of oral anticoagulation. J Clin Pathol. 2003; 56: 48–51.CrossrefMedlineGoogle Scholar
  • 11 Schmitt L, Speckman J, Ansell J. Quality assessment of anticoagulation dose management: comparative evaluation of measures of time-in-therapeutic range. J Thromb Thrombolysis. 2003; 15: 213–216.CrossrefMedlineGoogle Scholar
  • 12 Fitzmaurice DA, Hobbs FD, Murray ET, Holder RL, Allan TF, Rose PE. Oral anticoagulation management in primary care with the use of computerized decision support and near-patient testing: a randomized, controlled trial. Arch Intern Med. 2000; 160: 2343–2348.CrossrefMedlineGoogle Scholar
  • 13 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315: 629–634.CrossrefMedlineGoogle Scholar
  • 14 Neree C. Quality of oral anticoagulation in patients with atrial fibrillation: a cross-sectional study in general practice. Eur J Gen Pract. 2006; 12: 163–168.CrossrefMedlineGoogle Scholar
  • 15 Ansell J, Hollowell J, Pengo V, Martinez-Brotons F, Caro J, Drouet L. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management (ISAM). J Thromb Thrombolysis. 2007; 23: 83–91.CrossrefMedlineGoogle Scholar
  • 16 Burton C, Isles C, Norrie J, Hanson R, Grubb E. The safety and adequacy of antithrombotic therapy for atrial fibrillation: a regional cohort study. Br J Gen Pract. 2006; 56: 697–702.MedlineGoogle Scholar
  • 17 McBride D, Bruggenjurgen B, Roll S, Willich SN. Anticoagulation treatment for the reduction of stroke in atrial fibrillation: a cohort study to examine the gap between guidelines and routine medical practice. J Thromb Thrombolysis. 2007; 24: 65–72.CrossrefMedlineGoogle Scholar
  • 18 Gaughan GL, Dolan C, Wilk-Rivard E, Geary G, Libbey R, Gilman MA, Lanata H. Improving management of atrial fibrillation and anticoagulation in a community hospital. Jt Comm J Qual Improv. 2000; 26: 18–28.MedlineGoogle Scholar
  • 19 Copland M, Walker ID, Tait RC. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation. Arch Intern Med. 2001; 161: 2125–2128.CrossrefMedlineGoogle Scholar
  • 20 EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993; 342: 1255–1262.CrossrefMedlineGoogle Scholar
  • 21 Morocutti C, Amabile G, Fattapposta F, Nicolosi A, Matteoli S, Trappolini M, Cataldo G, Milanesi G, Lavezzari M, Pamparana F, Coccheri S; SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. Stroke. 1997; 28: 1015–1021.CrossrefMedlineGoogle Scholar
  • 22 Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994; 343: 687–691.MedlineGoogle Scholar
  • 23 Hellemons BS, Langenberg M, Lodder J, Vermeer F, Schouten HJ, Lemmens T, van Ree JW, Knottnerus JA. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ. 1999; 319: 958–964.CrossrefMedlineGoogle Scholar
  • 24 Anderson RJ. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service. J Manag Care Pharm. 2004; 10: 159–165.MedlineGoogle Scholar
  • 25 Menzin J, Boulanger L, Hauch O, Friedman M, Marple CB, Wygant G, Hurley JS, Pezzella S, Kaatz S. 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 Pharmacother. 2005; 39: 446–451.CrossrefMedlineGoogle Scholar
  • 26 Nichol MB, Knight TK, Dow T, Wygant G, Borok G, Hauch O, O'Connor R. Quality of anticoagulation monitoring in nonvalvular atrial fibrillation patients: comparison of anticoagulation clinic versus usual care. Ann Pharmacother. 2008; 42: 62–70.CrossrefMedlineGoogle Scholar
  • 27 Sarawate C, Sikirica MV, Willey VJ, Bullano MF, Hauch O. Monitoring anticoagulation in atrial fibrillation. J Thromb Thrombolysis. 2006; 21: 191–198.CrossrefMedlineGoogle Scholar
  • 28 Bratland B. Warfarin treatment in a general practice. [Norwegian]. Tidsskrift for Den Norske Laegeforening. 2006; 126: 162–165.MedlineGoogle Scholar
  • 29 Currie CJ, McEwan P, Emmas C, Morgan CL, Peters JR. Anticoagulation in patients with non-valvular atrial fibrillation: an evaluation of stability and early factors that predict longer-term stability on warfarin in a large UK population. Curr Med Res Opin. 2005; 21: 1905–1913.CrossrefMedlineGoogle Scholar
  • 30 Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart. 2005; 91: 472–477.CrossrefMedlineGoogle Scholar
  • 31 Malik AK, Taylor AJ. Can warfarin randomized trials be reproduced in “real life”? Adherence to warfarin guidelines for intensity of anticoagulation in a university-based warfarin clinic. South Med J. 2000; 93: 58–61.CrossrefMedlineGoogle Scholar
  • 32 Yousef ZR, Tandy SC, Tudor V, Jishi F, Trent RJ, Watson DK, Cowell RP. Warfarin for non-rheumatic atrial fibrillation: five year experience in a district general hospital. Heart. 2004; 90: 1259–1262.CrossrefMedlineGoogle Scholar
  • 33 Samsa GP, Matchar DB, Goldstein LB, Bonito AJ, Lux LJ, Witter DM, Bian J. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med. 2000; 160: 967–973.CrossrefMedlineGoogle Scholar
  • 34 McCormick D, Gurwitz JH, Goldberg RJ, Becker R, Tate JP, Elwell A, Radford MJ. Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting. Arch Intern Med. 2001; 161: 2458–2463.CrossrefMedlineGoogle Scholar
  • 35 Clua Espuny JL, mau Llorca MR, Aguilar MC, Grupo dT. Characteristics of oral anti-coagulation treatment in high-risk chronic auricular fibrillation. [Spanish]. Atencion Primaria. 2004; 34: 414–419.CrossrefMedlineGoogle Scholar
  • 36 Boulanger L, Kim J, Friedman M, Hauch O, Foster T, Menzin J. Patterns of use of antithrombotic therapy and quality of anticoagulation among patients with non-valvular atrial fibrillation in clinical practice. Int J Clin Pract. 2006; 60: 258–264.CrossrefMedlineGoogle Scholar
  • 37 Shalev V, Rogowski O, Shimron O, Sheinberg B, Shapira I, Seligsohn U, Berliner S, Misgav M. The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation. Thromb Res. 2007; 120: 201–206.CrossrefMedlineGoogle Scholar
  • 38 Abdelhafiz AH, Wheeldon NM. Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic. Clin Ther. 2004; 26: 1470–1478.CrossrefMedlineGoogle Scholar
  • 39 Kalra L, Yu G, Perez I, Lakhani A, Donaldson N. Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness. BMJ. 2000; 320: 1236–1239.CrossrefMedlineGoogle Scholar
  • 40 Pengo V, Legnani C, Noventa F, Palareti G. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding. A Multicenter Inception Cohort Study. Thromb Haemost. 2001; 85: 418–422.CrossrefMedlineGoogle Scholar
  • 41 Matchar DB, Samsa GP, Cohen SJ, Oddone EZ, Jurgelski AE. Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial. Am J Med. 2002; 113: 42–51.CrossrefMedlineGoogle Scholar
  • 42 Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991; 18: 349–355.CrossrefMedlineGoogle Scholar
  • 43 Pengo V, Zasso A, Barbero F, Banzato A, Nante G, Parissenti L, John N, Noventa F, Dalla Volta S. Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol. 1998; 82: 433–437.CrossrefMedlineGoogle Scholar
  • 44 Gullov AL, Koefoed BG, Petersen P, Pedersen TS, Andersen ED, Godtfredsen J, Boysen G. 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 Med. 1998; 158: 1513–1521.CrossrefMedlineGoogle Scholar
  • 45 Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006; 367: 1903–1912.CrossrefMedlineGoogle Scholar
  • 46 Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age Ageing. 2007; 36: 151–156.CrossrefMedlineGoogle Scholar
  • 47 Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003; 362: 1691–1698.CrossrefMedlineGoogle Scholar
  • 48 Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S, Halperin JL, Horrow J, Olsson SB, Petersen P, Vahanian A. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005; 293: 690–698.CrossrefMedlineGoogle Scholar
  • 49 Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 1998; 114: 511S–523S.CrossrefMedlineGoogle Scholar
  • 50 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17: 1–12.CrossrefMedlineGoogle Scholar
circcvoqCirc Cardiovasc Qual OutcomesCirculation: Cardiovascular Quality and OutcomesCirc Cardiovasc Qual Outcomes1941-77131941-7705Lippincott Williams & WilkinsCLINICAL PERSPECTIVE112008

To obtain optimal benefits of anticoagulation control, patients need to be maintained within their international normalized ratio reference range, which requires regular monitoring and appropriate modification of treatment. This study systematically examined the relationship between international normalized ratio control measurements and the prediction of adverse events in patients with atrial fibrillation on oral anticoagulation. In anticoagulated atrial fibrillation patients, time in therapeutic range and percentage of international normalized ratios in range effectively predict international normalized ratio control, and data from retrospective studies support the use of time in therapeutic range to accurately predict reductions in adverse events across populations. For example, a small increment in time in therapeutic range (7%) can lead to a reduction in major hemorrhage by 1 event per 100 patient-years of treatment. On the basis of our analysis, anticoagulation services should aim for a time in therapeutic range between 70% and 80% to optimize patient benefit and minimize harm.

Back to top