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Figure.
Association of Prior INR Values With Future Therapeutic Stability Among Patients With Atrial Fibrillation Taking Warfarin
Association of Prior INR Values With Future Therapeutic Stability Among Patients With Atrial Fibrillation Taking Warfarin

INR indicates international normalized ratio. The error bars indicate 95% CIs.

Table.  
Baseline Characteristics of Patients With Atrial Fibrillation Taking Warfarin
Baseline Characteristics of Patients With Atrial Fibrillation Taking Warfarin
1.
Wilke  T, Groth  A, Mueller  S,  et al.  Oral anticoagulation use by patients with atrial fibrillation in Germany.  Thromb Haemost. 2012;107(6):1053-1065.PubMedGoogle ScholarCrossref
2.
Ruff  CT, Giugliano  RP, Braunwald  E,  et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation.  Lancet. 2014;383(9921):955-962.PubMedGoogle ScholarCrossref
3.
Piccini  JP, Fraulo  ES, Ansell  JE,  et al.  Outcomes registry for better informed treatment of atrial fibrillation.  Am Heart J. 2011;162(4):606-612.e1.PubMedGoogle ScholarCrossref
4.
Hylek  EM, Skates  SJ, Sheehan  MA, Singer  DE.  An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation.  N Engl J Med. 1996;335(8):540-546.PubMedGoogle ScholarCrossref
5.
Singer  DE, Chang  Y, Fang  MC,  et al.  Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?  Circ Cardiovasc Qual Outcomes. 2009;2(4):297-304.PubMedGoogle ScholarCrossref
6.
Lip  GY, Laroche  C, Ioachim  PM,  et al.  Prognosis and treatment of atrial fibrillation patients by European cardiologists.  Eur Heart J. 2014;35(47):3365-3376.PubMedGoogle ScholarCrossref
Research Letter
August 9, 2016

Stability of International Normalized Ratios in Patients Taking Long-term Warfarin Therapy

Author Affiliations
  • 1Division of Cardiology, Duke University Medical Center, Durham, North Carolina
  • 2Mayo Clinic College of Medicine, Rochester, Minnesota
  • 3Boston University School of Medicine, Boston, Massachusetts
JAMA. 2016;316(6):661-663. doi:10.1001/jama.2016.9356

Warfarin substantially decreases stroke risk among patients with atrial fibrillation yet has a narrow therapeutic window (international normalized ratio [INR] values of 2.0-3.0) and is associated with multiple drug and food interactions.1 Non–vitamin K oral anticoagulants do not require drug monitoring and have similar or improved safety and efficacy relative to warfarin but are more costly.2 Whether patients previously stable on warfarin should be switched to non–vitamin K oral anticoagulants remains controversial but may be informed by determining whether patients receiving warfarin who have stable INR values remain stable over time.

Methods

Written informed consent was obtained for registry enrollment. The Duke institutional review board approved this study. Data were obtained from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a prospective registry of patients with atrial fibrillation from 176 clinics who were enrolled June 2010 through August 2011 and followed up for 3 years through November 2014.3 Patients receiving warfarin at baseline with 3 or more INR values in the first 6 months and 6 or more in the subsequent year were included. Stability was defined as 80% or more INRs in therapeutic range (2.0-3.0). An R2 value assessed stability in the first 6 months as a predictor of stability in the subsequent year (both continuous). A C index determined whether stable INR during the baseline 6 months discriminated stable INR in the subsequent year.

Sensitivity analyses assessed stability among patients having 100% of INRs in range at baseline and whether stable patients at baseline had any INR values well out of range (<1.5 or >4.0) in the subsequent year. Interpolated patient-level time in therapeutic range (TTR) was examined. Statistical significance was 5% with a 2-tailed test. SAS software (SAS Institute), version 9.3, was used.

Results

Of 10 132 registry patients, 6383 were not taking warfarin or had insufficient INR values and were excluded. Among 3749 patients taking warfarin (mean age, 75 years; women, 43%), 968 patients (26%) had 80% or more of INR values in 2.0-3.0 range during the first 6 months (median No. of INR measurements, 8 [interquartile range {IQR}, 6-10]) (Table). Of patients with stable INRs during the first 6 months, 34% (95% CI, 31%-37%) remained stable over the subsequent year (median No. of INR measurements, 13 [IQR, 10-16]) (Figure). Prior stability explained a small amount of variation in subsequent stability (R2, 11% [95% CI, 9%-13%]). Stability during the baseline period had limited predictive ability of stability over the subsequent year (C index, 0.61 [95% CI, 0.59-0.62]).

Of 376 patients (10%) with 100% of INR values in range during the first 6 months, 37% (95% CI, 32%-42%) had stability over the subsequent year. Among patients with 80% or more INRs in range at baseline, 36% (95% CI, 33%-39%) had 1 or more well-out-of-range INR in the following year, demonstrating limited predictive ability of stability on well-out-of-range INRs (C index, 0.57 [95% CI, 0.56-0.59]). Among patients with 100% of baseline INR values in range, 33% (95% CI, 29%-38%) had 1 or more well-out-of-range INR in the subsequent year. Using TTR, 1218 patients (32% [95% CI, 31%-34%]) had a TTR of 80% or more during the first 6 months, and, among those, 42% (95% CI, 39%-45%) had TTR of 80% or more during the subsequent 12 months, whereas 38% (95% CI, 35%-41%) had 1 or more INR well out of range.

Discussion

Only 26% of patients taking warfarin had stable INR values over a 6-month period; just 34% continued to have stable results in the subsequent year, whereas 36% had 1 or more extreme INR values.

Limitations include the assumption that patients’ target INR range was 2.0 to 3.0, when physicians could have targeted lower INR values due to bleeding or higher values for mechanical valves; results may not mirror community practice; and clinical end points with out-of-range INR values were not examined, but an association has been previously demonstrated.4,5

INR values were used to reflect the information most accessible and likely to be used at the bedside, whereas TTR analyses were similar. A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants.6 This analysis suggests warfarin stability is difficult to predict and challenges the notion that patients who have done well taking warfarin should maintain taking warfarin.

Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Article Information

Corresponding Author: Eric D. Peterson, MD, MPH, Division of Cardiology, Duke University Medical Center, DUMC 3236, Durham, NC 27710 (eric.peterson@duke.edu).

Author Contributions: Drs Pokorney and Peterson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Pokorney, Hylek, Peterson.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Pokorney.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Pokorney, Simon, Thomas.

Obtained funding: Piccini, Peterson.

Administrative, technical, or material support: Piccini, Peterson.

Study supervision: Piccini, Peterson.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Pokorney reports receiving grant support from AstraZeneca, Gilead, and Boston Scientific; consulting fees from Boston Scientific and Medtronic; and serving on the advisory board for Janssen. Dr Gersh reports receiving serving on boards for Medtronic, Baxter, InspireMD, Cardiovascular Research Foundation, Pharmaceutical Product Development, Boston Scientific, and St Jude. Dr Hylek reports receiving honoraria from Boehringer Ingelheim and Bayer, and consulting fees from Daiichi Sankyo, Ortho-McNeil-Janssen, Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, and Pfizer. Dr Piccini reports receiving grant support from Johnson & Johnson/Janssen; other support from Bayer (formerly Berlex Labs), Boston Scientific, and Johnson & Johnson; consulting fees from Forest Laboratories, Medtronic, and Johnson & Johnson/Janssen Pharmaceuticals. Dr Peterson reports receiving grant support from Eli Lilly, Janssen, and the American Heart Association; and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Genentech. No other disclosures are reported.

Disclaimer: Dr Peterson, an associate editor for JAMA, was not involved in the editorial review of or the decision to publish this article.

References
1.
Wilke  T, Groth  A, Mueller  S,  et al.  Oral anticoagulation use by patients with atrial fibrillation in Germany.  Thromb Haemost. 2012;107(6):1053-1065.PubMedGoogle ScholarCrossref
2.
Ruff  CT, Giugliano  RP, Braunwald  E,  et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation.  Lancet. 2014;383(9921):955-962.PubMedGoogle ScholarCrossref
3.
Piccini  JP, Fraulo  ES, Ansell  JE,  et al.  Outcomes registry for better informed treatment of atrial fibrillation.  Am Heart J. 2011;162(4):606-612.e1.PubMedGoogle ScholarCrossref
4.
Hylek  EM, Skates  SJ, Sheehan  MA, Singer  DE.  An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation.  N Engl J Med. 1996;335(8):540-546.PubMedGoogle ScholarCrossref
5.
Singer  DE, Chang  Y, Fang  MC,  et al.  Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?  Circ Cardiovasc Qual Outcomes. 2009;2(4):297-304.PubMedGoogle ScholarCrossref
6.
Lip  GY, Laroche  C, Ioachim  PM,  et al.  Prognosis and treatment of atrial fibrillation patients by European cardiologists.  Eur Heart J. 2014;35(47):3365-3376.PubMedGoogle ScholarCrossref
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