Incidence and predictors of excessive warfarin anticoagulation in patients with atrial fibrillation—The EWA study

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Abstract

Vitamin K antagonist warfarin is widely used in clinical practice and excessive anticoagulation is a well-known complication of this therapy. Little is known about permanent and temporary predictors for severe overanticoagulation. The aim of this study was to investigate the occurrence and predicting factors for episodes with very high (≥9) international normalized ratio (INR) values in warfarin treated patients with atrial fibrillation (AF). Excessive Warfarin Anticoagulation (EWA) study screened all patients (n = 13618) in the Turku University Hospital region with an INR ≥2 between years 2003–2015. Patients using warfarin anticoagulation for AF with very high (≥9) INR values (EWA Group) were identified (n = 412 patients) and their characteristics were compared to a control group (n = 405) of AF patients with stable INR during long-term follow-up. Over 20% (n = 92) of the EWA patients had more than one event of very high INR and in 105 (25.5%) patients EWA led to a bleeding event. Of the several temporary and permanent EWA risk factors observed, strongest were excessive alcohol consumption in 9.6% of patients (OR 24.4, 95% CI 9.9–50.4, p<0.0001) and reduced renal function (OR 15.2, 95% CI 5.67–40.7, p<0.0001). Recent antibiotic or antifungal medication, recent hospitalization or outpatient clinic visit and the first 6 months of warfarin use were the most significant temporary risk factors for EWA. Excessive warfarin anticoagulation can be predicted with several permanent and temporary clinical risk factors, many of which are modifiable.

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Most cited references 29

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Chronic kidney disease and mortality risk: a systematic review.

Marcello Tonelli, Natasha Wiebe, Bruce Culleton … (2006)

Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.

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Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.

Elaine Hylek, Carmella Evans-Molina, Carol Shea … (2007)

Warfarin is effective in the prevention of stroke in atrial fibrillation but is under used in clinical care. Concerns exist that published rates of hemorrhage may not reflect real-world practice. Few patients > or = 80 years of age were enrolled in trials, and studies of prevalent use largely reflect a warfarin-tolerant subset. We sought to define the tolerability of warfarin among an elderly inception cohort with atrial fibrillation. Consecutive patients who started warfarin were identified from January 2001 to June 2003 and followed for 1 year. Patients had to be > or = 65 years of age, have established care at the study institution, and have their warfarin managed on-site. Outcomes included major hemorrhage, time to termination of warfarin, and reason for discontinuation. Of 472 patients, 32% were > or = 80 years of age, and 91% had > or = 1 stroke risk factor. The cumulative incidence of major hemorrhage for patients > or = 80 years of age was 13.1 per 100 person-years and 4.7 for those or = 80 years, and international normalized ratio (INR) > or = 4.0 were associated with increased risk despite trial-level anticoagulation control. Within the first year, 26% of patients > or = 80 years of age stopped taking warfarin. Perceived safety issues accounted for 81% of them. Rates of major hemorrhage and warfarin termination were highest among patients with CHADS2 scores (an acronym for congestive heart failure, hypertension, age > or = 75, diabetes mellitus, and prior stroke or transient ischemic attack) of > or = 3. Rates of hemorrhage derived from younger noninception cohorts underestimate the bleeding that occurs in practice. This finding coupled with the short-term tolerability of warfarin likely contributes to its underutilization. Stroke prevention among elderly patients with atrial fibrillation remains a challenging and pressing health concern.

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Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.

Elaine Hylek, Alan S Go, Yuchiao Chang … (2003)

The incidence of stroke in patients with atrial fibrillation is greatly reduced by oral anticoagulation, with the full effect seen at international normalized ratio (INR) values of 2.0 or greater. The effect of the intensity of oral anticoagulation on the severity of atrial fibrillation-related stroke is not known but is central to the choice of the target INR. We studied incident ischemic strokes in a cohort of 13,559 patients with nonvalvular atrial fibrillation. Strokes were identified through hospitalization data bases and validated on the basis of medical records, which also provided information on the use of warfarin or aspirin, the INR at admission, and coexisting illnesses. The severity of stroke was graded according to a modified Rankin scale. Thirty-day mortality was ascertained from hospitalization and mortality files. Of 596 ischemic strokes, 32 percent occurred during warfarin therapy, 27 percent during aspirin therapy, and 42 percent during neither type of therapy. Among patients who were taking warfarin, an INR of less than 2.0 at admission, as compared with an INR of 2.0 or greater, independently increased the odds of a severe stroke in a proportional-odds logistic-regression model (odds ratio, 1.9; 95 percent confidence interval, 1.1 to 3.4) across three severity categories and the risk of death within 30 days (hazard ratio, 3.4; 95 percent confidence interval, 1.1 to 10.1). An INR of 1.5 to 1.9 at admission was associated with a mortality rate similar to that for an INR of less than 1.5 (18 percent and 15 percent, respectively). The 30-day mortality rate among patients who were taking aspirin at the time of the stroke was similar to that among patients who were taking warfarin and who had an INR of less than 2.0. Among patients with nonvalvular atrial fibrillation, anticoagulation that results in an INR of 2.0 or greater reduces not only the frequency of ischemic stroke but also its severity and the risk of death from stroke. Our findings provide further evidence against the use of lower INR target levels in patients with atrial fibrillation. Copyright 2003 Massachusetts Medical Society

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Author and article information

Contributors

Carmine Pizzi: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 20 April 2017

Publication date Collection: 2017

Volume: 12

Issue: 4

Electronic Location Identifier: e0175975

Affiliations

[1 ]Heart Center, Turku University Hospital and University of Turku, Turku, Finland

[2 ]Department of Acute Internal Medicine, Turku University Hospital and University of Turku, Turku, Finland

[3 ]Department of Cardiology, Turku City Hospital, Turku, Finland

[4 ]University of Turku, Turku, Finland

University of Bologna, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceptualization: KEJA SJ IN TOK.
Data curation: SJ IN MI.
Formal analysis: SJ IN TOK KEJA.
Funding acquisition: KEJA.
Investigation: MI SJ RV.
Methodology: KEJA IN TOK SJ.
Project administration: KEJA.
Resources: KEJA.
Software: IN.
Supervision: KEJA TOK.
Validation: IN SJ TOK KEJA.
Visualization: SJ.
Writing – original draft: SJ.
Writing – review & editing: SJ KEJA TOK MI RV IN.

* E-mail: juhani.airaksinen@ 123456tyks.fi

Author information

Samuli Jaakkola http://orcid.org/0000-0001-5944-6814

Article

Publisher ID: PONE-D-17-01667

DOI: 10.1371/journal.pone.0175975

PMC ID: 5398615

PubMed ID: 28426737

SO-VID: e497f67a-b45d-4fc9-9437-1daa486f04d1

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 13 January 2017

Date accepted : 3 April 2017

Page count

Figures: 2, Tables: 2, Pages: 11

Funding

Funded by: funder-id http://dx.doi.org/10.13039/501100005633, Sydäntutkimussäätiö;

Award ID: 140027

Funded by: State Clinical Research Fund (EVO) of Turku University Hospital, Turku, Finland

Award ID: 13016

Award Recipient :

ORCID: http://orcid.org/0000-0001-5944-6814

Samuli Jaakkola

This study was funded by The Finnish Foundation for Cardiovascular Research, Helsinki, Finland, (140027): State Clinical Research Fund (EVO) of Turku University Hospital, Turku, Finland (13016).

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Data Availability Access to data is regulated by Finnish law. Data are available from the Turku University Hospital for researchers who meet the criteria as required by the Finnish law for access to confidential data. Contact person who will distribute data upon request to qualified researchers: Tuija Vasankari, Heart Center, Turku University Hospital, PO BOX 52, FIN-20521, Turku, Finland; tuija.vasankari@ 123456tyks.fi .

Incidence and predictors of excessive warfarin anticoagulation in patients with atrial fibrillation—The EWA study

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Most cited references 29

Chronic kidney disease and mortality risk: a systematic review.

Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.

Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.

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