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Warfarin treatment quality in stroke prevention
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Ischemic stroke is a serious condition often associated to presence of atrial fibrillation (AF). Use of anticoagulants for AF patients greatly reduces the risk of stroke. Warfarin is the most commonly used anticoagulant in Sweden. The aim of this thesis was to study the impact of warfarin treatment quality in Swedish stroke prevention.

Methods

Study I, II and IV were relatively large multicentre, retrospective, cohort studies based on Swedish registries, especially AuriculA, a quality register for AF and anticoagulation. Background data as well as bleeding and thromboembolic complications were retrieved from the National Patient Register. The Cause of Death Register was used in study II and IV. The Swedish Prescribed Drug Register was used in study IV, for data on concomitant acetylsalicylic acid (ASA) use. Study period was January 1, 2006, to December 31, 2011. Study III enrolled all warfarin treated AF patients in Sundsvall, registered in AuriculA on January 1, 2010. This smaller cohort was followed until discontinuation or study-stop December 31, 2013. All used data were collected from each patient’s medical record.

Results

The annual risk of major bleedings and thromboembolic events for warfarin treated patients, including all different indications for warfarin, was relatively low (2.24% and 2.66%), with incidence of intracranial bleeding of 0.37% per treatment year. The overall mean time in therapeutic range (TTR) was 76.5%. Patients started on warfarin due to AF had a mean TTR of 68.6%, with an annual risk of major bleeding and thromboembolic events of 2.23% and 2.95%, and with 0.44% annual risk of intracranial bleeding. No significant differences in overall complications were found when comparing treatment monitored in anticoagulation clinics (ACC) with treatment monitored in primary health care centers (PHCC). There were significantly increased risk of both overall major bleedings and thromboembolic events for those warfarin treated AF patients receiving additional ASA treatment, having individual TTR (iTTR) below 70%, or having high international normalized ratio (INR) variability. AF patients with low INR variability had generally lower complication rates, compared with patients with high INR variability. There were however no alteration on cumulative incidence of complications due to INR variability, for AF patients with iTTR ≥70%. The overall proportion of persistence to warfarin treatment for stroke patients with AF was found to be 0.69 after 2 years treatment and 0.47 after 5 years. Stroke patients with diagnosed dementia at baseline were more than two-times likely of discontinuing warfarin than others. Excessive alcohol use, chronic obstructive pulmonary disease, cancer and chronic heart failure were baseline diagnoses each associated with over 20% increased risk of treatment discontinuation. Lower persistence to treatment was linked to increasing start-age and CHA2DS2-VASc scores. As documented reasons for warfarin treatment discontinuation in AF patients, we found regained sinus rhythm as the most common addressed cause (31.2%), followed by problematic monitoring and bleedings. We estimated that only half (49.5%) of the treatment discontinuations were clinically well motivated.

Conclusions

Quality of Swedish warfarin treatment in initiated stroke prevention is high, with generally low rates of complications and high TTRs, no matter treatment in ACC or PHCC, including high long time persistence to warfarin in secondary stroke prevention. For better outcome in future warfarin stroke prophylactic treatment clinicians should aim for iTTRs above 70%, avoid additional ASA therapy, support fragile patients like those with excessive alcohol use and dementia, and base decisions on treatment discontinuations on solid medical arguments.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 50 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1827
Keyword [en]
Anticoagulation, atrial fibrillation, complications, international normalized ratio (INR) variability, persistence, stroke, time in therapeutic range (TTR), treatment quality, warfarin
National Category
Cardiac and Cardiovascular Systems Hematology
Research subject
Medicine, cardiovascular disease
Identifiers
URN: urn:nbn:se:umu:diva-125998ISBN: 978-91-7601-513-1 (print)OAI: oai:DiVA.org:umu-125998DiVA: diva2:974276
Public defence
2016-10-21, Aulan, Utbildningslokalerna 1 trp, Sundsvalls sjukhus, Sundsvall, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2016-09-30 Created: 2016-09-26 Last updated: 2016-09-29Bibliographically approved
List of papers
1. Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden
Open this publication in new window or tab >>Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden
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2015 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, 216-220 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Warfarin treatment in Sweden holds a high standard with time in therapeutic range (TTR) over 75%. Internationally, specialized anticoagulation clinics (ACC) have shown higher TTR compared to primary health care centres (PHCC).

OBJECTIVES: To compare warfarin treatment quality in Sweden for ACC versus PHCC, thereby clarifying whether centralization is for the better.

PATIENTS/METHODS: In total 77.058 patients corresponding to 217.058 treatment years with warfarin in the Swedish national quality register AuriculA from 1. Jan 2006 to 31. Dec 2011. Information regarding TTR was calculated from AuriculA, while patient characteristics and complications were retrieved from the Swedish National Patient Register.

RESULTS: Of the 100.554 treatment periods examined, 78.7% were monitored at ACC. Mean TTR for INR 2-3 for all patients irrespective of intended target range was 76.5% with an annual risk of bleeding or thrombotic events of 2.24% and 2.66%, respectively. TTR was significantly higher in PHCC compared to ACC (79.6% vs. 75.7%, p<0.001), with no significant difference in overall risk of complications. Treatment periods for atrial fibrillation, except intended direct current conversion, showed similar results between ACC and PHCC without significant difference in annual risk of bleeding (2.50% vs. 2.51%) or thrombosis (3.09% vs. 3.16%). After propensity score matching there was still no significant difference in complication risk found.

CONCLUSIONS: Warfarin treatment quality is consistently high in both ACC and PHCC when monitored through AuriculA in Sweden, both measured as TTR and as risk of complications. In this setting, centralized warfarin monitoring is not likely to improve the results.

Place, publisher, year, edition, pages
Elsevier, 2015
National Category
Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-103943 (URN)10.1016/j.thromres.2015.04.016 (DOI)000363953000008 ()25935649 (PubMedID)
Available from: 2015-06-04 Created: 2015-06-04 Last updated: 2017-12-04Bibliographically approved
2. Warfarin persistence among stroke patients with atrial fibrillation
Open this publication in new window or tab >>Warfarin persistence among stroke patients with atrial fibrillation
2015 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 4, 744-748 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). For AF patients with stroke a warfarin persistence rate of 0.45 after 2years has previously been reported. No consistent predictors for discontinuation have been established.

AIMS: Evaluation of warfarin persistence and variables associated with discontinuation, in a large Swedish cohort with unselected stroke/TIA patients with AF treated with warfarin.

MATERIALS AND METHODS: 4 583 patients with stroke/TIA and AF in the Swedish National Patient Register (NPR), from 1. Jan 2006 to 31. Dec 2011, were matched with the Swedish national quality register AuriculA. They were followed until treatment cessation, death or end of study. Baseline characteristics and CHA2DS2VASc score were retrieved from NPR. Treatment-time was retrieved from AuriculA.

RESULTS: Overall proportion of warfarin persistence was 0.78 (95% confidence interval (CI) 0.76 to 0.80) after one year, 0.69 (95% CI 0.67 to 0.71) after 2years and 0.47 (95% CI 0.43 to 0.51) after 5years. Variables clearly associated with higher discontinuation were dementia (hazard ratio (HR) 2.22, CI 1.51-3.27) and alcohol abuse (HR 1.66, CI 1.19-2.33). Chronic obstructive pulmonary disease (COPD), cancer and chronic heart failure (CHF) were each associated with over 20% increased risk of treatment discontinuation. Higher CHA2DS2VASc score and start-age lead to lower persistence (p<0.001).

CONCLUSIONS: Persistence to warfarin in unselected stroke/TIA patients with AF is in Sweden greater than previously reported. Lower persistence is found among patients with high treatment start-age, incidence of dementia, alcohol abuse, cancer, CHF, COPD and/or high CHA2DS2VASc score.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
Atrial fibrillation, Discontinuation, Persistence, Stroke, Treatment, Warfarin
National Category
Cardiac and Cardiovascular Systems Hematology
Identifiers
urn:nbn:se:umu:diva-110298 (URN)10.1016/j.thromres.2015.07.028 (DOI)000365800600009 ()26254195 (PubMedID)
Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2017-12-01Bibliographically approved
3. Warfarin persistence among atrial fibrillation patients – why is treatment ended?
Open this publication in new window or tab >>Warfarin persistence among atrial fibrillation patients – why is treatment ended?
2016 (English)In: Cardiovascular Therapeutics, ISSN 1755-5914, Vol. 34, no 6, 468-474 p.Article in journal (Refereed) Published
Abstract [en]

Background and Aim

Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). Studies mainly focused on whether the proportion of warfarin persistence and discontinuationare clinically appropriate are absent. This study evaluates warfarin persistence with focus on predictors for, and reasons to, warfarin discontinuation in AF patients.

Methods

From the national quality register AuriculA, all AF patients in Sundsvall, Sweden, on warfarin treatment on January first, 2010 were included. These 478 patients were followed until discontinuation or study-stop December 31, 2013. By going through each patient’s medical record risk factors for thromboembolism, bleeding and causes of discontinuation were obtained.

Results

Proportion of warfarin persistence was 0.91 (95% confidence interval (CI) 0.89 to 0.93) after one year and 0.73 (95% CI 0.69 to 0.77) after four years. Previous intracranial bleeding, excessive alcohol use, anemia and pulmonary or peripheral emboli were each associated with over two times higher risk of discontinuation (hazard ratio (HR) 5.66, CI 2.23-14.36, HR 2.54, CI 1.48-4.37, HR 2.40, CI 1.38-4.17, and HR 2.13, CI 1.02-4.46). Among patients discontinuing, 50.5% were due to questionable causes, such as sinus rhythm (33.9%), patients demand (10.1%) and falls (8.2%). The majority (43.1%) of treatment discontinuers were changed to aspirin, while 40.4% of them were left without medical stroke prophylaxis.

Conclusions

Although persistence to warfarin among AF patients proves higher than previously reported, there is room for improvement since half of the discontinuers have questionable reasons for treatment stop and the majority of them receive no other efficient stroke prophylaxis.

Keyword
Atrial fibrillation, Discontinuation, Persistence, Stroke prophylaxis, Treatment, Warfarin
National Category
Hematology Cardiac and Cardiovascular Systems
Research subject
Medicine, cardiovascular disease
Identifiers
urn:nbn:se:umu:diva-125990 (URN)10.1111/1755-5922.12224 (DOI)000388370600010 ()27565120 (PubMedID)
Available from: 2016-09-26 Created: 2016-09-26 Last updated: 2017-11-21Bibliographically approved
4. Outcomes in a Warfarin-Treated Population With Atrial Fibrillation
Open this publication in new window or tab >>Outcomes in a Warfarin-Treated Population With Atrial Fibrillation
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2016 (English)In: JAMA cardiology, ISSN 2380-6591, Vol. 1, no 2, 172-180 p.Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE: Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs.

OBJECTIVES: To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications.

EXPOSURES: Use of warfarin with and without concomitant therapy with aspirin.

MAIN OUTCOMES AND MEASURES: Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding.

RESULTS: Of the 40 449 patients included in the study, 16 201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age ≥75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44% (0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07% (2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure were at higher risk of intracranial bleeding (hazard ratio, 2.25; 95% CI, 1.32-3.82). Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% (3.51-4.11) and 4.41% (4.09-4.73), respectively, and, in high INR variability, were 3.04% (2.85-3.24) and 3.48% (3.27-3.69), respectively. For patients with iTTR 70% or greater, the level of INR variability did not alter event rates.

CONCLUSIONS AND RELEVANCE: Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-124782 (URN)10.1001/jamacardio.2016.0199 (DOI)27437888 (PubMedID)
Available from: 2016-08-24 Created: 2016-08-24 Last updated: 2016-09-28Bibliographically approved

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