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Anticoagulation treatment in patients with a mechanical heart valve
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Every year about 2,500 patients in Sweden undergo surgery for heart valve disease, primarily in the aortic valve.  In contrast to the mitral valve, which can be repaired in 70% of the cases, the aortic valve is normally replaced by a mechanical or biological prosthesis. A mechanical heart valve (MHV) necessitates lifelong anticoagulation treatment with a vitamin K antagonist, most commonly warfarin, due to the high thrombogenicity of the prosthesis. The quality of the warfarin treatment is crucial in these patients. Compared to other countries, treatment quality in Sweden is very high; nonetheless, there is always room for improvement. One of the ways to achieve this improvement is to implement computerized dosing assistance. Treatment recommendations for anticoagulation intensity are based on few and old studies, making these recommendations uncertain. There is therefore a need for studies designed to establish the appropriate level of anticoagulation therapy.

Aim

The aim of these studies was to investigate the efficacy and safety of anticoagulation treatment among patients with mechanical heart valve prostheses in Sweden; to assess whether computerized dosing can increase the treatment quality; to investigate the influence of the treatment quality, measured by Time in Therapeutic Range (TTR) and INR variability, on the risk of complications and, finally, to establish the optimal intensity of anticoagulation treatment in this group of patients.

Methods

Data were obtained from AuriculA – a national quality registry established in 2006, which currently includes approximately 50% of all patients treated with oral anticoagulation in Sweden.

Study II used only data from AuriculA. 769,933 warfarin-dosing suggestions proposed by the dosing algorithm in AuriculA were analysed. Accepted dose suggestions (590,939) were compared with 178,994 manually-changed doses in regard to the resultant INR value, measured as mean error (deviation from target INR) and hit rate (number of INR samples within the target range 2-3).

In study III, AuriculA was used to identify patients in Sundsvall and Malmö in the period 2008 – 2011 who were receiving warfarin for a mechanical heart valve prosthesis, as well as to retrieve their INR data. Data on background characteristics and bleedings or thromboembolic complications were manually retrieved from medical records by two investigators.  A total of 534 patients with mechanical heart valve prostheses were divided into quartiles based on TTR and were compared regarding the risk of complications.

For Studies I and IV, data from AuriculA were merged with the Swedish National Patient Register, SWEDEHEART/ Heart surgery, and the Swedish Cause of Death Register, comprising in total 77,423 patients on warfarin with 217,804 treatment years. Every treatment period registered in AuriculA was given an individual identification number. During the study period a patient could have any number of treatment periods. The number of complications in total and in different patient groups within the study population was investigated. Complications were defined by ICD-10 codes. Major bleeding was defined as an event necessitating hospital treatment and given a discharge diagnosis with one of the ICD-10 codes reflecting bleeding, as listed in the Appendix. Bleeding events were divided into intracranial, gastrointestinal and other bleedings. Thromboembolic complications consist of venous events (deep vein thrombosis, pulmonary embolism, venous stroke) or arterial events (stroke, TIA, acute myocardial infarction, peripheral arterial embolism).

Data were analysed using both simple, descriptive statistical methods and various tests such as Mann-Whitney (or two sample Wilcoxon), T-test, Chi 2 test, ANOVA, multivariate analysis with logistic regression and survival analysis with Cox Regression with proportional hazard assumption.

Results

Treatment quality 

Mean TTR among all patients in Study I was 76.5% whereas patients with mechanical heart valve prostheses had a TTR of 74.5%. The annual incidence of major bleeding or thromboembolic events among all patients was 2.24% and 2.65%, respectively. The incidence of intracranial bleeding was 0.37% per year in the general population and 0.51% among patients with mechanical heart valve prostheses, who also had a higher bleeding rate in total (3.37% per year).

Both the mean and median errors were smaller (0.44 vs. 0.48 and 0.3 vs. 0.4, respectively) and the hit rate was higher (0.72 vs. 0.67) when the dose suggested by the algorithm was accepted, compared to when it was manually changed.

TTR 

In Study III there was no significant difference in the risk of thromboembolism regardless of TTR level. Risk of bleeding in quartiles I and II was more than two times higher than in the quartile with TTR >82.9.

In Study IV, lower TTR (≤70%) was associated with a significantly higher rate of complications when compared with TTR >70%. Bleeding risk was higher in the group with lower TTR (HR=2.43, CI 2.02-2.89, p<0.001). After dividing patients into TTR quartiles, the rate of complications in total was significantly higher in quartiles I to III compared with quartile IV, which had the highest TTR. Risk of thromboembolism, major bleeding and death was higher in the first and second quartile compared to the quartile with the highest TTR.

INR variability 

Higher INR variability above mean (≥0.40) was related to a higher rate of complications compared with lower INR variability (<0.40) as shown in Study IV. Bleeding risk was higher in the group with INR variability ≥0.40 (HR = 2.15, CI 1.75-2.61, p<0.001).

Comparison of quartile IV, which had the lowest INR variability, with the other three revealed that quartiles I and II, which had the highest INR variability, had significantly worse outcomes for all complications except for thromboembolic events, plus also death in quartile II.

TTR and INR variability combined 

High variability and low TTR combined was associated with a higher risk of bleedings (HR 2.50, CI 1.99-3.15), death (3.34, CI 2.62-4-27) and thrombosis (1.55, CI 1.21-1.99) compared to the best group.

Level of anticoagulation

Higher warfarin treatment intensity (mean INR 2.8-3.2 vs. 2.2-2.7) was associated with a higher rate of bleedings (HR 1.29, CI 1.06-1.58), death (1.73, CI 1.38-2.16) and complications in total (1.24, CI 1.06-1.41) after adjustment for MHV position, age and comorbidity.

Conclusion

Warfarin treatment quality is crucial for patients with mechanical heart valve prostheses. Computerized dosing assistance could help maintain high warfarin treatment quality.

Well-managed treatment with TTR ≥70% and INR variability below mean <0.40 is associated with a lower risk of serious complications compared with a lower TTR and higher INR variability.

No benefit of higher warfarin treatment intensity was found for any valve type or position.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2016. , 72 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1831
Keyword [en]
Mechanical heart valve, anticoagulation, warfarin, Time in Therapeutic Range (TTR), INR variability
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-128355ISBN: 978-91-7601-539-1 (print)OAI: oai:DiVA.org:umu-128355DiVA: diva2:1051613
Public defence
2017-01-13, Aulan, Sundsvalls sjukhus, Lasarettsvägen, Sundsvall, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2016-12-21 Created: 2016-12-02 Last updated: 2016-12-21Bibliographically approved
List of papers
1. Safety and efficacy of well managed warfarin: a report from the Swedish quality register Auricula
Open this publication in new window or tab >>Safety and efficacy of well managed warfarin: a report from the Swedish quality register Auricula
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2015 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 113, no 6, 1370-1377 p.Article in journal (Refereed) Published
Abstract [en]

The safety and efficacy of warfarin in a large, unselected cohort of warfarin-treated patients with high quality of care is comparable to that reported for non-vitamin K antagonists. Warfarin is commonly used for stroke prevention in atrial fibrillation, as well as for treatment and prevention of venous thromboembolism. While reducing risk of thrombotic/embolic incidents, warfarin increases the risk of bleeding. The aim of this study was to elucidate risks of bleeding and thromboembolism for patients on warfarin treatment in a large, unselected cohort with rigorously controlled treatment. This was a retrospective, registry-based study, covering all patients treated with warfarin in the Swedish national anticoagulation register Auricula, which records both primary and specialised care. The study included 77,423 unselected patients with 100,952 treatment periods of warfarin, constituting 217,804 treatment years. Study period was January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68%). The mean time in therapeutic range of the international normalised ratio (INR) 2.0-3.0 was 76.5%. The annual incidence of I severe bleeding was 2.24% and of thromboembolism 2.65%. The incidence of intracranial bleeding was 0.37% per treatment year in the whole population, and 0.38% among patients with atrial fibrillation. In conclusion, warfarin treatment where patients spend a high proportion of time in the therapeutic range is safe and effective, and will continue to be a valid treatment option in the era of newer oral anticoagulants.

National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-106015 (URN)10.1160/TH14-10-0859 (DOI)000355776400026 ()25716771 (PubMedID)
Available from: 2015-07-06 Created: 2015-07-03 Last updated: 2017-02-13Bibliographically approved
2. Computer aided warfarin dosing in the Swedish national quality registry AuriculA: algorithmic suggestions are performing better than manually changed doses
Open this publication in new window or tab >>Computer aided warfarin dosing in the Swedish national quality registry AuriculA: algorithmic suggestions are performing better than manually changed doses
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2013 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 2, 130-134 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Warfarin treatment with a high time in therapeutic range (TTR) is correlated to fewer complications. The TTR in Sweden is generally high but varies partly depending on local expertise and traditions. A dosing algorithm could minimize variations and increase treatment quality. Here we evaluate the performance of a computerized dosing algorithm.

MATERIALS AND METHODS: 53.779 warfarin treated patients from 125 centers using the Swedish national quality registry AuriculA. If certain criteria are met, the algorithm gives one of seven possible dose suggestions, which can be unchanged, decreased or increased weekly dose by 5, 10 or 15%. The outcome evaluated by the resulting INR value was compared between dose suggestions arising from the algorithm that were accepted and those that were manually changed. There were no randomization, and outcomes were retrospectively analyzed.

RESULTS: Both the algorithm-based and the manually changed doses had worse outcome if only two instead of three previous INR values were available. The algorithm suggestions were superior to manual dosing regarding percent samples within the target range 2-3 (hit-rate) or deviation from INR 2.5 (mean error). Of the seven possible outcomes from the algorithm, six were significantly superior and one equal to the manually changed doses when three previous INR:s were present.

CONCLUSIONS: The algorithm-based dosing suggestions show better outcome in most cases. This can make dosing of warfarin easier and more efficient. There are however cases where manual dosing fares better. Here the algorithm will be improved to further enhance its dosing performance in the future.

Keyword
Anticoagulation, Atrial fibrillation, Computer-assisted therapy, INR, Warfarin
National Category
Cardiac and Cardiovascular Systems Hematology
Identifiers
urn:nbn:se:umu:diva-66123 (URN)10.1016/j.thromres.2012.11.016 (DOI)000313719400009 ()23232091 (PubMedID)
Available from: 2013-02-15 Created: 2013-02-15 Last updated: 2016-12-19Bibliographically approved
3. Mechanical heart valve prosthesis and warfarin: treatment quality and prognosis
Open this publication in new window or tab >>Mechanical heart valve prosthesis and warfarin: treatment quality and prognosis
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2014 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 133, no 5, 795-798 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Every year about 2500 patients in Sweden undergo surgery due to heart valve disease. A mechanical heart valve prosthesis causes risk of thromboembolic stroke or thrombus formation in the valve while anticoagulant treatment increases the risk of bleeding. Treatment quality with warfarin is crucial for patients with mechanical valve prostheses. It has previously been shown that poorly controlled warfarin treatment increases mortality in this patient group. TTR (Time in Therapeutic Range) on warfarin has been shown to affect the risk of complications in atrial fibrillation, but has not been studied in patients with mechanical heart valves. Our aim is to evaluate the impact of TTR on the risk of complications in this patient group. Materials and Methods: A non-randomized, prospective study of 534 adults with mechanical heart valve prostheses from Malmo and Sundsvall registered in the Swedish National Quality Registry Auricula between 01.01.2008 and 31.12.2011. Quartiles regarding individual TTR levels were compared regarding risk of complications. Results: The risk of complications was significantly higher at lower TTR levels for all complications (p = 0.005), bleeding (p = 0.01) and death (p = 0.018) but not for thromboembolism. In multivariate analysis the risk was significantly increased at lower TTR levels for bleeding and all complications but not for death or thromboembolism. Conclusion: Patients with a lower warfarin treatment quality measured by TTR have a higher risk of complications such as severe bleeding or death. A TTR of 83% or higher at the individual level should be obtained for best outcome.

Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
TTR, Warfarin, Mechanical heart valve prosthesis
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-89216 (URN)10.1016/j.thromres.2014.02.031 (DOI)000334739100017 ()
Available from: 2014-05-28 Created: 2014-05-26 Last updated: 2016-12-02Bibliographically approved
4. Warfarin treatment quality and prognosis in patients with mechanical heart valve prosthesis
Open this publication in new window or tab >>Warfarin treatment quality and prognosis in patients with mechanical heart valve prosthesis
Show others...
2017 (English)In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 103, no 3, 198-203 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To study the impact of time in therapeutic range (TTR) and international normalised ratio (INR) variability on the risk of thromboembolic events, major bleeding complications and death after mechanical heart valve (MHV) implantation. Additionally, the importance of different target INR levels was elucidated.

METHODS: A retrospective, non-randomised multicentre cohort study including all patients with mechanical heart valve (MVH) prosthesis registered in the Swedish National Quality Registry Auricula from 2006 to 2011. Data were merged with the Swedish National Patient Registry, SWEDEHEART and Cause of Death Registry.

RESULTS: In total 4687 ordination periods, corresponding to 18 022 patient-years on warfarin, were included. High INR variability (above mean ≥0.40) or lower TTR (≤70%) was associated with a higher risk of bleeding (rate per 100 years 4.33 (95% CI 3.87 to 4.82) vs 2.08 (1.78 to 2.41); HR 2.15 (1.75 to 2.61) and 5.13 (4.51 to 5.82) vs 2.30 (2.03 to 2.60); HR 2.43 (2.02 to 2.89)), respectively. High variability and low TTR combined was associated with an even higher risk of bleedings (rate per 100 years 4.12 (95% CI 3.68 to 4.51) vs 2.02 (1.71 to 2.30); HR 2.16 (1.71 to 2.58) and 4.99 (4.38 to 5.52) vs 2.36 (2.06 to 2.60); HR 2.38 (2.05 to 2.85)) compared with the best group.Higher treatment intensity (mean INR 2.8-3.2 vs 2.2-2.7) was associated with higher rate of bleedings (2.92 (2.39 to 3.47) vs 2.48 (2.21 to 2.77); HR 1.29 (1.06 to 1.58)), death (3.36 (2.79 to 4.02) vs 1.89 (1.64 to 2.17), HR 1.65 (1.31 to 2.06)) and complications in total (6.61 (5.74 to 7.46) vs 5.65 (5.20 to 6.06); HR 1.24 (1.06 to 1.41)) after adjustment for MHV position, age and comorbidity.

CONCLUSIONS: A high warfarin treatment quality improves outcome after MHV implantation, both measured with TTR and INR variability. No benefit was found with higher treatment intensity (mean INR 2.8-3.2 vs 2.2-2.7).

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2017
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-127525 (URN)10.1136/heartjnl-2016-309585 (DOI)000394510200008 ()27590664 (PubMedID)
Available from: 2016-11-15 Created: 2016-11-15 Last updated: 2017-04-12Bibliographically approved

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