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Efficacy and safety of warfarin treatment in venous thromboembolic disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

As a major cause of morbidity and mortality treatment of venous thromboembolism is important, with the correct use of anticoagulants it is possible to greatly reduce both mortality and morbidity. Warfarin is among the most widely used anticoagulants being effective in treatment and prevention of venous thromboembolism with few negative side effects other than bleeding complications. With a narrow therapeutic window warfarin treatment requires constant monitoring and adjustments to stay effective without an increased bleeding risk.

The aim of this thesis was to study the efficacy and safety of warfarin treatment in venous thromboembolic disease.

Methods

Using AuriculA, the Swedish national quality register for atrial fibrillation and anticoagulation, a cohort was created of patients registered with warfarin treatment during the study time January 1st 2006 to December 31th 2011, including all different indications for anticoagulation. In all four studies the study design was retrospective with information added to the cohort from the Swedish national patient register about background data and endpoints in form of bleeding complications in all studies and thromboembolic events in study 1 and 2. In study 3 and 4 information was added from the cause of death register about occurrence of death and in study 3 cause of death. In study 3, information from the prescribed drugs register about retrieved prescriptions of acetylsalicylic acid was added.

Results

In study 1 the mean TTR was found to be high both among patients managed at primary healthcare centres and specialised anticoagulation clinics at 79.6% and 75.7%. There was no significant difference in rate of bleeding between the two types of managing centres being 2.22 and 2.26 per 100 treatment years. In study 2 no reduction in complication rate with increasing centre TTR was seen for patients with atrial fibrillation with few centres having centre TTR below 70% (2.9%), in contrast to previous findings by Wan et al(1). For those with warfarin due to VTE where a larger proportion of the centres had centre TTR below 70% (9.1%) there was a reduction in complication rate with increasing centre TTR. Among the 13859 patients with treatment for VTE in study 3 age (HR 1.02, CI 95% 1.01-1.03), hypertension (HR 1.29, CI 95%1.02-1.64), Cardiac failure (HR 1.55, CI 95% 1.13-2.11), chronic obstructive pulmonary disease (HR 1.43, CI 95% 1.04- 1.96), alcohol abuse (HR 3.35, CI 95% 1.97-5.71), anaemia (HR 1.77, CI 95% 1.29-2.44) and a history of major bleeding (HR 1.75, CI 95% 1.27-2.42) increased the risk of bleeding during warfarin treatment. In study 4 both those with high iTTR and those with low INR variability had a low rate of bleedings at 1.27 (1.14-1.41) or 1.20 (0.94-1.21) per 100 treatment years compared to those with low iTTR and high INR variability having a rate of bleeding at 2.91 (2.61-3.21) or 2.61 (2.36-2.86) respectively. Those with the combination of both low iTTR and high INR variability had an increased risk of bleeding, hazard ratio HR 3.47 (CI 95 % 2.89-4.17). The quartile with both the lowest iTTR and the highest INR variability had an increased risk of bleeding with a hazard ratio 4.03 (3.20-5.08) and 3.80 (CI 95%, 3.01-4.79) compared to the quartile with the highest iTTR and lowest INR variability.

Conclusion

It is possible to achieve a safe warfarin treatment both in specialised anticoagulation centres and in primary health care. At initiation of treatment some of the patients at high risk of bleeding can be identified using knowledge about their background. With the use of quality indicators as TTR and INR variability during treatment those at high risk of complications can be identified and analysing treatment quality on centre level gives an opportunity to identify improvement areas among managing centres. With the addition of new treatment options warfarin can still be the most suitable option for some patients, being safe and effective when well managed.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2017. , 61 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1895
Keyword [en]
Warfarin, Venous thromboembolism, Bleeding
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-133618ISBN: 978-91-7601-701-2 (print)OAI: oai:DiVA.org:umu-133618DiVA: diva2:1088847
Public defence
2017-05-12, E04_R1, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2017-04-21 Created: 2017-04-17 Last updated: 2017-05-05Bibliographically 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
Show others...
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: 2017-04-17Bibliographically approved
2. Warfarin treatment complications do not correlate to cTTR when above 70%
Open this publication in new window or tab >>Warfarin treatment complications do not correlate to cTTR when above 70%
2015 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 6, 1185-1189 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The mean time in target range for each centre, cTTR, has previously been shown to correlate to the rate of complications in poorly managed warfarin treatment. However less is known about the correlation when warfarin treatment is well managed.

OBJECTIVES: The aim of this study was to examine the correlation between cTTR and the rate of complications in a real life setting with cTTR above 70%, with focus on patients with warfarin due to atrial fibrillation or secondary prevention of a VTE.

PATIENTS/METHODS: In total 66,605 patients with 89,293 treatment periods, corresponding to 179,624treatmentyears, with warfarin treatment due to VTE or AF between January 1st 2006 and December 31th 2011, was retrieved from the national quality register AuriculA. The cohort was matched with the National Patient Register in Sweden for complications and background characteristics.

RESULTS: We found 172 centres and 68,797 treatment periods for AF and 166 centres and 20,496 treatment periods for VTE. Over 90% of the patients had a target range between INR 2-3. We found no correlation between increasing cTTR and reduction in the rate of complications for the AF patients. However, for VTE patients we saw a correlation between increasing cTTR and a reduced complication rate.

CONCLUSIONS: Our results show that at very high cTTR levels, above 70%, further improvements in cTTR do not correlate to less treatment complications at least for patients with AF.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
Warfarin, Atrial fibrillation, Venous thromboembolism, Center TTR, Haemorrhage
National Category
Cardiac and Cardiovascular Systems Hematology
Research subject
Internal Medicine
Identifiers
urn:nbn:se:umu:diva-112215 (URN)10.1016/j.thromres.2015.10.031 (DOI)000366712800027 ()26508465 (PubMedID)
Available from: 2015-12-04 Created: 2015-12-04 Last updated: 2017-04-19Bibliographically approved
3. Bleeding complications in venous thrombosis patients on well-managed warfarin
Open this publication in new window or tab >>Bleeding complications in venous thrombosis patients on well-managed warfarin
2016 (English)In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 41, no 2, 351-358 p.Article in journal (Refereed) Published
Abstract [en]

Anticoagulation treatment is effective in preventing both death and recurrence in patients with venous thromboembolism (VTE), but at the same time confers a substantial risk of bleeding complications. The aim of this study was to examine the rate of and predictors for bleeding complications in VTE patients on warfarin with high treatment quality. In total 13,859 patients on warfarin for VTE between January 1st 2006 and December 31th 2011 were retrieved from the national quality register Auricula. The cohort was matched with the Swedish National Patient Register for complications and background characteristics, the Cause of Death Register for date and cause of death and the Swedish Prescribed Drug Register for retrieved medication. The rate of major bleeding was 2.36 per 100 treatment years, increasing with age from 1.25 to 4.33 for those under 60 or over 80 years of age, respectively. Factors found to independently increase the risk of bleeding complications were increasing age HR 1.02, cardiac failure HR 1.39, Chronic pulmonary disease HR 1.41, alcohol abuse HR 3.33, anaemia HR 1.75, hypertension HR 1.29 and a history of major bleeding HR 1.69. Warfarin as treatment for VTE is safe with a low rate of bleeding complications at least for the younger patient. In an era of NOAK, warfarin has a comparable safety profile among VTE patients and is still a valid treatment option.

Keyword
Venous thromboembolism, Bleeding, Warfarin, TTR
National Category
Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-117396 (URN)10.1007/s11239-015-1305-4 (DOI)000369338900016 ()26660340 (PubMedID)
Note

Special Issue: Measurement Tools and Antidotes for Non-Vitamin K Oral Anticoagulants

Available from: 2016-04-05 Created: 2016-02-29 Last updated: 2017-04-17Bibliographically approved
4. Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR
Open this publication in new window or tab >>Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR
2017 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, no 1, 27-32 p.Article in journal (Refereed) Published
Abstract [en]

High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66-1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61-3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36-2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89-4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02-4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.

Keyword
TTR, INR variability, venous thromboembolism, bleeding, warfarin, all-cause mortality
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-127526 (URN)10.1160/TH16-06-0489 (DOI)000391350600006 ()27652593 (PubMedID)
Available from: 2016-11-15 Created: 2016-11-15 Last updated: 2017-04-17Bibliographically approved

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