INR variability and outcomes in patients with mechanical heart valve prosthesis

doi:10.1016/j.thromres.2015.10.044

Thrombosis Research

Volume 136, Issue 6, December 2015, Pages 1211-1215

https://doi.org/10.1016/j.thromres.2015.10.044 Get rights and content

Highlights

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INR variability has been shown to predict thrombosis and bleeding events.
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We examine INR variability and TTR and their association to adverse events.
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They predict a combined endpoint equally in patients with mechanical heart valves.
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INR variability adds important information on top of TTR.

Abstract

Background

The quality of treatment with warfarin is mainly assessed by the time in therapeutic range (TTR) in patients with mechanical heart valve prosthesis (MHV). Our aim was to evaluate if International Normalized Ratio (INR) variability predicted a combined endpoint of thromboembolism, major bleeding and death better than TTR.

Methods and results

We included 394 patients at one center with MHV during 2008–2011 with adverse events and death followed prospectively. TTR 2.0–4.0 and log-transformed INR variability was calculated for all patients. In order to make comparisons between the measures, the gradient of the risk per one standard deviation (SD) was assessed. INR variability performed equal as TTR 2.0–4.0 per one SD unit adjusted for covariates, hazard ratio (HR) 1.30 (95% CI 1.1–1.5) and 0.71 (95% CI 0.6–0.8) respectively for the combined endpoint, and performed better for mortality HR 1.47 (95% CI 1.1–1.9) and 0.70 (95% CI 0.6–0.8). INR variability was categorized into high and low group and TTR into tertiles. High variability within the low and high TTR, had a HR 2.0 (95% CI 1.7–3.6) and 2.2 (95% CI 1.1–4.1) respectively, of the combined endpoint compared to the low variability/high TTR group. INR values < 2.0 greatly increased the rate of thromboembolism whereas the rate of major bleeding increased moderately between INR 3.0 and 4.0 and increased substantially after INR > 4.0.

Conclusion

The INR variability is an equal predictor as TTR of the combined endpoint of thromboembolism, major bleeding and death, and adds important information on top of TTR in patients with MHV.

Section snippets

Background

In order to choose the optimum INR target range for patients with mechanical heart valve prosthesis (MHV), the guidelines recommend that valve model and patient risk factors should be considered. Given the gravity of the adverse events, paramount importance must be given to identify patients that are at highest risk. The time in therapeutic range (TTR) has in many studies been accepted as a surrogate marker for the quality of anticoagulation treatment given. A tight control of the

Method

All patients with MHV on anticoagulation treatment in Malmö, Sweden was prospectively followed and monitored in the Swedish national quality register for atrial fibrillation and anticoagulation, AuriculA, during 01/01/2008–31/12/2011. All outpatients who are treated with warfarin at these centers are referred to regional anticoagulation clinics to have their treatment monitored regularly in AuriculA. The register includes a web-based dosing program and decision support that uses an algorithm to

Statistics

TTR was calculated according to Rosendaal's method which uses linear interpolation to assign an INR value to each day between successive observed INR values [2]. INR variability was calculated using Fihn's method which only considers the achieved INR value deviation from the previous one and accordingly considers pure INR variability [5]. The INR variability was logarithmically transformed due to skewed distributions and to minimize influence of extreme observations. The linear association

Baseline characteristics

The primary cohort consisted of 407 patients, with 13 patients excluded from baseline which yielded 394 patients. The 13 patients were excluded because of few INR measurements to estimate INR variability and TTR. Our cohort was predominantly patients with aortic valve replacement (AVR) (69%) with a mean age of 70 years and a TTR 2.0–4.0 of 91% (Table 1). The achieved mean INR (± SD) was 2.85 (± 0.25) for AVR and 2.89 (± 0.22) for mitral valve replacement (MVR). During the study period, a total of

Discussion

The result of this study shows that the variability of INR, which measures another aspect of anticoagulation control, namely the stability and not the intensity of INR, is a significant predictor of a combined endpoint in patients with MHV. We demonstrate that the Log INR variability expressed per one SD has an equal predictive ability as TTR 2.0–4.0 for the combined endpoint and performs even better for mortality. Secondly, our results indicate that the risk of suffering from the combined

Conflict of interest

None declared.

Acknowledgments

The study was supported by the Anna and Edwin Bergers Foundation.

References (19)

B. Grzymala-Lubanski et al.
Mechanical heart valve prosthesis and warfarin — treatment quality and prognosis
Thromb. Res.
(2014)
M. Lind et al.
Variability of INR and its relationship with mortality, stroke, bleeding and hospitalisations in patients with atrial fibrillation
Thromb. Res.
(2012)
S. Ibrahim et al.
The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate
Journal of Thrombosis and Haemostasis: JTH
(2013)
Y. van Leeuwen et al.
Prediction of hemorrhagic and thrombotic events in patients with mechanical heart valve prostheses treated with oral anticoagulants
Journal of Thrombosis and Haemostasis: JTH
(2008)
B. Grzymala-Lubanski et al.
Computer aided warfarin dosing in the Swedish national quality registry AuriculA — algorithmic suggestions are performing better than manually changed doses
Thromb. Res.
(2013)
C.W. Akins et al.
Guidelines for reporting mortality and morbidity after cardiac valve interventions
J. Thorac. Cardiovasc. Surg.
(2008)
S. Schulman et al.
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients
J. Thromb. Haemost.
(2005)
A. Oden et al.
Optimal INR for prevention of stroke and death in atrial fibrillation: a critical appraisal
Thromb. Res.
(2006)
C. Dauphin et al.
Comparison of INR stability between self-monitoring and standard laboratory method: preliminary results of a prospective study in 67 mechanical heart valve patients
Archives of Cardiovascular Diseases
(2008)

There are more references available in the full text version of this article.

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We found a low rate of thromboembolic events and major bleeding events for low-moderate risk ACHD patients with good quality of VKA anticoagulation. The target of TTR>65% for ACHD patients is recommended.
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Citation Excerpt :
Consequently, VKAs require constant INR monitoring and careful continuous dose adjustments.13 High INR variability is a predictor of poor survival,14 and hypertension, diabetes, heart failure, and a PHV in mitral position of are all associated with a shorter permanence in the target therapeutic range (TTR).15 In any given patient, the search for an optimal balance between TE and bleeding risk start from the evaluation of her/his unique specific profile.
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Warfarin is an anticoagulant indicated for patients who had undergone mechanical heart valve(s) replacement (MHVR). In these patients, time in therapeutic range (TTR) is important in predicting the bleeding and thrombotic risks.
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Full Length ArticleINR variability and outcomes in patients with mechanical heart valve prosthesis

Highlights

Abstract

Background

Methods and results

Conclusion

Section snippets

Background

Method

Statistics

Baseline characteristics

Discussion

Conflict of interest

Acknowledgments

Thromb. Res.

Thromb. Res.

Journal of Thrombosis and Haemostasis: JTH

Journal of Thrombosis and Haemostasis: JTH

Thromb. Res.

J. Thorac. Cardiovasc. Surg.

J. Thromb. Haemost.

Thromb. Res.

Archives of Cardiovascular Diseases

Full Length Article
INR variability and outcomes in patients with mechanical heart valve prosthesis