Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease

SummaryDuring treatment with vitamin K antagonists, International Normalized Ratios (INR) are determined periodically to maintain a therapeutic level of anticoagulation. We evaluated two existing methods for therapeutic quality control (linear interpolation and equidivision), with regard to their validity and reproducibility. In addition, we proposed and evaluated a (hybrid) method that takes into account potential effects of dosage modifications when INRs are far out of the target range. Validity was assessed by deleting intermediary INR results and estimating this INR based on the two surrounding INRs with each of the three methods. The estimated INRs were then compared with the observed INR.Reproducibility of time spent in an INR range was evaluated for each of the three methods by deleting at random increasing proportions of INRs and comparing these estimates with the situation without deletions. We found that estimates of time spent in INR categories obtained with equidivision were most reproducible, but least valid. The hybrid method showed slightly higher validity and reproducibility in comparison with linear interpolation. Since these differences were small, linear interpolation is preferable to the hybrid method, since the calculations involved are easier.

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Control of anticoagulation with vitamin K antagonists: overestimation of median time in therapeutic range when assessed by linear interpolation

Thrombosis and Haemostasis ◽

10.1160/th16-03-0184 ◽

2016 ◽

Vol 116 (10) ◽

pp. 679-686 ◽

Cited By ~ 5

Author(s):

Felix J. M. van der Meer ◽

Henk J. Adriaansen ◽

Frank W. G. Leebeek ◽

Marieke J. H. A. Kruip ◽

A. M. H. P. van den Besselaar ◽

...

Keyword(s):

Vitamin K ◽

Therapeutic Range ◽

Vitamin K Antagonists ◽

Linear Interpolation ◽

Target Range ◽

Rank Test ◽

Induction Phase ◽

Time In Therapeutic Range ◽

Significant Difference

SummaryPatients receiving vitamin K–antagonists are monitored by regular assessment of the International Normalized Ratio (INR). There are two popular methods for therapeutic control of anticoagulation in patient groups: 1) Time in Therapeutic Range (TTR) assessed by linear interpolation of successive INR measurements; 2) the cross-sectional proportion (CSP) of all patients’ last INRs within range. The purpose of the present study is to compare the two methods using data from 53 Dutch Thrombosis Centres and to develop a semi-quantitative model for TTR based on different types of INR change. Different groups of around 400,000 patients in four consecutive years were evaluated: patients in the induction phase, short-term, long-term, low-target range, high-target range, receiving either acenocoumarol or phenprocoumon, and performing self-management. Each Centre provided TTR and CSP results for each patient group. TTR and CSP were compared using the Wilcoxon signed-rank test. Separately, we analysed the relationship between consecutive INR results regarding in or out of range and their frequency of occurrence in patients of two different cohorts. Good correlation was observed between TTR and CSP (correlation coefficient 0.694–0.950 in low-target range). In long-term acenocoumarol patients (low-target range) the median TTR was significantly higher than CSP (80.0 % and 78.7 %, respectively; p<0.001). In long-term phenprocoumon patients (low-target range) there was no significant difference between median TTR (83.0 %) and median CSP (82.6 %). In conclusion, the correlation between TTR assessed by linear interpolation and CSP was good. TTR assessed by linear interpolation was higher than CSP in patients on acenocoumarol.

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Tendency towards Minor Bleeding in Women Is Associated with a Reduced Risk for Major Bleeding, without Apparent Differences in Level of Anticoagulation during Treatment with Vitamin K Antagonist.

Blood ◽

10.1182/blood.v108.11.889.889 ◽

2006 ◽

Vol 108 (11) ◽

pp. 889-889

Author(s):

Nic J.G.M. Veeger ◽

Margriet Piersma-Wichers ◽

Jan van der Meer

Keyword(s):

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Secondary Prophylaxis ◽

Incidence Rates ◽

Target Range ◽

Minor Bleeding ◽

Bleeding Tendency ◽

Men And Women ◽

Reduced Risk

Abstract Easy bruising is frequently found in healthy women. This mild bleeding tendency may be enhanced by treatment with vitamin K antagonists. This may result in more intense monitoring of the level of anticoagulation (INR) to improve the individual time within target range (ITTR) and consequently to reduce the risk of major bleeding. We performed a retrospective study in 6758 consecutive patients receiving vitamin K antagonists for primary or secondary prophylaxis of venous or arterial thrombosis (mean age 67, 51% male and 189762 INRs in 6681 person-years) to evaluate differences in gender on the occurrence of minor and major bleeding, as well as the ITTR. The incidence rates (IR, per 100 person-years) of minor and major bleeding were assessed and survival analysis performed to obtain adjusted hazard ratios (HR, 95%CI) for major bleeding in men versus women with or without prior minor bleeding, controlling for significant patient characteristics. Minor bleeding occurred more frequently in women than men (IR=33.2 versus 21.1, respectively; HR=1.5, 95%CI 1.4–1.7, p<0.001), whereas major bleeding showed a tendency towards a higher incidence in men (IR=1.6 versus 2.0; HR=1.3, 95%CI 0.9–1.8, p=0.20). Figure Figure However, in women with prior minor bleeding, the incidence of major bleeding was low (IR=1.3, 95% CI 0.7–2.1), when compared to men with minor bleeding (3.3, 95%C 2.2–4.7) (HR =2.7, 95% CI 1.4–5.0, p=0.002). Men and women without prior minor bleeding had comparable incidences of major bleeding (IR 1.8, 95% CI 1.3–2.5, and 1.5, 95% CI 1.1–2.1, respectively), but both were higher than in women with prior minor bleeding (HR 1.4 (0.8–2.5, p=0.30 and 1.2 (0.7–2.2, p=0.55)). These differences were even more pronounced in patients at high risk of major bleeding due to a strongly reduced ITTR (ITTR below 30%, lowest quartile). Considering the actually achieved level of anticoagulation, there were no differences between men and women with or without prior minor bleeding that could explain the reduced risk of major bleeding in women with prior minor bleeding. With 42% to 43%, the ITTR was comparable, as was the time spend above INR 5.0 (6% to 7%). In conclusion, more frequent minor bleeding in women was associated with a reduced incidence of major bleeding, whereas in men, such a reversed association was not present. Differences in intensity of INR monitoring in patients with or without minor bleeding and as a result in actual level of anticoagulation, could not be demonstrated.

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Valvular heart disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0690 ◽

2018 ◽

pp. 2863-2866

Author(s):

Petronella G. Pieper ◽

Bernard Iung

Keyword(s):

Heart Disease ◽

High Risk ◽

Aortic Stenosis ◽

Vitamin K ◽

Valvular Heart Disease ◽

Mitral Stenosis ◽

Vitamin K Antagonists ◽

First Trimester ◽

Valve Thrombosis ◽

Stenotic Lesions

Valvular heart disease is a frequent underlying heart disease in pregnant women. Mitral stenosis is often rheumatic in origin, while aortic stenosis is more often congenital. Stenotic lesions carry a high risk of complications. Mitral stenosis with a valve area less than 1.5 cm2 should be considered for pre-pregnancy intervention, especially when balloon valvulotomy is an option, since the risk of maternal and fetal complications is high. For women with aortic stenosis, pre-pregnancy intervention should be considered when the woman is symptomatic, or when left ventricular function or exercise testing is abnormal. Regurgitant lesions carry a lower risk than stenotic lesions. Women with a mechanical prosthesis have a high risk of complications during pregnancy and should be managed in a centre of expertise. Vitamin K antagonists are associated with embryopathy, but only in the first trimester and mainly when higher dosages are needed. Vitamin K antagonists are superior to prevent valve thrombosis. Vitamin K antagonists are advised in the first trimester when the daily dose requirement is low, and are preferred in the second and third trimester. During the first trimester, alternative options are unfractionated or low-molecular-weight heparins with intensive monitoring of anticoagulation effect. Heparins are also used from the 36th week of pregnancy until delivery. Most women with valvular disease can deliver vaginally.

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Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists

Journal of Thrombosis and Haemostasis ◽

10.1111/jth.13051 ◽

2015 ◽

Vol 13 (9) ◽

pp. 1590-1596 ◽

Cited By ~ 29

Author(s):

E. S. Eerenberg ◽

S. Middeldorp ◽

M. Levi ◽

A. W. Lensing ◽

H. R. Büller

Keyword(s):

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Clinical Impact

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The impact of acute diarrhea on the coagulation status of patients with vitamin K antagonists

Scientific Reports ◽

10.1038/s41598-021-91316-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Johannes Schweinfurth ◽

Alexander Bauer ◽

Frederic Bauer ◽

Felix Sebastian Seibert ◽

Benjamin Rohn ◽

...

Keyword(s):

Vitamin K ◽

Acute Diarrhea ◽

Data Extraction ◽

Vitamin K Antagonists ◽

Target Range ◽

Close Monitoring ◽

Exclusion Criteria ◽

Increased Risk ◽

Coagulation Status ◽

The Impact

AbstractAcute diarrhea is associated with a reduced absorption of both vitamin K antagonists (VKA) and vitamin K itself. To date, the net effect on the coagulation status of subjects with VKA remains elusive. We performed a systematic retrospective single-center analysis using an electronic data extraction approach to identify subjects with plasmatic anticoagulation (either VKA or direct oral anticoagulant (DOAC)) and diarrhea in a German University Hospital over a period of eight years. Acute diarrhea and complete documentation of coagulation status on admission were defined as inclusion criteria, anticoagulation other than VKA/DOAC and obvious inadherence as exclusion criteria. Subjects with VKA/DOAC admitted for hypertension served as control group. Data extraction yielded 356 subjects with gastrointestinal diagnoses and 198 hypertensive subjects, 55 and 83 of whom fulfilled all in- and exclusion criteria. INR values of subjects with VKA were significantly higher in subjects with diarrhea than in hypertensive controls (4.3 ± 3.7 vs. 2.3 ± 0.7, p < 0.001). The distribution of subjects having INR values lower, higher or within the target range differed significantly among groups with a substantially higher prevalence of overanticoagulation in the diarrhea group (46.4% vs. 14.3%, p < 0.001). In a multinomial logistic regression model, acute diarrhea was significantly associated with overanticoagulation (odds ratio 7.2, 95% confidence interval 2.163–23.921; p < 0.001), whereas age, sex, creatinine, and indication of anticoagulation were not (p > 0.05 each). Acute diarrhea is associated with a highly increased risk for overanticoagulation in patients with VKA. Thus, gastroenteritis necessitates a close monitoring of INR in order to identify subjects needing a temporary pause of VKA therapy.

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Vitamin K antagonists in heart disease: Current status and perspectives (Section III)

Thrombosis and Haemostasis ◽

10.1160/th13-06-0443 ◽

2013 ◽

Vol 110 (12) ◽

pp. 1087-1107 ◽

Cited By ~ 251

Author(s):

Raffaele Caterina ◽

Steen Husted ◽

Lars Wallentin ◽

Felicita Andreotti ◽

Harald Arnesen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Heart Disease ◽

Vitamin K ◽

Heart Valves ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Coagulation Factors ◽

Current Status ◽

Cardiovascular Therapy ◽

Specific Disorders

SummaryOral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting γ-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves.

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CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation

Genes ◽

10.3390/genes11070822 ◽

2020 ◽

Vol 11 (7) ◽

pp. 822

Author(s):

Stefan Cristian Vesa ◽

Sonia Irina Vlaicu ◽

Vitalie Vacaras ◽

Sorin Crisan ◽

Octavia Sabin ◽

...

Keyword(s):

Heart Disease ◽

Ischemic Heart Disease ◽

Vitamin K ◽

Cardiac Disease ◽

Carotid Plaque ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Plaque Formation ◽

Ischemic Heart ◽

Subsequent Decrease

Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. Patients and Methods: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. Results: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. Conclusions: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development.

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