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ORIGINAL ARTICLE
Risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists Facteurs de risque associés à un évènement thrombotique ou hémorragique chez des patients traités par antivitamines K J. Béné a,∗, A.-E. Dubart b, C. Senis c, M. Auffret a, J. Caron a, S. Gautier a a
Centre régional de pharmacovigilance, faculté de médecine, université Lille 2, centre hospitalier de Lille, 1, place de Verdun, 59045 Lille, France b Service des urgences, centre hospitalier Germon-et-Gauthier, 62408 Béthune, France c Service pharmacie, centre hospitalier Germon-et-Gauthier, 62408 Béthune, France Received 13 December 2013; accepted 17 April 2014
KEYWORDS Vitamin K antagonists; Bleeding; Thrombosis; Adverse drug events; Risk factors; Case-control study
∗
Summary Aim. — To identify, in a case-control study, the risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists. Materials and methods. — We performed a single-centre observational study during a threemonth period where we consecutively included patients admitted to the emergency department of a secondary-level hospital and treated with vitamin K antagonists, regardless the reason for admission. Patients admitted for a thrombotic or bleeding event were included as cases and the other patients served as controls. Main thrombotic or bleeding risk factors during vitamin K antagonist therapy were a priori identified in literature and tested in conditional logistic regression. Results. — Two hundred and forty subjects were identified, 40 of which (17%) were admitted for a bleeding event, 19 (8%) for a thrombotic event and 181 (75%) for another reason. Over 85% of patients were treated with fluindione. No risk factor was significantly associated with bleeding or thrombotic event in patients treated with vitamin K antagonist. Patients presenting a thrombotic event were however more likely to have a chronic respiratory disease.
Corresponding author. E-mail address: [email protected] (J. Béné).
http://dx.doi.org/10.1016/j.jmv.2014.04.002 0398-0499/© 2014 Elsevier Masson SAS. All rights reserved.
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J. Béné et al. Conclusions. — In this study, no risk factor significantly associated with a bleeding or thrombotic event in patients treated with vitamin K antagonist were identified. The occurrence of these events supposes other risk factors, including potential genetic polymorphisms that should be considered in future studies. © 2014 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Antivitamines K ; Étude cas-témoin ; Facteurs de risque ; Hémorragies ; Thromboses
Résumé Objectif. — Analyser, à partir d’une étude cas-témoins, les facteurs de risque associés à un évènement thrombotique ou hémorragique chez des patients traités par antivitamines K et hospitalisés dans un service d’urgences. Patients et méthodes. — Cette étude observationnelle monocentrique réalisée sur une période de 3 mois incluait de manière consécutive des patients traités par antivitamines K, admis dans un service d’urgences d’un hôpital secondaire, quel que soit le motif d’admission. Les patients admis pour une thrombose ou un évènement hémorragique ont été considérés comme des cas et les autres patients comme des témoins. Les facteurs de risque testés dans cette analyse ont été identifiés au préalable dans la littérature, puis testés dans un modèle de régression logistique conditionnelle. Résultats. — Deux cent quarante sujets ont été inclus, dont 40 (17 %) ont été admis pour un évènement hémorragique, 19 (8 %) pour un évènement thrombotique et 181 (75 %) pour une autre raison. Plus de 85 % des patients étaient traités par fluindione. Aucun facteur de risque n’était associé de manière significative à un évènement thrombotique ou hémorragique. Les patients présentant un évènement thrombotique avaient cependant tendance à présenter plus de maladies respiratoires chroniques. Conclusions. — Dans cette étude, aucun facteur de risque n’était significativement associé à l’apparition d’un évènement thrombotique ou hémorragique lors de la prise d’antivitamines K. La survenue de ces évènements suppose la présence d’autres facteurs de risque, et notamment l’existence de certains polymorphismes génétiques, qui seront à l’avenir intéressants à rechercher. © 2014 Elsevier Masson SAS. Tous droits réservés.
Introduction Vitamin K antagonists (VKA) are drugs that are very widely used, and 1% of the population is estimated to be treated by these molecules [1]. This proportion is rapidly increasing due to an aging population and the increased incidence of agerelated cardiovascular disorders such as atrial fibrillation. One might think that after over a 60-year handling experience and widespread use of this drug that safety would be at its highest. This is not the case however, as these molecules are currently the main cause of hospital admissions for drugrelated adverse events in France and the third cause in the United Kingdom [1,2]. A study carried out in 1998 showed that VKA-related bleeding events were the principal cause of hospitalisation for adverse drug events (13%), and that they accounted for about 17,000 hospital admissions a year, half of which were avoidable [3]. The results of the EMIR study in 2007 confirmed these findings: VKA were responsible for the highest incidence of hospital admissions for adverse drug effects (12.3%) [4]. The annual incidence of major bleeding related to VKA is estimated at 7% and that of fatal bleeding at 1% [5]. In France, the frequency of serious hemorrhage is estimated at between 1.6 and 5.6% per patient and per year [6]. Excessively high VKA doses, notably in patients with an INR greater than 4, are associated with an increased risk of hemorrhage, which is due, moreover, to the pharmacological properties of these molecules.
Even when the patient is receiving an anticoagulant, thrombotic events are not rare, but such a clinical situation, indicative of ineffective treatment, is still very little described in the literature. The aim of this study was to identify, in a case-control study, the risk factors associated with a thrombotic or bleeding event in patients treated with VKA and admitted to an emergency department.
Material and methods Study design This single-center cross-sectional observational study was carried out over a three-month period (from March 1, 2012 to May 31, 2012) and included patients consecutively being admitted to the emergency department of Bethune Hospital and treated with an oral anticoagulant, regardless the reason for admission. Bethune Hospital is a secondary-level hospital with just over 300 beds, which serves a population of about 270,000 inhabitants.
Patients Patients inclusion criteria were admission to the emergency department of Bethune Hospital between March 1 and May 31, 2012, an International Normalized Ratio (INR) ordered
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Thrombotic or bleeding event and vitamin K antagonists: Risk factors by the emergency department on the day of admission, and treatment by oral anticoagulant at home. Patients admitted for thrombotic or bleeding events were included as cases and the other patients served as controls. Cases and controls were identified through the systematic INR requests made by the emergency department and carried out by the hospital biology laboratory. This test request identified a priori those patients who were likely to be treated by oral anticoagulants at home.
3 240 patients: - 40 bleeding events - 19 thrombotic events - 181 other events 3 extreme ages on bleeding event
3 extreme ages on thrombotic event
Data collection Variables collected were age, gender, type of oral anticoagulant, indication and duration of treatment, dose and reason for hospital admission. Associated treatments and laboratory results on the day of admission (INR, serum creatinine) were also recorded. According to literature data, the main comorbid conditions identified or discussed to be risk factors associated with bleeding or thrombotic events were also collected. For bleeding events, risk factors recorded were renal failure, cancer, stroke history, arterial hypertension, atrial fibrillation and ulcerative disease [7—13]. Risk factors selected for thrombotic events were cancer, chronic respiratory disease, chronic cardiovascular disease, disability, history of thrombotic event, body mass index and history of ischemic heart disease [9,14—16].
Statistical analysis Independent quantitative variables were compared using the Student t-test or the Wilcoxon-Mann-Whitney test and independent qualitative variables were compared with Pearson’s Chi2 test or Fisher’s test. For case-control study, each case was matched with two controls. Matching was done by patients’ age (within a 5year range) and gender. Matched quantitative variables were compared with Wilcoxon’s non-parametric test and matched qualitative variables were compared with McNemar’s Chi2 test. Conditional logistic regression was performed in the casecontrol studies in order to determine the factors associated with occurrence of a thrombotic event (for patients with thrombosis) and with occurrence of a bleeding event (for patients with bleeding). For each case-control, a univariate analysis was performed and the variables (initially identified as risk factors in literature) with a P-value < 0.2 in the univariate analysis were then included in the multivariate model. Odds Ratios (OR) were presented with their 95% confidence intervals (95% CI). The threshold of significance was fixed at 5%. Statistical analysis was carried out using SAS 9.1® software (SAS Institute, South Carolina, USA).
Results General characteristics of the population Over a 3-month period, 240 subjects treated with oral anticoagulants at home and admitted to the emergency
159 patients: - 37 cases of bleeding - 16 cases of thrombosis - 106 controls
Figure 1 Flow-chart illustrating the selection of the cases. Flow-chart illustrant la sélection des cas.
department of Bethune Hospital were identified. Of these patients, 40 (17%) were admitted for a bleeding event, 19 (8%) for a thrombotic event and 181 (75%) for another reason. The mean age of these patients was 75 years (± 13 years) and the sex ratio was 0.7. Their mean INR on emergency admission was 2.8 (± 1.5). To perform the case-control study, and according to matching criteria, three hemorrhagic cases (among 40 patients) and three thrombotic cases (among 19 patients) were excluded because of their extreme age (Fig. 1).
Bleeding events General characteristics of cases and controls Thirty-seven cases of bleeding events were compared with 74 controls. The general characteristics of the patients are presented in Table 1. No significant difference was found between the two groups for the variables studied. Eightyseven per cent of cases and controls were treated with fluindione and 13% of cases and controls with warfarin. No patients were receiving acenocoumarol or one of the new oral anticoagulants. Cases nevertheless tended to receive a higher dose of fluindione than controls (P = 0.06) and to have been treated for a shorter period (P = 0.08). INR was in the normal range in 57% of cases, and higher than 5 in 14% of cases. The INR did not significantly differ between cases and controls.
Bleeding events leading to admission of cases Of the 37 cases, 14 patients (38%) presented with epistaxis, 7 (19%) with hematoma, 4 (11%) with hematuria, two (6%) with hemoptysis, two (6%) with intracranial hemorrhage, two (6%) with hemorrhagic stroke, two patients (6%) with melena, two (6%) with rectal bleeding, one (3%) with hematemesis and one (3%) with gastrointestinal bleeding. Among these 37 cases, 16 were considered as major bleeding (bleeding into a site associated with significant morbidity (e.g. intracranial), requirement for blood transfusion, and/or anaemia).
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J. Béné et al. Table 1 Characteristics of cases with bleeding events and controls. Caractéristiques des cas « hémorragiques » et de leurs témoins. Variables
Cases
Controls
n
n
P
Age, years (m ± SD)
37
76.8 ± 8.3
74
77.0 ± 8.9
1
Male gender, n (%)
37
25 (68)
74
50 (68)
1
BMI, kg/m (m ± SD)
26
28.3 ± 5.7
42
30.4 ± 8.0
0.39
Type of anticoagulant, n (%) Fluindione Warfarin
37
Reason for prescription, n (%) Atrial fibrillation Thromboembolic event Cardiac valve Ischemic heart disease Heart rhythm disorder Stroke Myocardial infarction
36
2
74 32 (87) 5 (13)
1.00 64 (87) 10 (13)
71 28 (78) 5 (13) 2 (6) 0 0 0 1 (3)
0.81 56 (80) 8 (11) 3 (4) 1 (1) 2 (3) 1 (1) 0
Dose Fluindione (m ± SD), mg Warfarin (m ± SD), mg
29 5
22 ± 9 2±1
43 8
18 ± 8 4±3
0.06 0.12
Treated for ≤ 90 days, n (%)
34
7 (21)
37
2 (5)
0.08
Hemoglobin levels (m ± SD), g/dL
34
12.2 (3.1)
71
12.4 (2.3)
0.71
INR levels INR (m ± SD) 2 ≤ INR ≤ 3, n (%) INR > 5, n (%)
37 37 37
3.4 ± 2.9 21 (57) 5 (14)
74 74 74
2.8 ± 1.5 31 (42) 6 (8)
0.27 0.14 0.37
INR: International Normalized Ratio.
Drug interactions Patient exposure to treatments likely to contribute to a bleeding event was compared between cases and controls (Table 2). The number of drug interactions per patient did not significantly differ between cases and controls
Table 2 Drug interactions likely to contribute to a bleeding event. Interaction médicamenteuse pouvant potentialiser un évènement hémorragique. Cases (n = 36) n (%)
Controls (n = 72) n (%)
Number of interactions 0 1 ≥2
3 (8) 12 (33) 21 (58)
10 (14) 29 (40) 33 (46)
Drug interaction Contraindicated association Unadvisable association Restricted use Caution
0 4 (11) 33 (89) 2 (5)
0 0 62 (84) 0
Variables
P
0.54
(overall test, P = 0.54). No contraindicated drug interaction was identified in the groups compared. However, cases were more often receiving an unadvisable association of drugs than controls (P = 0.01) (in 4 cases, patients with an active gastroduodenal ulcer had taken aspirin). With regard to drugs taken in spite of restrictions for use, the drugs most often involved (cases and controls together) were hypolipidemic agents in 58% of patients, amiodarone in 15%, acetaminophen in 12% and allopurinol in 9%. Risk factors associated with a bleeding event In the univariate model, among the variables selected in the literature as being most often associated with a bleeding event in patients receiving a VKA and included, none of them were highly associated with bleeding event in this study (Table 3). We performed a separate analysis for major bleeding and no variable was statistically associated with such an event.
Thrombotic events 1.00 0.01 0.44 0.11
General characteristics of cases and controls Case-control analysis compared 16 cases of thrombotic events with 32 controls. The patients’ general characteristics are presented in Table 4. No significant difference was
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Thrombotic or bleeding event and vitamin K antagonists: Risk factors Table 3 Variables associated with occurrence of a bleeding event on oral anticoagulants. Variables associées à l’apparition d’un évènement hémorragique sous anticoagulants oraux. Variables
Univariate analysis OR [95% CI]
p
Renal failurea Cancer Number of drug interactions ≥ 2 vs < 2 Treatment started < 90 days History of stroke Arterial hypertension Atrial fibrillation Ulcerative disease
0.6 [0.2—1.6] 2.5 [0.7—9.3] 1.7 [0.7—3.9]
0.30 0.17 0.22
a
2.3 0.6 0.6 0.9 1.1
[0.4—12.5] [0.2—2.1] [0.1—2.4] [0.4—2.3] [0.5—2.4]
0.35 0.45 0.46 0.87 0.89
CrCl < 60 mL/min/1.73 m2 .
found between the two groups for the variables studied. Cases of thrombosis and their controls showed identical distribution according to type of anticoagulant treatment, with a majority of patients receiving fluindione and none receiving the new oral anticoagulants. The reason for prescription and the doses, whatever the VKA given, were also identical in the two populations. INR was in normal range in 44% of cases, and lower than 2 in 50% of cases. Twenty one percent
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of the cases were treated for less than 90 days. The INR (continuous values) of cases tended to be lower than that of controls (P < 0.08). Thrombotic events leading to admission of cases Of the 16 cases, 7 patients (44%) presented with a stroke, 3 patients (19%) a transient ischemic accident, 3 patients (19%) phlebitis, two patients (12%) myocardial infarction and one patient (6%) pulmonary embolism. Among these 16 cases, 10 were severe thrombotic events requiring hospitalization. In 3 cases of venous thrombosis, VKA was prescribed in VTE prevention. Risk factors associated with a thrombotic event Multivariate logistic regression (Table 5) revealed no risk factor significantly associated with a thrombotic event in these patients treated with VKA. Patients presenting with a thrombotic event were however more likely to have a chronic respiratory disease. Separate analysis for arterial thrombotic events was performed, giving the same results.
Discussion Bleeding events In the ninth edition of the Recommendations of the American College of Chest Physicians (ACCP) published in 2012, the
Table 4 Characteristics of cases with thrombosis events and controls. Caractéristiques des cas « thrombotiques » et de leurs témoins. Variables
Cases
Controls
n
n
P
Age, years (m ± SD)
16
72.4 ± 16.8
32
72.7 ± 16.8
1.00
Male gender, n (%)
16
5 (31)
32
10 (31)
1.00
BMI, kg/m (m ± SD)
14
30.7 ± 7.6
18
33.2 ± 10.3
0.30
Type of anticoagulant, n (%) Fluindione Warfarin Acenocoumarol
16
Reason for prescription, n (%) Atrial fibrillation Thromboembolic event Cardiac valve Ischemic heart disease Stroke
15
Dose (mean ± SD), mg Fluindione Warfarin Acenocoumarol
15
2
INR levels INR (m ± SD) 2 ≤ INR ≤ 3, n (%) INR < 2, n (%)
32 14 (88) 2 (12) 0 31 8 (53) 6 (40) 1 (7) 0 0
0.73 19 (61) 8 (26) 1 (3) 2 (6) 1 (3)
30 20 ± 9 3±2 —
16 16 16
1.00 28 (88) 3 (9) 1 (3)
1.9 ± 0.7 7 (44) 8 (50)
32 32 32
17 ± 11 4±2 4
0.44 0.78 —
2.5 ± 1.1 15 (47) 11 (34)
0.08 0.84 0.30
INR: International Normalized Ratio.
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J. Béné et al. Table 5 Variables associated with occurrence of a thrombotic event on oral anticoagulants. Variables associées à l’apparition d’un évènement thrombotique sous anticoagulants oraux. Variables
Chronic respiratory disease Chronic cardiovascular diseasea Disabilityb History of thrombotic event BMI > 25 vs BMI ≤ 25 History of ischemic heart disease Cancer
Univariate analysis OR [95% CI]
P
4.6 0.4 2.4 1.5 1.6 1.0 —
0.07 0.30 0.36 0.51 0.51 1.00 1.00
[0.9—23.8] [0.07—2.2] [0.4—15.0] [0.4—5.6] [0.4—6.0] [0.2—4.3]
a Arterial hypertension, atrial fibrillation, heart failure, other heart rhythm disorders. b Bed-ridden state, cognitive disorders.
main risk factors for hemorrhage while on VKA therapy are intensity of anticoagulation therapy, comorbid conditions, and drug interactions [12]. The intensity of anticoagulation, evaluated by the INR, appears to be the major risk factor. The studies confirming this are numerous: some authors found an increase in bleeding events over an INR threshold of 2 [17], others for a higher threshold, generally 3 [18]. We found no significant difference between the INR of patients with a bleeding event and of controls, and the proportion of these subjects whose INR was between 2 and 3 was not different. It appears, moreover, that fluctuations of anticoagulation, reflected by variations in INR, may also be associated with an increased risk of bleeding independently of the mean INR [19]. The duration for which INR values remain within the target range is therefore a variable of considerable importance: a meta-analysis published in 2004 estimated, in a population treated with warfarin for atrial fibrillation and with a target INR between 2 and 3, that for 61% of the time patients were in the target range, for 13% of the time their INR was greater than 3 and for 26% it was less than 2 [18]. These studies underline the value of regular monitoring and follow-up of the INR and raise the question of the usefulness of INR self-measurement devices. With regard to the comorbid conditions contributing to the onset of a bleeding event, among the diseases most often cited are a history of bleeding events [11,12]: gastro-duodenal ulcer in particular [9,11,20]), arterial hypertension [8,21,22], history of ischemic stroke [8,11,21], diabetes [21], renal failure [9,17,19,20,23] and cancerous diseases [9,10,23—25]. However, these variables, in particular renal failure and cancerous disease, are not systematically associated with a bleeding event, as has been shown by studies similar to ours [26]. Drug interactions are also among the factors that may contribute to a VKA-related bleeding event. The general effect of most interactions with anticoagulants is an increase in the INR, explaining the increased risk of bleeding [27]. Some studies have closely examined these exposures, like the team of Suh et al. who demonstrated that patients exposed to these drugs presented more bleeding events than non-exposed patients (OR = 1.26, P = 0.047) [28]. As in our study, the majority of their patients (about 80%)
were exposed to a drug interaction. In the same study, the risk of a bleeding event increased with the number of drug interactions identified for each patient. Numerous studies were coherent with these findings and the drugs most often reported were non-steroidal anti-inflammatory agents, other anticoagulants, antibiotics and anti-platelet drugs [28—30]. We found that the majority of interactions with VKA were related in particular to hypolipidemic agents and amiodarone. Lastly, some studies like ours have shown that the risk of a bleeding event is markedly increased during the first 90 days of VKA treatment even if the results were not statistically significant [17,20,24]. In one of these studies [20], the probability of experiencing a bleeding event under VKA treatment during this period was six times greater than during prolonged treatment (OR = 5.83, P = 0.0064). During the initial period of treatment, patients are particularly exposed to excessively high doses and to complications: this could be explained by inadequate monitoring of the INR and/or to difficulty experienced by prescribers in stabilizing it during this period. In our study, the majority of the patients were treated for more than 90 days.
Thrombotic events The majority of studies on this subject address thrombotic events occurring after discontinuation of anticoagulants, and not during treatment. However, according to some authors, 3 to 6% of patients with long-term anticoagulant treatment may present a risk of a recurrent thromboembolic event, in particular during the first three months of treatment [14]. We found a higher proportion with 8% of thrombotic event in our total population and 32% among all cases. This case-control study aiming to identify risk factors associated with a thrombotic event during VKA treatment did not reveal any variable significantly associated with such an event. Patients who had experienced a thrombotic event were however more likely to have a chronic respiratory disease than controls. These findings are in agreement with the literature, as some authors have identified chronic respiratory diseases as an independent risk factor for a thrombotic event in patients receiving VKA [14]. These patients may be less physically mobile, leading to possible venous stasis and increased thrombotic risk. Conversely, in our analysis, other factors that could potentially contribute to decreased mobility, such as overweight or obesity (BMI > 25) or a disability, were not associated with occurrence of a thrombotic event. Among the other most commonly described risk factors for thrombotic events with VKA treatment, a cancerous disease seems to be most often reported: the risk may increase two to six-fold, depending on the studies [9,14,25]. Risk level is affected by chemotherapy and the degree of spread of the cancer. The mechanism involved in this effect is not as yet clearly identified at present: it could be related to the production of procoagulant factors such as tissue factor or factor X-activating cysteine protease. In our analysis, no cases had a cancerous disease. Cancer is followed by chronic cardiovascular diseases, a recognized risk factor for thrombotic events [14]. The literature, though sparse on this subject, also cites a low level of anticoagulation as a risk
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Thrombotic or bleeding event and vitamin K antagonists: Risk factors factor for a thrombotic event, in particular INR less than 2, or age above 70 years. Our findings are in agreement with the data on thrombotic risk and low level of anticoagulation: the risk tends to increase for an INR below 1.5.
Study limitations The initial protocol for matching cases and controls led us to exclude seven cases (four bleeding events and three thrombotic events) because of the patients’ advanced age, as no matching controls were available in this population. These seven exclusions lowered the power of this analysis, while the series was already small. Moreover, the small number of cases in each analysis, in particular for thrombosis, limits the power of the statistical analysis. Other risk factors identified in literature were not taken into account in analysis, such as ethanol abuse or excessive fall risk [7] as they were not systematically mentioned in the patient records. Because of the small population size, we were not able to perform separate analysis for severe and non-severe events and for venous and arterial thrombotic events. It should be pointed out that the large majority of international studies, deal with patients treated with coumarin derivatives and warfarin in particular. Fluindione therefore does not figure in these studies and this issue certainly deserves deeper analysis: are risk factors different in patients who are receiving coumarin derivatives rather than indanediones? Lastly, genetic variants of cytochrome P450 2C9 (CYP2C9*2 and *3) involved in warfarin metabolism and VKORC1 (vitamin K epoxide reductase complex 1) involved in the vitamin K cycle could explain variations in VKA sensibility [31]. These data seem interesting to predict individual VKA response; indeed, few authors have already demonstrated that genotype-guided warfarine dosing was superior to standard dosing at the initiation of warfarin therapy [32,33].
Conclusion At the time when new oral anticoagulants take their place on the market, the question of the anticoagulant survey deserves the full attention of by health professionals. In spite of 60 years of experience and knowledge of VKA, their use still seems complex and remains difficult to master. In this study, no risk factor significantly associated with a bleeding or thrombotic event in patients treated with VKA were identified. The occurrence of these events supposes genetic polymorphisms that should be considered in future studies.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgments We would like to thank Dr Odile Crepin and Dr Gérard Dupuis of the Biology Laboratory, Centre Hospitalier de Béthune, for providing us the results of INR.
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This study has been presented to the following congress: • Oral presentation: ◦ Béné J, Senis C, Auffret M, Gautier S, Dubart AE. Epidémiologie des patients sous anticoagulants admis dans un service d’urgence (SAU). 7ème Congrès de la Société Francaise de Médecine d’Urgences 2013 Paris ; • Poster: ◦ Risk factors for hemorrhagic and thrombotic accidents in patients treated with oral anticoagulants: a casecontrol study. Béné J, Dubart AE, Auffret M, Senis C, Gautier S. ISOP 2013, Pise ; ◦ Risk factors for hemorrhagic and thrombotic accidents in patients treated with oral anticoagulants: a casecontrol study. Béné J, Dubart AE, Auffret M, Senis C, Gautier S. P2T 2013, Angers.
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[13] Poli D, Antonucci E, Testa S, Tosetto A, Ageno W, Palareti G, et al. Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation. Circulation 2011;124:824—9. [14] Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000;160:3431—6. [15] Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100: 3484—8. [16] Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078—83. [17] Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993;118:511—20. [18] Reynolds MW, Fahrbach K, Hauch O, Wygant G, Estok R, Cella C, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004;126:1938—45. [19] Stroke Prevention in Atrial Fibrillation Investigators. Adjusteddose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996;348:633—8. [20] Al Hajje AH, Calop N, Bosson JL, Calop J, Allenet B. Which factors are associated to hemorrhagic adverse drug events related to antivitamin K? Ann Pharm Fr 2010;68:36—43. [21] Ariesen MJ, Tangelder MJ, Lawson JA, Eikelboom BC, Grobbee DE, Algra A, et al. Risk of major haemorrhage in patients after infrainguinal venous bypass surgery: therapeutic consequences? The Dutch BOA (Bypass Oral Anticoagulants or Aspirin) Study. Eur J Vasc Endovasc Surg 2005;30:154—9. [22] Lundström T, Rydén L. Haemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis. J Intern Med 1989;225:137—42.
[23] White RH, Beyth RJ, Zhou H, Romano PS. Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 1999;107:414—24. [24] Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT) Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996;348:423—8. [25] Hutten BA, Lensing AW, Kraaijenhagen RA, Prins MH. Safety of treatment with oral anticoagulants in the elderly. A systematic review. Drugs Aging 1999;14:303—12. [26] Colnat-Coulbois S, Cosserat F, Klein O, Audibert G, Virion J-M, Trechot P, et al. Prognosis factors of oral-anticoagulantrelated intracranial haemorrhages: an analysis of 186 cases. Neurochirurgie 2009;55:11—6. [27] Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th ed.). Chest 2008;133, 160S—198S. [28] Suh DC, Nelson WW, Choi JC, Choi I. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. Clin Ther 2012;34: 1569—82. [29] Hauta-Aho M, Tirkkonen T, Vahlberg T, Laine K. The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients. Ann Med 2009;41: 619—28. [30] Zhang K, Young C, Berger J. Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions. J Manag Care Pharm 2006;12:640—8. [31] Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369:2294—303. [32] Johnson M, Richard C, Bogdan R, Kidd R. Warfarin dosing in a patient with CYP2C9(*)3(*)3 and VKORC1-1639 AA genotypes. Case Rep Genet 2014;2014:413743. [33] Yang J, Chen Y, Li X, Wei X, Chen X, Zhang L, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013;168:4234—43.
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ORIGINAL ARTICLE
Risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists Facteurs de risque associés à un évènement thrombotique ou hémorragique chez des patients traités par antivitamines K J. Béné a,∗, A.-E. Dubart b, C. Senis c, M. Auffret a, J. Caron a, S. Gautier a a
Centre régional de pharmacovigilance, faculté de médecine, université Lille 2, centre hospitalier de Lille, 1, place de Verdun, 59045 Lille, France b Service des urgences, centre hospitalier Germon-et-Gauthier, 62408 Béthune, France c Service pharmacie, centre hospitalier Germon-et-Gauthier, 62408 Béthune, France Received 13 December 2013; accepted 17 April 2014
KEYWORDS Vitamin K antagonists; Bleeding; Thrombosis; Adverse drug events; Risk factors; Case-control study
∗
Summary Aim. — To identify, in a case-control study, the risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists. Materials and methods. — We performed a single-centre observational study during a threemonth period where we consecutively included patients admitted to the emergency department of a secondary-level hospital and treated with vitamin K antagonists, regardless the reason for admission. Patients admitted for a thrombotic or bleeding event were included as cases and the other patients served as controls. Main thrombotic or bleeding risk factors during vitamin K antagonist therapy were a priori identified in literature and tested in conditional logistic regression. Results. — Two hundred and forty subjects were identified, 40 of which (17%) were admitted for a bleeding event, 19 (8%) for a thrombotic event and 181 (75%) for another reason. Over 85% of patients were treated with fluindione. No risk factor was significantly associated with bleeding or thrombotic event in patients treated with vitamin K antagonist. Patients presenting a thrombotic event were however more likely to have a chronic respiratory disease.
Corresponding author. E-mail address: [email protected] (J. Béné).
http://dx.doi.org/10.1016/j.jmv.2014.04.002 0398-0499/© 2014 Elsevier Masson SAS. All rights reserved.
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J. Béné et al. Conclusions. — In this study, no risk factor significantly associated with a bleeding or thrombotic event in patients treated with vitamin K antagonist were identified. The occurrence of these events supposes other risk factors, including potential genetic polymorphisms that should be considered in future studies. © 2014 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Antivitamines K ; Étude cas-témoin ; Facteurs de risque ; Hémorragies ; Thromboses
Résumé Objectif. — Analyser, à partir d’une étude cas-témoins, les facteurs de risque associés à un évènement thrombotique ou hémorragique chez des patients traités par antivitamines K et hospitalisés dans un service d’urgences. Patients et méthodes. — Cette étude observationnelle monocentrique réalisée sur une période de 3 mois incluait de manière consécutive des patients traités par antivitamines K, admis dans un service d’urgences d’un hôpital secondaire, quel que soit le motif d’admission. Les patients admis pour une thrombose ou un évènement hémorragique ont été considérés comme des cas et les autres patients comme des témoins. Les facteurs de risque testés dans cette analyse ont été identifiés au préalable dans la littérature, puis testés dans un modèle de régression logistique conditionnelle. Résultats. — Deux cent quarante sujets ont été inclus, dont 40 (17 %) ont été admis pour un évènement hémorragique, 19 (8 %) pour un évènement thrombotique et 181 (75 %) pour une autre raison. Plus de 85 % des patients étaient traités par fluindione. Aucun facteur de risque n’était associé de manière significative à un évènement thrombotique ou hémorragique. Les patients présentant un évènement thrombotique avaient cependant tendance à présenter plus de maladies respiratoires chroniques. Conclusions. — Dans cette étude, aucun facteur de risque n’était significativement associé à l’apparition d’un évènement thrombotique ou hémorragique lors de la prise d’antivitamines K. La survenue de ces évènements suppose la présence d’autres facteurs de risque, et notamment l’existence de certains polymorphismes génétiques, qui seront à l’avenir intéressants à rechercher. © 2014 Elsevier Masson SAS. Tous droits réservés.
Introduction Vitamin K antagonists (VKA) are drugs that are very widely used, and 1% of the population is estimated to be treated by these molecules [1]. This proportion is rapidly increasing due to an aging population and the increased incidence of agerelated cardiovascular disorders such as atrial fibrillation. One might think that after over a 60-year handling experience and widespread use of this drug that safety would be at its highest. This is not the case however, as these molecules are currently the main cause of hospital admissions for drugrelated adverse events in France and the third cause in the United Kingdom [1,2]. A study carried out in 1998 showed that VKA-related bleeding events were the principal cause of hospitalisation for adverse drug events (13%), and that they accounted for about 17,000 hospital admissions a year, half of which were avoidable [3]. The results of the EMIR study in 2007 confirmed these findings: VKA were responsible for the highest incidence of hospital admissions for adverse drug effects (12.3%) [4]. The annual incidence of major bleeding related to VKA is estimated at 7% and that of fatal bleeding at 1% [5]. In France, the frequency of serious hemorrhage is estimated at between 1.6 and 5.6% per patient and per year [6]. Excessively high VKA doses, notably in patients with an INR greater than 4, are associated with an increased risk of hemorrhage, which is due, moreover, to the pharmacological properties of these molecules.
Even when the patient is receiving an anticoagulant, thrombotic events are not rare, but such a clinical situation, indicative of ineffective treatment, is still very little described in the literature. The aim of this study was to identify, in a case-control study, the risk factors associated with a thrombotic or bleeding event in patients treated with VKA and admitted to an emergency department.
Material and methods Study design This single-center cross-sectional observational study was carried out over a three-month period (from March 1, 2012 to May 31, 2012) and included patients consecutively being admitted to the emergency department of Bethune Hospital and treated with an oral anticoagulant, regardless the reason for admission. Bethune Hospital is a secondary-level hospital with just over 300 beds, which serves a population of about 270,000 inhabitants.
Patients Patients inclusion criteria were admission to the emergency department of Bethune Hospital between March 1 and May 31, 2012, an International Normalized Ratio (INR) ordered
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Thrombotic or bleeding event and vitamin K antagonists: Risk factors by the emergency department on the day of admission, and treatment by oral anticoagulant at home. Patients admitted for thrombotic or bleeding events were included as cases and the other patients served as controls. Cases and controls were identified through the systematic INR requests made by the emergency department and carried out by the hospital biology laboratory. This test request identified a priori those patients who were likely to be treated by oral anticoagulants at home.
3 240 patients: - 40 bleeding events - 19 thrombotic events - 181 other events 3 extreme ages on bleeding event
3 extreme ages on thrombotic event
Data collection Variables collected were age, gender, type of oral anticoagulant, indication and duration of treatment, dose and reason for hospital admission. Associated treatments and laboratory results on the day of admission (INR, serum creatinine) were also recorded. According to literature data, the main comorbid conditions identified or discussed to be risk factors associated with bleeding or thrombotic events were also collected. For bleeding events, risk factors recorded were renal failure, cancer, stroke history, arterial hypertension, atrial fibrillation and ulcerative disease [7—13]. Risk factors selected for thrombotic events were cancer, chronic respiratory disease, chronic cardiovascular disease, disability, history of thrombotic event, body mass index and history of ischemic heart disease [9,14—16].
Statistical analysis Independent quantitative variables were compared using the Student t-test or the Wilcoxon-Mann-Whitney test and independent qualitative variables were compared with Pearson’s Chi2 test or Fisher’s test. For case-control study, each case was matched with two controls. Matching was done by patients’ age (within a 5year range) and gender. Matched quantitative variables were compared with Wilcoxon’s non-parametric test and matched qualitative variables were compared with McNemar’s Chi2 test. Conditional logistic regression was performed in the casecontrol studies in order to determine the factors associated with occurrence of a thrombotic event (for patients with thrombosis) and with occurrence of a bleeding event (for patients with bleeding). For each case-control, a univariate analysis was performed and the variables (initially identified as risk factors in literature) with a P-value < 0.2 in the univariate analysis were then included in the multivariate model. Odds Ratios (OR) were presented with their 95% confidence intervals (95% CI). The threshold of significance was fixed at 5%. Statistical analysis was carried out using SAS 9.1® software (SAS Institute, South Carolina, USA).
Results General characteristics of the population Over a 3-month period, 240 subjects treated with oral anticoagulants at home and admitted to the emergency
159 patients: - 37 cases of bleeding - 16 cases of thrombosis - 106 controls
Figure 1 Flow-chart illustrating the selection of the cases. Flow-chart illustrant la sélection des cas.
department of Bethune Hospital were identified. Of these patients, 40 (17%) were admitted for a bleeding event, 19 (8%) for a thrombotic event and 181 (75%) for another reason. The mean age of these patients was 75 years (± 13 years) and the sex ratio was 0.7. Their mean INR on emergency admission was 2.8 (± 1.5). To perform the case-control study, and according to matching criteria, three hemorrhagic cases (among 40 patients) and three thrombotic cases (among 19 patients) were excluded because of their extreme age (Fig. 1).
Bleeding events General characteristics of cases and controls Thirty-seven cases of bleeding events were compared with 74 controls. The general characteristics of the patients are presented in Table 1. No significant difference was found between the two groups for the variables studied. Eightyseven per cent of cases and controls were treated with fluindione and 13% of cases and controls with warfarin. No patients were receiving acenocoumarol or one of the new oral anticoagulants. Cases nevertheless tended to receive a higher dose of fluindione than controls (P = 0.06) and to have been treated for a shorter period (P = 0.08). INR was in the normal range in 57% of cases, and higher than 5 in 14% of cases. The INR did not significantly differ between cases and controls.
Bleeding events leading to admission of cases Of the 37 cases, 14 patients (38%) presented with epistaxis, 7 (19%) with hematoma, 4 (11%) with hematuria, two (6%) with hemoptysis, two (6%) with intracranial hemorrhage, two (6%) with hemorrhagic stroke, two patients (6%) with melena, two (6%) with rectal bleeding, one (3%) with hematemesis and one (3%) with gastrointestinal bleeding. Among these 37 cases, 16 were considered as major bleeding (bleeding into a site associated with significant morbidity (e.g. intracranial), requirement for blood transfusion, and/or anaemia).
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J. Béné et al. Table 1 Characteristics of cases with bleeding events and controls. Caractéristiques des cas « hémorragiques » et de leurs témoins. Variables
Cases
Controls
n
n
P
Age, years (m ± SD)
37
76.8 ± 8.3
74
77.0 ± 8.9
1
Male gender, n (%)
37
25 (68)
74
50 (68)
1
BMI, kg/m (m ± SD)
26
28.3 ± 5.7
42
30.4 ± 8.0
0.39
Type of anticoagulant, n (%) Fluindione Warfarin
37
Reason for prescription, n (%) Atrial fibrillation Thromboembolic event Cardiac valve Ischemic heart disease Heart rhythm disorder Stroke Myocardial infarction
36
2
74 32 (87) 5 (13)
1.00 64 (87) 10 (13)
71 28 (78) 5 (13) 2 (6) 0 0 0 1 (3)
0.81 56 (80) 8 (11) 3 (4) 1 (1) 2 (3) 1 (1) 0
Dose Fluindione (m ± SD), mg Warfarin (m ± SD), mg
29 5
22 ± 9 2±1
43 8
18 ± 8 4±3
0.06 0.12
Treated for ≤ 90 days, n (%)
34
7 (21)
37
2 (5)
0.08
Hemoglobin levels (m ± SD), g/dL
34
12.2 (3.1)
71
12.4 (2.3)
0.71
INR levels INR (m ± SD) 2 ≤ INR ≤ 3, n (%) INR > 5, n (%)
37 37 37
3.4 ± 2.9 21 (57) 5 (14)
74 74 74
2.8 ± 1.5 31 (42) 6 (8)
0.27 0.14 0.37
INR: International Normalized Ratio.
Drug interactions Patient exposure to treatments likely to contribute to a bleeding event was compared between cases and controls (Table 2). The number of drug interactions per patient did not significantly differ between cases and controls
Table 2 Drug interactions likely to contribute to a bleeding event. Interaction médicamenteuse pouvant potentialiser un évènement hémorragique. Cases (n = 36) n (%)
Controls (n = 72) n (%)
Number of interactions 0 1 ≥2
3 (8) 12 (33) 21 (58)
10 (14) 29 (40) 33 (46)
Drug interaction Contraindicated association Unadvisable association Restricted use Caution
0 4 (11) 33 (89) 2 (5)
0 0 62 (84) 0
Variables
P
0.54
(overall test, P = 0.54). No contraindicated drug interaction was identified in the groups compared. However, cases were more often receiving an unadvisable association of drugs than controls (P = 0.01) (in 4 cases, patients with an active gastroduodenal ulcer had taken aspirin). With regard to drugs taken in spite of restrictions for use, the drugs most often involved (cases and controls together) were hypolipidemic agents in 58% of patients, amiodarone in 15%, acetaminophen in 12% and allopurinol in 9%. Risk factors associated with a bleeding event In the univariate model, among the variables selected in the literature as being most often associated with a bleeding event in patients receiving a VKA and included, none of them were highly associated with bleeding event in this study (Table 3). We performed a separate analysis for major bleeding and no variable was statistically associated with such an event.
Thrombotic events 1.00 0.01 0.44 0.11
General characteristics of cases and controls Case-control analysis compared 16 cases of thrombotic events with 32 controls. The patients’ general characteristics are presented in Table 4. No significant difference was
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Thrombotic or bleeding event and vitamin K antagonists: Risk factors Table 3 Variables associated with occurrence of a bleeding event on oral anticoagulants. Variables associées à l’apparition d’un évènement hémorragique sous anticoagulants oraux. Variables
Univariate analysis OR [95% CI]
p
Renal failurea Cancer Number of drug interactions ≥ 2 vs < 2 Treatment started < 90 days History of stroke Arterial hypertension Atrial fibrillation Ulcerative disease
0.6 [0.2—1.6] 2.5 [0.7—9.3] 1.7 [0.7—3.9]
0.30 0.17 0.22
a
2.3 0.6 0.6 0.9 1.1
[0.4—12.5] [0.2—2.1] [0.1—2.4] [0.4—2.3] [0.5—2.4]
0.35 0.45 0.46 0.87 0.89
CrCl < 60 mL/min/1.73 m2 .
found between the two groups for the variables studied. Cases of thrombosis and their controls showed identical distribution according to type of anticoagulant treatment, with a majority of patients receiving fluindione and none receiving the new oral anticoagulants. The reason for prescription and the doses, whatever the VKA given, were also identical in the two populations. INR was in normal range in 44% of cases, and lower than 2 in 50% of cases. Twenty one percent
5
of the cases were treated for less than 90 days. The INR (continuous values) of cases tended to be lower than that of controls (P < 0.08). Thrombotic events leading to admission of cases Of the 16 cases, 7 patients (44%) presented with a stroke, 3 patients (19%) a transient ischemic accident, 3 patients (19%) phlebitis, two patients (12%) myocardial infarction and one patient (6%) pulmonary embolism. Among these 16 cases, 10 were severe thrombotic events requiring hospitalization. In 3 cases of venous thrombosis, VKA was prescribed in VTE prevention. Risk factors associated with a thrombotic event Multivariate logistic regression (Table 5) revealed no risk factor significantly associated with a thrombotic event in these patients treated with VKA. Patients presenting with a thrombotic event were however more likely to have a chronic respiratory disease. Separate analysis for arterial thrombotic events was performed, giving the same results.
Discussion Bleeding events In the ninth edition of the Recommendations of the American College of Chest Physicians (ACCP) published in 2012, the
Table 4 Characteristics of cases with thrombosis events and controls. Caractéristiques des cas « thrombotiques » et de leurs témoins. Variables
Cases
Controls
n
n
P
Age, years (m ± SD)
16
72.4 ± 16.8
32
72.7 ± 16.8
1.00
Male gender, n (%)
16
5 (31)
32
10 (31)
1.00
BMI, kg/m (m ± SD)
14
30.7 ± 7.6
18
33.2 ± 10.3
0.30
Type of anticoagulant, n (%) Fluindione Warfarin Acenocoumarol
16
Reason for prescription, n (%) Atrial fibrillation Thromboembolic event Cardiac valve Ischemic heart disease Stroke
15
Dose (mean ± SD), mg Fluindione Warfarin Acenocoumarol
15
2
INR levels INR (m ± SD) 2 ≤ INR ≤ 3, n (%) INR < 2, n (%)
32 14 (88) 2 (12) 0 31 8 (53) 6 (40) 1 (7) 0 0
0.73 19 (61) 8 (26) 1 (3) 2 (6) 1 (3)
30 20 ± 9 3±2 —
16 16 16
1.00 28 (88) 3 (9) 1 (3)
1.9 ± 0.7 7 (44) 8 (50)
32 32 32
17 ± 11 4±2 4
0.44 0.78 —
2.5 ± 1.1 15 (47) 11 (34)
0.08 0.84 0.30
INR: International Normalized Ratio.
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J. Béné et al. Table 5 Variables associated with occurrence of a thrombotic event on oral anticoagulants. Variables associées à l’apparition d’un évènement thrombotique sous anticoagulants oraux. Variables
Chronic respiratory disease Chronic cardiovascular diseasea Disabilityb History of thrombotic event BMI > 25 vs BMI ≤ 25 History of ischemic heart disease Cancer
Univariate analysis OR [95% CI]
P
4.6 0.4 2.4 1.5 1.6 1.0 —
0.07 0.30 0.36 0.51 0.51 1.00 1.00
[0.9—23.8] [0.07—2.2] [0.4—15.0] [0.4—5.6] [0.4—6.0] [0.2—4.3]
a Arterial hypertension, atrial fibrillation, heart failure, other heart rhythm disorders. b Bed-ridden state, cognitive disorders.
main risk factors for hemorrhage while on VKA therapy are intensity of anticoagulation therapy, comorbid conditions, and drug interactions [12]. The intensity of anticoagulation, evaluated by the INR, appears to be the major risk factor. The studies confirming this are numerous: some authors found an increase in bleeding events over an INR threshold of 2 [17], others for a higher threshold, generally 3 [18]. We found no significant difference between the INR of patients with a bleeding event and of controls, and the proportion of these subjects whose INR was between 2 and 3 was not different. It appears, moreover, that fluctuations of anticoagulation, reflected by variations in INR, may also be associated with an increased risk of bleeding independently of the mean INR [19]. The duration for which INR values remain within the target range is therefore a variable of considerable importance: a meta-analysis published in 2004 estimated, in a population treated with warfarin for atrial fibrillation and with a target INR between 2 and 3, that for 61% of the time patients were in the target range, for 13% of the time their INR was greater than 3 and for 26% it was less than 2 [18]. These studies underline the value of regular monitoring and follow-up of the INR and raise the question of the usefulness of INR self-measurement devices. With regard to the comorbid conditions contributing to the onset of a bleeding event, among the diseases most often cited are a history of bleeding events [11,12]: gastro-duodenal ulcer in particular [9,11,20]), arterial hypertension [8,21,22], history of ischemic stroke [8,11,21], diabetes [21], renal failure [9,17,19,20,23] and cancerous diseases [9,10,23—25]. However, these variables, in particular renal failure and cancerous disease, are not systematically associated with a bleeding event, as has been shown by studies similar to ours [26]. Drug interactions are also among the factors that may contribute to a VKA-related bleeding event. The general effect of most interactions with anticoagulants is an increase in the INR, explaining the increased risk of bleeding [27]. Some studies have closely examined these exposures, like the team of Suh et al. who demonstrated that patients exposed to these drugs presented more bleeding events than non-exposed patients (OR = 1.26, P = 0.047) [28]. As in our study, the majority of their patients (about 80%)
were exposed to a drug interaction. In the same study, the risk of a bleeding event increased with the number of drug interactions identified for each patient. Numerous studies were coherent with these findings and the drugs most often reported were non-steroidal anti-inflammatory agents, other anticoagulants, antibiotics and anti-platelet drugs [28—30]. We found that the majority of interactions with VKA were related in particular to hypolipidemic agents and amiodarone. Lastly, some studies like ours have shown that the risk of a bleeding event is markedly increased during the first 90 days of VKA treatment even if the results were not statistically significant [17,20,24]. In one of these studies [20], the probability of experiencing a bleeding event under VKA treatment during this period was six times greater than during prolonged treatment (OR = 5.83, P = 0.0064). During the initial period of treatment, patients are particularly exposed to excessively high doses and to complications: this could be explained by inadequate monitoring of the INR and/or to difficulty experienced by prescribers in stabilizing it during this period. In our study, the majority of the patients were treated for more than 90 days.
Thrombotic events The majority of studies on this subject address thrombotic events occurring after discontinuation of anticoagulants, and not during treatment. However, according to some authors, 3 to 6% of patients with long-term anticoagulant treatment may present a risk of a recurrent thromboembolic event, in particular during the first three months of treatment [14]. We found a higher proportion with 8% of thrombotic event in our total population and 32% among all cases. This case-control study aiming to identify risk factors associated with a thrombotic event during VKA treatment did not reveal any variable significantly associated with such an event. Patients who had experienced a thrombotic event were however more likely to have a chronic respiratory disease than controls. These findings are in agreement with the literature, as some authors have identified chronic respiratory diseases as an independent risk factor for a thrombotic event in patients receiving VKA [14]. These patients may be less physically mobile, leading to possible venous stasis and increased thrombotic risk. Conversely, in our analysis, other factors that could potentially contribute to decreased mobility, such as overweight or obesity (BMI > 25) or a disability, were not associated with occurrence of a thrombotic event. Among the other most commonly described risk factors for thrombotic events with VKA treatment, a cancerous disease seems to be most often reported: the risk may increase two to six-fold, depending on the studies [9,14,25]. Risk level is affected by chemotherapy and the degree of spread of the cancer. The mechanism involved in this effect is not as yet clearly identified at present: it could be related to the production of procoagulant factors such as tissue factor or factor X-activating cysteine protease. In our analysis, no cases had a cancerous disease. Cancer is followed by chronic cardiovascular diseases, a recognized risk factor for thrombotic events [14]. The literature, though sparse on this subject, also cites a low level of anticoagulation as a risk
Please cite this article in press as: Béné J, et al. Risk factors associated with a thrombotic or bleeding event in patients treated with vitamin K antagonists. J Mal Vasc (2014), http://dx.doi.org/10.1016/j.jmv.2014.04.002
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Thrombotic or bleeding event and vitamin K antagonists: Risk factors factor for a thrombotic event, in particular INR less than 2, or age above 70 years. Our findings are in agreement with the data on thrombotic risk and low level of anticoagulation: the risk tends to increase for an INR below 1.5.
Study limitations The initial protocol for matching cases and controls led us to exclude seven cases (four bleeding events and three thrombotic events) because of the patients’ advanced age, as no matching controls were available in this population. These seven exclusions lowered the power of this analysis, while the series was already small. Moreover, the small number of cases in each analysis, in particular for thrombosis, limits the power of the statistical analysis. Other risk factors identified in literature were not taken into account in analysis, such as ethanol abuse or excessive fall risk [7] as they were not systematically mentioned in the patient records. Because of the small population size, we were not able to perform separate analysis for severe and non-severe events and for venous and arterial thrombotic events. It should be pointed out that the large majority of international studies, deal with patients treated with coumarin derivatives and warfarin in particular. Fluindione therefore does not figure in these studies and this issue certainly deserves deeper analysis: are risk factors different in patients who are receiving coumarin derivatives rather than indanediones? Lastly, genetic variants of cytochrome P450 2C9 (CYP2C9*2 and *3) involved in warfarin metabolism and VKORC1 (vitamin K epoxide reductase complex 1) involved in the vitamin K cycle could explain variations in VKA sensibility [31]. These data seem interesting to predict individual VKA response; indeed, few authors have already demonstrated that genotype-guided warfarine dosing was superior to standard dosing at the initiation of warfarin therapy [32,33].
Conclusion At the time when new oral anticoagulants take their place on the market, the question of the anticoagulant survey deserves the full attention of by health professionals. In spite of 60 years of experience and knowledge of VKA, their use still seems complex and remains difficult to master. In this study, no risk factor significantly associated with a bleeding or thrombotic event in patients treated with VKA were identified. The occurrence of these events supposes genetic polymorphisms that should be considered in future studies.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgments We would like to thank Dr Odile Crepin and Dr Gérard Dupuis of the Biology Laboratory, Centre Hospitalier de Béthune, for providing us the results of INR.
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This study has been presented to the following congress: • Oral presentation: ◦ Béné J, Senis C, Auffret M, Gautier S, Dubart AE. Epidémiologie des patients sous anticoagulants admis dans un service d’urgence (SAU). 7ème Congrès de la Société Francaise de Médecine d’Urgences 2013 Paris ; • Poster: ◦ Risk factors for hemorrhagic and thrombotic accidents in patients treated with oral anticoagulants: a casecontrol study. Béné J, Dubart AE, Auffret M, Senis C, Gautier S. ISOP 2013, Pise ; ◦ Risk factors for hemorrhagic and thrombotic accidents in patients treated with oral anticoagulants: a casecontrol study. Béné J, Dubart AE, Auffret M, Senis C, Gautier S. P2T 2013, Angers.
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