- Email: [email protected]
Anticoagulants in frail patients. Seven situations at risk
JMV—Journal de Médecine Vasculaire (2018) 43, 302—309
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
REVIEW
Anticoagulants in frail patients. Seven situations at risk Anticoagulants chez les patients fragiles, sept situations à risque I. Elalamy a, O. Hanon b, G. Deray c,d, V. Launay-Vacher c,d,∗ a
Hematology department, Tenon Hospital, 75020 Paris, France Geriatrics department, Broca Hospital, 75013 Paris, France c Service ICAR, Pitié-Salpêtrière Hospital, 75013 Paris, France d Nephrology department, Pitié-Salpêtrière Hospital, 75013 Paris, France b
Received 18 October 2017; accepted 30 June 2018 Available online 31 July 2018
KEYWORDS Chronic kidney disease; Frailty; Polypharmacy; Cancer; Pregnancy
MOTS CLÉS Insuffisance rénale ; Fragilité ; Polypharmacie ; Cancer ; Grossesse
∗
Summary In the case of venous thromboembolic disease (VTE), physicians are facing more and more difficulties in managing VTE and their treatment in frail patients. These patients could present several risk situations such as: chronic kidney disease (CKD), underweight or malnourished, falls, cognitive impairment, multi-medicated patients, cancer and pregnancy. Guidelines typically recommend anticoagulation. There are multiple challenges in the safe use of anticoagulation in frail patients, including bleeding risk, monitoring and adherence, and polypharmacy. The objective of this review is to explore these at-risk situations and to suggest adequate anticoagulation therapy, when possible, in each of these complex situations. © 2018 Elsevier Masson SAS. All rights reserved.
Résumé En cardiologie et en médecine vasculaire, les médecins sont de plus en plus confrontés aux difficultés de la gestion des évènements thromboemboliques veineux (ETEV) et de leur traitement chez les patients fragiles. En effet, ces patients pourraient présenter au moins une de ces situations à risque : insuffisance rénale chronique (IRC), insuffisance pondérale ou malnutrition, chutes, troubles cognitifs, polymédication, cancer et grossesse. Les recommandations proposent généralement de recourir à des anticoagulants dans le traitement ou la prophylaxie des ETEV. Ainsi, il est nécessaire de prendre en charge ces patients fragiles lors de l’utilisation
Corresponding author. Service ICAR, Pitié-Salpêtrière Hospital, 83, boulevard de l’Hôpital, 75013 Paris, France. E-mail address: [email protected] (V. Launay-Vacher).
https://doi.org/10.1016/j.jdmv.2018.07.003 2542-4513/© 2018 Elsevier Masson SAS. All rights reserved.
Anticoagulants in frail patients. Seven situations at risk
303
des anticoagulants, en tenant compte du risque thrombotique et du risque de saignement, mais également du suivi, de l’observance et de la polymédication. L’objectif de cette revue est d’étudier les risques et la gestion des anticoagulants chez ces patients fragiles. © 2018 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Introduction The direct oral anticoagulants (DOAC) represent a new era of anticoagulation for patients with venous thromboembolism (VTE). These agents may (or may not) offer advantages to patients in whom the use of traditional anticoagulants is typically challenging. For the medical practitioner, an assessment of the patient’s vulnerability to treatment involves an examination of the clinical situation and the patient profile, together with the monitoring of the thromboembolic and bleeding risk which are intimately linked one to another in the VTE situation. In fact, these situations are often interconnected and seven different types of at risk situations can be described: • • • • • • •
chronic kidney disease (CKD); underweight or malnourished; falls; cognitive impairment; multi-medicated patients; cancer; pregnancy.
For each of these situations, it is necessary to assess the vascular risk, identify different anticoagulant treatment options, and choose the one that seems the more suitable to control the risk of thrombosis and bleeding. Elderly patients often have a combination of these situations (except pregnancy) and this underlines the importance of such a reflexion. This review discusses the main data on the anticoagulant management in each of these seven situations in frail patients.
Seven situations at risk Chronic kidney disease In the situation of renal insufficiency, the physiopathological mechanisms of hemostasis are complex and diverse and they lead to an imbalance coagulation/fibrinolysis equilibrium involving oxidative stress and inflammation [1—4]. Patients with renal insufficiency have a higher risk of both venous thrombosis, and bleeding [5,6]. This cumulative over-risk represents a two-fold constraint, making an anticoagulation treatment difficult to manage in CKD patients [7]. At least one third of the patients with MTEV have a moderate renal insufficiency and between 5 and 10% have a severe renal insufficiency [5,8].
In such a situation, risk management with vitamin K antagonists (VKA) is detrimental to the patient’s health [9] leading to an increased risk of bleeding [10]. Furthermore, interstitial nephritis and glomerular bleeding induced by VKA have been reported [9]. In a small French study on 24 patients, 33.3% of the acute interstitial nephritis cases were attributed to VKAs [11]. The anticoagulant-related nephropathy is associated with CKD and increased mortality. It was initially named ‘‘warfarinrelated nephropathy’’ as warfarin has been the only available and commonly used oral anticoagulant until recently [12]. Nevertheless, the term currently used is anticoagulant-related nephropathy, since DOAC have been also associated with episodes of glomerular haematuria and acute kidney injury as well [13—15]. However, an Asian study reported that among AF patients, dabigatran was associated with a lower risk of acute kidney failure than warfarin [16]. Consequently, it seems premature to use the term of anticoagulant-related nephropathy. For heparins, there is a fundamental relationship between their structure and how they act. The longer polysaccharide chains are eliminated by the reticuloendothelial system whereas the shorter chains are eliminated via the renal pathways [17]. Low molecular weight heparins (LMWH) are a very heterogeneous group and it is important to take their composition into account [17,18]. Because of its smaller molecular mass, enoxaparin binds less to plasma proteins, macrophages, and endothelial cells, thereby conferring a more reliable dose—response relationship and longer plasma half-life when compared with unfractionated heparin (UFH) [19,20]. Several studies have highlighted the risk of accumulation in patients with kidney failure as a function of the molecular weight of the polysaccharide chains in the LMWHs. LMWHs with short chains are essentially eliminated through the urine and those with long chains pass through the reticuloendothelial system. These studies have shown that this accumulation does not take place with every type of LMWH. This has the potential to increase the risk of bleeding depending on the clinical context and therapy chosen [17]. In fact, the use of LMWHs with short polysaccharide chains, in both curative and prophylactic doses, showed an increased risk of bleeding in patients with kidney failure, whereas this was not found to be the case with LMWH with long polysaccharide chains [21,22]. The clinical value of DOAC in VTE patients has been demonstrated in large randomized trials, compared to warfarin [23]. In this meta-analysis from four phase III trials, the elderly populations represented 12 to 18% of the total
304 population and CKD patients represented 5 to 8% of the total populations. In elderly patients (more than 75 years old), a meta-analysis showed a 45% reduction in thrombosis and a 61% reduction in serious bleeding. In CKD patients, these benefits were pointing in the same direction but were not statistically significant due to the lower number of patients with such a profile [23]. In cases of patients with moderate CKD, the dose of DOAC should be adjusted for patients with AF, but this has not been confirmed in cases of VTE as these reduced doses have not been studied.
The underweight, malnourished patient Malnutrition is common in the elderly. It affects 30 to 60% of hospitalized elderly patients. It is defined by a weight loss of at least 10% in six months (or 5% in a month), and a serum albumin of less than 35 g/L or a body mass index of under 21 kg/m2 [24]. Oral anticoagulants, particularly VKA, and to a lesser extent, DOAC, bind to plasma proteins and specially to albumin [25]. This can potentially influence their bioavailability and increase the risk of all bleeding in cases of hypoalbuminaemia in VKA patients (OR = 1.95; 95%CI = 1.17—3.25) [26]. Monitoring the INR should be considered for these patients in order to reduce the risk of overdose. Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45—0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant non-major bleeding occurred significantly less in DOAC recipients [27]. However, depending on the molecule under consideration, plasma protein binding ranges from 34 to 93% [25]. A study with 156 elderly patients, treated with 0.61—1.1 mg/kg/12 h enoxaparin sodium, showed that minor or major bleeding was observed in 5.8% of these patients. The results suggest that low bodyweight is associated with a higher risk of bleeding (≤ 55 kg, OR = 5.63) [28]. Therefore, testing for malnutrition is important in the care of elderly patients being treated with anticoagulants in order to adjust the dose appropriately and in order to monitor the level of anticoagulation [29]. The vitamin K intake, from the diet or as a dietary supplement, may interfere with the INR and complicate its stabilization [30—32].
Falls Any fall naturally increases the risk of bleeding when using antithrombotics, whether they are anticoagulant or antiplatelet types. For this reason, fall risk was found to be one of the leading physician reasons (26.7%) for not prescribing anticoagulants [33]. However, the benefit/risk balance for anticoagulants remains favourable in the patient who has suffered from a fall [34]. A systematic and comprehensive assessment of the risk of fall should be carried out to identify any treatable factors and to search for known risk factor of falls [35]. The signs of seriousness related to the consequences of the fall are: rhabdomyolysis, hypothermia, pressure sore, significant fractures and also those that have had a high number of falls (> 2 falls a year) without any curable factor being identified [35]. Furthermore, several drugs at risk of fall
I. Elalamy et al. have been identified in the elderly, such as anticonvulsants, antipsychotics. . . [36]. Vitamin D has been shown to play a role in thrombosis via hemostatic factors like the tissue factor pathway inhibitor [37]. Doses of 700 IU to 1000 IU supplemental vitamin D a day could reduce falls by 19% or by up to 26% [38]. However; the clinical use of vitamin D doses below 700 IU a day for the prevention of falls among older individuals is not effective. A 25(OH)D concentration of at least 60 nmol/L is required for fall prevention; therefore, a daily intake of at least 700 IU supplemental vitamin D is warranted in all individuals aged 65 and older [38]. Notably, good adherence is essential for the effect of vitamin D on falls. Furthermore, it is possible that greater benefits may be achieved with the use of vitamin D3 instead of vitamin D2 [38].
Cognitive impairment Dementia is associated with increased mortality in AF patients [39]. Several studies have clearly established the fact that cognitive impairment increases the risk of thromboembolic and bleeding [40]. In case of cognitive impairment, the patient can: • forget to take their treatment, risking a recurrence of thrombosis; • take the treatment more than once (having forgotten that they have already taken it) thereby exposing themselves to overdosage and to a risk of bleeding complications. Therefore, it is very important to identify patients with cognitive disorders. The classic test is the Mini-Mental State Examination (MMSE) [40]. However, this test has thirty questions and takes a long time to complete. Consequently, it is not used very much in practice. The Memory Impairment Screen (MIS) test is simpler and faster [41]. The patient must try to remember four words written on a sheet of paper (for example, mackerel, onion, rose, willow). After being shown the list of words, they are asked to return it ten minutes later [41]. If the patient cannot recall a word, he can be offered a clue to help them (‘‘tree’’ for willow or ‘‘fish’’ for mackerel). If they cannot remember the word despite being given the clue, they may potentially have cognitive impairment. The presence of a cognitive disorder is not a contraindication for anticoagulation treatment because the considerable stroke risk without oral anticoagulants often exceeds the bleeding risk of oral anticoagulants in patients with cognitive dysfunction [42]. However, it is necessary to closely monitor the patient’s drug intake. For example, it is possible to ask someone else to check that the medicine is being taken properly. Using a pill organizer is a practical method and it could be filled weekly. Regular checks by a nurse, especially if LMWH are being injected or tablets are being taken orally, is the best option to make sure the treatment is being followed properly. Regarding the choice of anticoagulants in patients with cognitive disorders, all treatment options (VKA, DOAC, LMWH) are possible, with help from a third party. Regular
Anticoagulants in frail patients. Seven situations at risk visits by a nurse to the patient’s home are the best way to ensure that the anticoagulation medication is being taken properly.
305 use several agents that alter haemostasis, whatever it is a pharmacological or an adverse effect.
Cancer The multi-medicated patient Elderly patients are frequently in a situation involving multiple diseases and polypharmacy [43]. Median drug intake increases with age, from 3.3 drugs at 65—74 years, to 4 drugs at 75—84 years, and finally to 4.6 for patients over 85 years [44]. Because many drugs could potentially interfere with VKA treatment, the probability of a drug—drug interaction is heavily increased in polypharmacy patients. Paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs can alter the INR and increase the risk of bleeding [36,45]. Search for a medication by paracetamol or nonsteroidal anti-inflammatory drugs may explain an INR unbalance in case of an auto-medication by these drugs. Paracetamol still remains the standard medication for pain and fever in patients taking an anticoagulant treatment. Postmarketing data has reported few isolated cases of elevated INR of clinical significance during concomitant of treat® ment of warfarin and esomeprazole (EMA, Nexium SmPC, www.ema.europa.eu). Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarin derivatives. With DOAC, there are fewer drug—drug interactions than with VKAs. Only powerful metabolic pathway inhibitors such as hepatic cytochromes should be checked [26]. CYP3A4 is involved in rivaroxaban and apixaban hepatic metabolism. Strong CYP3A4 inhibition or induction may affect plasma concentrations and efficacy or safety. Non-renal clearance of apixaban is diverse (metabolism, biliary excretion, and direct excretion into the intestine), with a moderate contribution of CYP3A4, which makes CYP3A4 interactions of less importance for this drug. Liver metabolism involving CYP3A4 is minimal for edoxaban and null for dabigatran [26]. These two drugs are therefore theoretically less exposed to drug interactions with CYP3A4. Furthermore, an important interaction mechanism for all DOAC consists of significant re-secretion over a Pglycoprotein (P-gp) transporter after absorption in the gut. Moreover, the P-gp transporter may also be involved in renal clearance: competitive inhibition of this pathway will therefore result in increased plasma levels. Indeed, several drugs used in AF patients are P-gp inhibitors (verapamil, dronedarone, amiodarone, quinidine. . .) [26]. In summary, co-medication management with DOAC appears to be less restrictive than with VKA, but it is important to remain cautious with molecules that use the hepatic cytochrome pathways and P-gp. For LMWH, this problem clearly appears to be less significant. Given the elimination pathways of LMWH, the risk from co-medication is much lower since they do not use P-gp and cytochrome systems. In all cases, it is important to minimize the duration of the association between anticoagulant and antiplatelet drugs that simultaneously inhibit the pathways of both primary haemostasis and actual plasma coagulation, increasing the risk of clinical bleeding. Finally, it is important not to
Cancer patients are more exposed to VTE [46]. In fact, 20% of all VTE cases occur in patients with cancer [46]. In addition, VTE can affect up to 20% of patients with cancer, but it has been reported in up to half of cancer patients coming to post-mortem examination, highlighting the fact that the true extent of this complication may be underestimated [46]. The pathophysiology of thrombosis associated with cancer is complex. Cancer patients have a prothrombotic state resulting from the synergic activity of factors involved in the so-called Virchow’s triad: • stasis of the blood caused by bed rest or by tumour compression; • vascular injury caused by intravasation of cancer cells, drugs, or therapeutic devices; • blood hypercoagulability due to the release of cancer cell pro-coagulant factors, which affect the haemostasis process, including platelet functions and clotting cascade [47]. There were several risk factors of VTE related to the tumour (fast growing, biologically aggressive tumours, primary site of cancer, metastatic disease at the time of diagnosis. . .), the patient (elderly, chronic co-morbidities. . .) and the treatments (recent major surgery, long-term central venous catheters. . .) [48]. Furthermore, cancer patients had a high incidence of fatal recurrent pulmonary embolism or fatal bleeding [49]. VTE was also found to be a risk factor of mortality in cancer patients [50]. In fact, survival was particularly poor when the diagnosis of cancer was concurrent with VTE and when cancer was diagnosed within 1 year after an episode of primary VTE [50]. Furthermore, the adjusted 10-year cumulative VTE recurrence rate in active cancer patients was 28.6% and the cumulative incidence of first VTE recurrence was also higher in patients with active cancer than patients without [51]. Finally, VTE was reported to be the second most common cause of death in cancer patients [46,48]. The efficacy of VKA in reducing the risk of thrombosis in cancer patients is half that of LMWHs, with no improvement in controlling the risk of bleeding [52]. The CLOT study [53] reported no significant difference between dalteparin and VKA in the rates of major bleeding, any bleeding, and mortality at six months. These trends were confirmed in the CATCH study [54] which reported similar recurrent VTE rates, major bleeding, and overall mortality between tinzaparin and VKA. However, in the LITE study [55], cancer patients receiving tinzaparin had less recurrent VTE and haemorrhagic complications compared with VKA. A number of clinical studies have compared the efficacy of different types of ACG treatments in cancer patients. The RECOVER studies [56,57] showed no significant difference between dabigatran and warfarin for cancer patients at baseline. In the AMPLIFY trial [58], recurrent VTE and major bleeding were not statistically different between
306 apixaban and enoxaparin/warfarin. The EINSTEIN studies [59,60] showed similar recurrent VTE and major bleeding for rivaroxaban and warfarin patients [61], and rivaroxaban has been suggested as an acceptable therapy in cancer patients [62]. Additionally, the HOKUZAI trial showed less frequent occurrence of VTE with edoxaban compared to warfarin (4% vs 7%, P = 0.0007), less clinically relevant bleeding (12% vs 19%, P = 0.017), and similar major bleeding rates (3%) [63]. A meta-analysis [61] reported that, comparing DOAC to VKA, the relative risks were non-significantly in favour of DOAC for both recurrent VTE and major bleeding. An indirect comparison of LMWH and DOAC shows that DOAC were not more efficient (recurrent VTE) than LMWH in cancer patients and were not more at risk of major bleeding [61]. The American Society of Clinical Oncology recommends LMWH over UFH for the initial 5 to 10 days of anticoagulation for the cancer patient with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance < 30 mL/min). For long-term anticoagulation, LMWH for at least 6 months is preferred due to improved efficacy over VKA. However, VKA are an acceptable alternative for long-term therapy if LMWH is not available. Anticoagulation with LMWH or VKA beyond the initial 6 months may be considered for select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. The use of DOAC for either prevention or treatment of VTE in cancer patients is not recommended [64]. The International Initiative on Thrombosis and Cancer [65] recommends LMWH for the initial treatment of established VTE (first 10 days) in patients with cancer (grade 1B). They further state that LMWH is easier to use than unfractionated heparin and that once-per-day regimen of LMWH is recommended, unless a twice-per-day regimen is required because of patient characteristics. Fondaparinux and UFH can also be used for the initial treatment of established VTE in patients with cancer, but there is a lower level of evidence (grade 2D), and fondaparinux is easier to use than UFH. For the early maintenance (10 days to 3 months) and long-term treatments (> 3 months), LMWHs are preferred over (grade 1A) and should be used for a minimum of 3 months to treat established VTE in patients with cancer (grade 1A). DOAC can be considered for VTE treatment of patients with stable cancer not receiving systemic anticancer therapy, and in cases where VKA is an acceptable, but not an available, treatment choice (guidance).
Pregnancy Pregnancy is associated with major physiological alterations in the coagulation and fibrinolytic systems that aim to maintain placental function and prevent excessive bleeding at delivery [66,67]. These alterations mostly promote a procoagulant state and thus unfortunately enhance the risk of thromboembolism. There is an estimated 4.5-fold increase in thrombotic risk throughout gestation and the postpartum period [67—69] and 22-fold risk in the 6-week period following delivery [67,70]. Pulmonary embolism remains the leading cause of direct maternal deaths in developed countries and accounts for approximately 20% of pregnancyrelated deaths [67,71].
I. Elalamy et al. Treatment with VKA is not recommended during pregnancy, especially in early pregnancy, given the risk of fetopathy, and in late pregnancy, given the risk of bleeding [72,73]. Finally, evidence-based data presented on the website GPR (www.sitegpr.com), which provides information on the Good Clinical Use of Medicines, reports that warfarin and acenocoumarol are not recommended during pregnancy and that heparins, UFH or LMWH, should be preferably used [74]. Concerning breastfeeding, only warfarin and acenocoumarol are authorized. LMWH is the treatment of choice for VTE management during pregnancy on the basis of observational data or registers, despite the absence of any randomized studies [72]. Both UFH and LMWH do not cross the placenta and are not secreted in breast milk. Advantages of LMWH include superior bioavailability (90% vs 30%) longer half-life, once daily dosing, more predictable and stable anticoagulation, thus avoiding the need for laboratory monitoring, a lower incidence of heparin-induced thrombocytopenia (HIT) and fewer allergic reactions [73,75]. Osteopenia and osteoporosis are of less concern with LMWH [73,76], and prospective data suggest that symptomatic osteoporosis occurs in 0.1% of pregnant patients [77]. Only few data are available about the exposition of pregnant women to DOAC since most of the large clinical trial did not include these women (or breastfeeding women). However, 10 patients became pregnant during the edoxaban clinical trial with exposure occurring in the first trimester and lasting about 6 weeks. There were six live births (two preterm), one first trimester spontaneous abortion and three elective pregnancy terminations [78]. Furthermore, two publications reported few cases of pregnant women exposed to rivaroxaban [78,79]. Because of their small size, DOAC can pass easily through the foetal-placental barrier and get into the milk. Apixaban rapidly crosses the ex vivo term human placenta from maternal-to-fetal circulation. Foetal apixaban levels in vivo are estimated to be 35—90% of the corresponding maternal levels [80]. A study reported that there was a rapid transfer of rivaroxaban across the human placenta in both the maternal-to-foetal and foetal-to-maternal directions, as evidenced by transfer ratios of 0.69 and 0.69, respectively [81]. For dabigatran; another study reported that there was a slower transfer of dabigatran with a median fetal-tomaternal concentration ratio was 0.33. Furthermore, the pro-drug (dabigatran etexilate mesylate) had limited placental transfer as characterized by a foetal-to-maternal ratio of 0.17 [82]. A recent review analysed 233 unique cases of pregnancy women exposed to DOAC. They reported that the risk of embryopathy after DOAC exposure seems to be at least not higher than the approximately 7% rate reported for VKA related embryopathy. Currently, the use of DOAC is not recommended during pregnancy and lactation [72,74].
Conclusion Patient vulnerability is rarely the result of a single clinical condition, but more of several combined factors. In these situations, the management of VTE continues to be a delicate balancing act. A strategic choice must be made by
Anticoagulants in frail patients. Seven situations at risk the physician after a careful analysis of all of these factors, taking into account the benefit/risk balance between giving antithrombotic treatment, the risk of VTE and the risk of bleeding, in order to find the optimal treatment for these particularly vulnerable patients.
Disclosure of interest The authors have not supplied their declaration of competing interest.
References [1] Pépion C, Jacob L, Samama C-M. Insuffisance rénale chronique et thrombose. Sang Thrombose Vaisseaux 2003;15:193—201. [2] Ocak G, Vossen CY, Lijfering WM, et al. Role of hemostatic factors on the risk of venous thrombosis in people with impaired kidney function. Circulation 2014;129:683—91. [3] Pepion C, Jacob L, Samama C-M. Insuffisance rénale chronique et syndrome hémorragique. Sang Thrombose Vaisseaux 2003;15:442—8. [4] Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med 2014;370:847—59. [5] Bottger B, Wehling M, Bauersachs RM, et al. Prevalence of renal insufficiency in hospitalised patients with venous thromboembolic events: a retrospective analysis based on 6,725 VTE patients. Thromb Res 2014;134:1014—9. [6] Parikh AM, Spencer FA, Lessard D, et al. Venous thromboembolism in patients with reduced estimated GFR: a populationbased perspective. Am J Kidney Dis 2011;58:746—55. [7] Janus N, Mahé I, Launay-Vacher V, Laroche JP, Deray G. Renal function and venous thromboembolic diseases. J Mal Vasc 2016;41:389—95. [8] Cook LM, Kahn SR, Goodwin J, et al. Frequency of renal impairment, advanced age, obesity and cancer in venous thromboembolism patients in clinical practice. J Thromb Haemost 2007;5:937—41. [9] Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 2011;80:181—9. [10] Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009;20:912—21. [11] Leven C, Hudier L, Picard S, et al. Prospective study of drug-induced interstitial nephritis in eleven French nephrology units. Presse Med 2014;43:e369—76. [12] Kalaitzidis RG, Duni A, Liapis G, et al. Anticoagulant-related nephropathy: a case report and review of the literature of an increasingly recognized entity. Int Urol Nephrol 2017;49:1401—7. [13] Ryan M, Ware K, Qamri Z, et al. Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats. Nephrol Dial Transplant 2014;29:2228—34. [14] Shafi ST, Negrete H, Roy P, et al. A case of dabigatran-associated acute renal failure. Wmj 2013;112, 173—5; quiz 6. [15] Wendte J, Voss G, VanOverschelde B. Influence of apixaban on antifactor Xa levels in a patient with acute kidney injury. Am J Health Syst Pharm 2016;73:563—7. [16] Chan YH, Yeh YH, See LC, et al. Acute kidney injury in Asians with atrial fibrillation treated with dabigatran or warfarin. J Am Coll Cardiol 2016;68:2272—83.
307 [17] Rey J-B, Launay-Vacher V. Utilisation des héparines de bas poids moléculaire (HBPM) chez le patient insuffisant rénal en milieu hospitalier. J Pharm Clin 2011;30:61—74. [18] Bisio A, Vecchietti D, Citterio L, et al. Structural features of low-molecular-weight heparins affecting their affinity to antithrombin. Thromb Haemost 2009;102:865—73. [19] Chan KE, Thadhani RI, Maddux FW. No difference in bleeding risk between subcutaneous enoxaparin and heparin for thromboprophylaxis in end-stage renal disease. Kidney Int 2013;84:555—61. [20] Lai S, Coppola B. Use of enoxaparin in end-stage renal disease. Kidney Int 2013;84:433—6. [21] Atiq F, van den Bemt PM, Leebeek FW, et al. A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency. Eur J Clin Pharmacol 2015;71: 921—9. [22] Gouin-Thibault I, Pautas E, Siguret V. Safety profile of different low-molecular weight heparins used at therapeutic dose. Drug Saf 2005;28:333—49. [23] Geldhof V, Vandenbriele C, Verhamme P, et al. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J 2014;12:21. [24] Haute Autorité de Santé. Clinical Practice Guidelines. Nutritional support strategy for protein-energy malnutrition in the elderly; 2007. [25] Bauersachs RM. Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups. Eur J Intern Med 2014;25:600—6. [26] Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17: 1467—507. [27] van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968—75. [28] Levin A, Ben-Artzi M, Beckerman P, et al. Factors associated with bleeding in elderly hospitalized patients treated with enoxaparin sodium: a prospective, open-label, observational study. Drugs Aging 2009;26:77—85. [29] Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141, e24S-e43S. [30] ANSM (Agence nationale de sécurité du médicament et des produits de santé). Les anticoagulants en France en 2014 : état des lieux, synthèse et surveillance; 2014. Available from: http://ansm.sante.fr/content/download/61981/795269/ version/2/file/ANSM-rapport NACOs-avril+2014.pdf. [31] Theuwissen E, Teunissen KJ, Spronk HM, et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: doseresponse relationship in healthy volunteers. J Thromb Haemost 2013;11:1085—92. [32] Ford SK, Misita CP, Shilliday BB, et al. Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios. J Thromb Thrombolysis 2007;24:23—7. [33] McGrath ER, Go AS, Chang Y, et al. Use of oral anticoagulant therapy in older adults with atrial fibrillation after acute ischemic stroke. J Am Geriatr Soc 2017;65:241—8. [34] Donze J, Clair C, Hug B, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med 2012;125:773—8. [35] Haute Autorité de Santé. Evaluation and management of elderly patients at risk of falls; 2009.
308 [36] American Geriatrics Society 2015 Updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227—46. [37] Topaloglu O, Arslan MS, Karakose M, et al. Is there any association between thrombosis and tissue factor pathway inhibitor levels in patients with vitamin D deficiency? Clin Appl Thromb Hemost 2015;21:428—33. [38] Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. Bmj 2009;339:b3692. [39] Jacobs LG, Billett HH, Freeman K, et al. Anticoagulation for stroke prevention in elderly patients with atrial fibrillation, including those with falls and/or early-stage dementia: a single-center, retrospective, observational study. Am J Geriatr Pharmacother 2009;7:159—66. [40] Flaker GC, Pogue J, Yusuf S, et al. Cognitive function and anticoagulation control in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2010;3:277—83. [41] de Rotrou J, Battal-Merlet L, Wenisch E, et al. Relevance of 10-min delayed recall in dementia screening. Eur J Neurol 2007;14:144—9. [42] Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37: 2893—962. [43] Armand-Branger S, Rhalimi M, 3 KM. Aging of the French population and its consequences. J Pharm Clin 2011;30: 159—66. [44] Cecile M, Seux V, Pauly V, et al. Adverse drug events in hospitalized elderly patients in a geriatric medicine unit: study of prevalence and risk factors. Rev Med Interne 2009;30: 393—400. [45] Caldeira D, Costa J, Barra M, et al. How safe is acetaminophen use in patients treated with vitamin K antagonists? A systematic review and meta-analysis. Thromb Res 2015;135: 58—61. [46] Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011;117:1334—49. [47] Khalil J, Bensaid B, Elkacemi H, et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J Surg Oncol 2015;13:204. [48] Scotte F, Rey JB, Launay-Vacher V. Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads. Support Care Cancer 2012;20:3033—42. [49] Farge D, Trujillo-Santos J, Debourdeau P, et al. Fatal events in cancer patients receiving anticoagulant therapy for venous thromboembolism. Medicine (Baltimore) 2015;94:e1235. [50] Søgaard M, Thomsen RW, Bossen KS, et al. The impact of comorbidity on cancer survival: a review. Clin Epidemiol 2013;5:3—29. [51] Chee CE, Ashrani AA, Marks RS, et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 2014;123:3972—8. [52] Akl EA, Kahale L, Barba M, et al. Anticoagulation for the longterm treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2014. Cd006650. [53] Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146—53. [54] Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314:677—86.
I. Elalamy et al. [55] Hull RD, Pineo GF, Brant RF, et al. Self-managed long-term lowmolecular-weight heparin therapy: the balance of benefits and harms. Am J Med 2007;120:72—82. [56] Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342—52. [57] Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764—72. [58] Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 2015;13:2187—91. [59] Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287—97. [60] Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499—510. [61] Posch F, Konigsbrugge O, Zielinski C, et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res 2015;136:582—9. [62] Wells PS, Theberge IA, Bowdridge JC, et al. PO-41 - Rivaroxaban is effective therapy for high risk cancer patients with venous thromboembolic disease. Thromb Res 2016;140:S191—2. [63] Raskob GE, van Es N, Segers A, et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016;3:e379—87. [64] Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015;33:654—6. [65] Farge D, Bounameaux H, Brenner B, et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2016;17:e452—66. [66] Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004;114:409—14. [67] Othman M, McLintock C, Kadir R. Thrombosis and hemostasis related issues in women and pregnancy. Semin Thromb Hemost 2016;42:693—5. [68] Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697—706. [69] Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008;6:632—7. [70] Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2012;156:366—73. [71] Panting-Kemp A, Geller SE, Nguyen T, et al. Maternal deaths in an urban perinatal network, 1992-1998. Am J Obstet Gynecol 2000;183:1207—12. [72] Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141, e691S-e736S. [73] Bauersachs RM. Treatment of venous thromboembolism during pregnancy. Thromb Res 2009;123:S45—50. [74] GPR [Internet]. Bon Usage Clinique du Médicament [26 Juin 2018]. Available from: http://www.sitegpr.com/.
Anticoagulants in frail patients. Seven situations at risk [75] Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy–how safe are they? Curr Opin Obstet Gynecol 2007;19:573—7. [76] Rodger MA, Kahn SR, Cranney A, et al. Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J Thromb Haemost 2007;5:1600—6. [77] Bauersachs RM, Dudenhausen J, Faridi A, et al. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007;98:1237—45. [78] Myers B, Neal R, Myers O, et al. Unplanned pregnancy on a direct oral anticoagulant (Rivaroxaban): A warning. Obstet Med 2016;9:40—2.
309 [79] Konigsbrugge O, Langer M, Hayde M, et al. Oral anticoagulation with rivaroxaban during pregnancy: a case report. Thromb Haemost 2014;112:1323—4. [80] Bapat P, Pinto LS, Lubetsky A, et al. Examining the transplacental passage of apixaban using the dually perfused human placenta. J Thromb Haemost 2016;14:1436—41. [81] Bapat P, Pinto LS, Lubetsky A, et al. Rivaroxaban transfer across the dually perfused isolated human placental cotyledon. Am J Obstet Gynecol 2015;213, 710.e1-6. [82] Bapat P, Kedar R, Lubetsky A, et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2014;123:1256—61.
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
REVIEW
Anticoagulants in frail patients. Seven situations at risk Anticoagulants chez les patients fragiles, sept situations à risque I. Elalamy a, O. Hanon b, G. Deray c,d, V. Launay-Vacher c,d,∗ a
Hematology department, Tenon Hospital, 75020 Paris, France Geriatrics department, Broca Hospital, 75013 Paris, France c Service ICAR, Pitié-Salpêtrière Hospital, 75013 Paris, France d Nephrology department, Pitié-Salpêtrière Hospital, 75013 Paris, France b
Received 18 October 2017; accepted 30 June 2018 Available online 31 July 2018
KEYWORDS Chronic kidney disease; Frailty; Polypharmacy; Cancer; Pregnancy
MOTS CLÉS Insuffisance rénale ; Fragilité ; Polypharmacie ; Cancer ; Grossesse
∗
Summary In the case of venous thromboembolic disease (VTE), physicians are facing more and more difficulties in managing VTE and their treatment in frail patients. These patients could present several risk situations such as: chronic kidney disease (CKD), underweight or malnourished, falls, cognitive impairment, multi-medicated patients, cancer and pregnancy. Guidelines typically recommend anticoagulation. There are multiple challenges in the safe use of anticoagulation in frail patients, including bleeding risk, monitoring and adherence, and polypharmacy. The objective of this review is to explore these at-risk situations and to suggest adequate anticoagulation therapy, when possible, in each of these complex situations. © 2018 Elsevier Masson SAS. All rights reserved.
Résumé En cardiologie et en médecine vasculaire, les médecins sont de plus en plus confrontés aux difficultés de la gestion des évènements thromboemboliques veineux (ETEV) et de leur traitement chez les patients fragiles. En effet, ces patients pourraient présenter au moins une de ces situations à risque : insuffisance rénale chronique (IRC), insuffisance pondérale ou malnutrition, chutes, troubles cognitifs, polymédication, cancer et grossesse. Les recommandations proposent généralement de recourir à des anticoagulants dans le traitement ou la prophylaxie des ETEV. Ainsi, il est nécessaire de prendre en charge ces patients fragiles lors de l’utilisation
Corresponding author. Service ICAR, Pitié-Salpêtrière Hospital, 83, boulevard de l’Hôpital, 75013 Paris, France. E-mail address: [email protected] (V. Launay-Vacher).
https://doi.org/10.1016/j.jdmv.2018.07.003 2542-4513/© 2018 Elsevier Masson SAS. All rights reserved.
Anticoagulants in frail patients. Seven situations at risk
303
des anticoagulants, en tenant compte du risque thrombotique et du risque de saignement, mais également du suivi, de l’observance et de la polymédication. L’objectif de cette revue est d’étudier les risques et la gestion des anticoagulants chez ces patients fragiles. © 2018 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Introduction The direct oral anticoagulants (DOAC) represent a new era of anticoagulation for patients with venous thromboembolism (VTE). These agents may (or may not) offer advantages to patients in whom the use of traditional anticoagulants is typically challenging. For the medical practitioner, an assessment of the patient’s vulnerability to treatment involves an examination of the clinical situation and the patient profile, together with the monitoring of the thromboembolic and bleeding risk which are intimately linked one to another in the VTE situation. In fact, these situations are often interconnected and seven different types of at risk situations can be described: • • • • • • •
chronic kidney disease (CKD); underweight or malnourished; falls; cognitive impairment; multi-medicated patients; cancer; pregnancy.
For each of these situations, it is necessary to assess the vascular risk, identify different anticoagulant treatment options, and choose the one that seems the more suitable to control the risk of thrombosis and bleeding. Elderly patients often have a combination of these situations (except pregnancy) and this underlines the importance of such a reflexion. This review discusses the main data on the anticoagulant management in each of these seven situations in frail patients.
Seven situations at risk Chronic kidney disease In the situation of renal insufficiency, the physiopathological mechanisms of hemostasis are complex and diverse and they lead to an imbalance coagulation/fibrinolysis equilibrium involving oxidative stress and inflammation [1—4]. Patients with renal insufficiency have a higher risk of both venous thrombosis, and bleeding [5,6]. This cumulative over-risk represents a two-fold constraint, making an anticoagulation treatment difficult to manage in CKD patients [7]. At least one third of the patients with MTEV have a moderate renal insufficiency and between 5 and 10% have a severe renal insufficiency [5,8].
In such a situation, risk management with vitamin K antagonists (VKA) is detrimental to the patient’s health [9] leading to an increased risk of bleeding [10]. Furthermore, interstitial nephritis and glomerular bleeding induced by VKA have been reported [9]. In a small French study on 24 patients, 33.3% of the acute interstitial nephritis cases were attributed to VKAs [11]. The anticoagulant-related nephropathy is associated with CKD and increased mortality. It was initially named ‘‘warfarinrelated nephropathy’’ as warfarin has been the only available and commonly used oral anticoagulant until recently [12]. Nevertheless, the term currently used is anticoagulant-related nephropathy, since DOAC have been also associated with episodes of glomerular haematuria and acute kidney injury as well [13—15]. However, an Asian study reported that among AF patients, dabigatran was associated with a lower risk of acute kidney failure than warfarin [16]. Consequently, it seems premature to use the term of anticoagulant-related nephropathy. For heparins, there is a fundamental relationship between their structure and how they act. The longer polysaccharide chains are eliminated by the reticuloendothelial system whereas the shorter chains are eliminated via the renal pathways [17]. Low molecular weight heparins (LMWH) are a very heterogeneous group and it is important to take their composition into account [17,18]. Because of its smaller molecular mass, enoxaparin binds less to plasma proteins, macrophages, and endothelial cells, thereby conferring a more reliable dose—response relationship and longer plasma half-life when compared with unfractionated heparin (UFH) [19,20]. Several studies have highlighted the risk of accumulation in patients with kidney failure as a function of the molecular weight of the polysaccharide chains in the LMWHs. LMWHs with short chains are essentially eliminated through the urine and those with long chains pass through the reticuloendothelial system. These studies have shown that this accumulation does not take place with every type of LMWH. This has the potential to increase the risk of bleeding depending on the clinical context and therapy chosen [17]. In fact, the use of LMWHs with short polysaccharide chains, in both curative and prophylactic doses, showed an increased risk of bleeding in patients with kidney failure, whereas this was not found to be the case with LMWH with long polysaccharide chains [21,22]. The clinical value of DOAC in VTE patients has been demonstrated in large randomized trials, compared to warfarin [23]. In this meta-analysis from four phase III trials, the elderly populations represented 12 to 18% of the total
304 population and CKD patients represented 5 to 8% of the total populations. In elderly patients (more than 75 years old), a meta-analysis showed a 45% reduction in thrombosis and a 61% reduction in serious bleeding. In CKD patients, these benefits were pointing in the same direction but were not statistically significant due to the lower number of patients with such a profile [23]. In cases of patients with moderate CKD, the dose of DOAC should be adjusted for patients with AF, but this has not been confirmed in cases of VTE as these reduced doses have not been studied.
The underweight, malnourished patient Malnutrition is common in the elderly. It affects 30 to 60% of hospitalized elderly patients. It is defined by a weight loss of at least 10% in six months (or 5% in a month), and a serum albumin of less than 35 g/L or a body mass index of under 21 kg/m2 [24]. Oral anticoagulants, particularly VKA, and to a lesser extent, DOAC, bind to plasma proteins and specially to albumin [25]. This can potentially influence their bioavailability and increase the risk of all bleeding in cases of hypoalbuminaemia in VKA patients (OR = 1.95; 95%CI = 1.17—3.25) [26]. Monitoring the INR should be considered for these patients in order to reduce the risk of overdose. Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45—0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant non-major bleeding occurred significantly less in DOAC recipients [27]. However, depending on the molecule under consideration, plasma protein binding ranges from 34 to 93% [25]. A study with 156 elderly patients, treated with 0.61—1.1 mg/kg/12 h enoxaparin sodium, showed that minor or major bleeding was observed in 5.8% of these patients. The results suggest that low bodyweight is associated with a higher risk of bleeding (≤ 55 kg, OR = 5.63) [28]. Therefore, testing for malnutrition is important in the care of elderly patients being treated with anticoagulants in order to adjust the dose appropriately and in order to monitor the level of anticoagulation [29]. The vitamin K intake, from the diet or as a dietary supplement, may interfere with the INR and complicate its stabilization [30—32].
Falls Any fall naturally increases the risk of bleeding when using antithrombotics, whether they are anticoagulant or antiplatelet types. For this reason, fall risk was found to be one of the leading physician reasons (26.7%) for not prescribing anticoagulants [33]. However, the benefit/risk balance for anticoagulants remains favourable in the patient who has suffered from a fall [34]. A systematic and comprehensive assessment of the risk of fall should be carried out to identify any treatable factors and to search for known risk factor of falls [35]. The signs of seriousness related to the consequences of the fall are: rhabdomyolysis, hypothermia, pressure sore, significant fractures and also those that have had a high number of falls (> 2 falls a year) without any curable factor being identified [35]. Furthermore, several drugs at risk of fall
I. Elalamy et al. have been identified in the elderly, such as anticonvulsants, antipsychotics. . . [36]. Vitamin D has been shown to play a role in thrombosis via hemostatic factors like the tissue factor pathway inhibitor [37]. Doses of 700 IU to 1000 IU supplemental vitamin D a day could reduce falls by 19% or by up to 26% [38]. However; the clinical use of vitamin D doses below 700 IU a day for the prevention of falls among older individuals is not effective. A 25(OH)D concentration of at least 60 nmol/L is required for fall prevention; therefore, a daily intake of at least 700 IU supplemental vitamin D is warranted in all individuals aged 65 and older [38]. Notably, good adherence is essential for the effect of vitamin D on falls. Furthermore, it is possible that greater benefits may be achieved with the use of vitamin D3 instead of vitamin D2 [38].
Cognitive impairment Dementia is associated with increased mortality in AF patients [39]. Several studies have clearly established the fact that cognitive impairment increases the risk of thromboembolic and bleeding [40]. In case of cognitive impairment, the patient can: • forget to take their treatment, risking a recurrence of thrombosis; • take the treatment more than once (having forgotten that they have already taken it) thereby exposing themselves to overdosage and to a risk of bleeding complications. Therefore, it is very important to identify patients with cognitive disorders. The classic test is the Mini-Mental State Examination (MMSE) [40]. However, this test has thirty questions and takes a long time to complete. Consequently, it is not used very much in practice. The Memory Impairment Screen (MIS) test is simpler and faster [41]. The patient must try to remember four words written on a sheet of paper (for example, mackerel, onion, rose, willow). After being shown the list of words, they are asked to return it ten minutes later [41]. If the patient cannot recall a word, he can be offered a clue to help them (‘‘tree’’ for willow or ‘‘fish’’ for mackerel). If they cannot remember the word despite being given the clue, they may potentially have cognitive impairment. The presence of a cognitive disorder is not a contraindication for anticoagulation treatment because the considerable stroke risk without oral anticoagulants often exceeds the bleeding risk of oral anticoagulants in patients with cognitive dysfunction [42]. However, it is necessary to closely monitor the patient’s drug intake. For example, it is possible to ask someone else to check that the medicine is being taken properly. Using a pill organizer is a practical method and it could be filled weekly. Regular checks by a nurse, especially if LMWH are being injected or tablets are being taken orally, is the best option to make sure the treatment is being followed properly. Regarding the choice of anticoagulants in patients with cognitive disorders, all treatment options (VKA, DOAC, LMWH) are possible, with help from a third party. Regular
Anticoagulants in frail patients. Seven situations at risk visits by a nurse to the patient’s home are the best way to ensure that the anticoagulation medication is being taken properly.
305 use several agents that alter haemostasis, whatever it is a pharmacological or an adverse effect.
Cancer The multi-medicated patient Elderly patients are frequently in a situation involving multiple diseases and polypharmacy [43]. Median drug intake increases with age, from 3.3 drugs at 65—74 years, to 4 drugs at 75—84 years, and finally to 4.6 for patients over 85 years [44]. Because many drugs could potentially interfere with VKA treatment, the probability of a drug—drug interaction is heavily increased in polypharmacy patients. Paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs can alter the INR and increase the risk of bleeding [36,45]. Search for a medication by paracetamol or nonsteroidal anti-inflammatory drugs may explain an INR unbalance in case of an auto-medication by these drugs. Paracetamol still remains the standard medication for pain and fever in patients taking an anticoagulant treatment. Postmarketing data has reported few isolated cases of elevated INR of clinical significance during concomitant of treat® ment of warfarin and esomeprazole (EMA, Nexium SmPC, www.ema.europa.eu). Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarin derivatives. With DOAC, there are fewer drug—drug interactions than with VKAs. Only powerful metabolic pathway inhibitors such as hepatic cytochromes should be checked [26]. CYP3A4 is involved in rivaroxaban and apixaban hepatic metabolism. Strong CYP3A4 inhibition or induction may affect plasma concentrations and efficacy or safety. Non-renal clearance of apixaban is diverse (metabolism, biliary excretion, and direct excretion into the intestine), with a moderate contribution of CYP3A4, which makes CYP3A4 interactions of less importance for this drug. Liver metabolism involving CYP3A4 is minimal for edoxaban and null for dabigatran [26]. These two drugs are therefore theoretically less exposed to drug interactions with CYP3A4. Furthermore, an important interaction mechanism for all DOAC consists of significant re-secretion over a Pglycoprotein (P-gp) transporter after absorption in the gut. Moreover, the P-gp transporter may also be involved in renal clearance: competitive inhibition of this pathway will therefore result in increased plasma levels. Indeed, several drugs used in AF patients are P-gp inhibitors (verapamil, dronedarone, amiodarone, quinidine. . .) [26]. In summary, co-medication management with DOAC appears to be less restrictive than with VKA, but it is important to remain cautious with molecules that use the hepatic cytochrome pathways and P-gp. For LMWH, this problem clearly appears to be less significant. Given the elimination pathways of LMWH, the risk from co-medication is much lower since they do not use P-gp and cytochrome systems. In all cases, it is important to minimize the duration of the association between anticoagulant and antiplatelet drugs that simultaneously inhibit the pathways of both primary haemostasis and actual plasma coagulation, increasing the risk of clinical bleeding. Finally, it is important not to
Cancer patients are more exposed to VTE [46]. In fact, 20% of all VTE cases occur in patients with cancer [46]. In addition, VTE can affect up to 20% of patients with cancer, but it has been reported in up to half of cancer patients coming to post-mortem examination, highlighting the fact that the true extent of this complication may be underestimated [46]. The pathophysiology of thrombosis associated with cancer is complex. Cancer patients have a prothrombotic state resulting from the synergic activity of factors involved in the so-called Virchow’s triad: • stasis of the blood caused by bed rest or by tumour compression; • vascular injury caused by intravasation of cancer cells, drugs, or therapeutic devices; • blood hypercoagulability due to the release of cancer cell pro-coagulant factors, which affect the haemostasis process, including platelet functions and clotting cascade [47]. There were several risk factors of VTE related to the tumour (fast growing, biologically aggressive tumours, primary site of cancer, metastatic disease at the time of diagnosis. . .), the patient (elderly, chronic co-morbidities. . .) and the treatments (recent major surgery, long-term central venous catheters. . .) [48]. Furthermore, cancer patients had a high incidence of fatal recurrent pulmonary embolism or fatal bleeding [49]. VTE was also found to be a risk factor of mortality in cancer patients [50]. In fact, survival was particularly poor when the diagnosis of cancer was concurrent with VTE and when cancer was diagnosed within 1 year after an episode of primary VTE [50]. Furthermore, the adjusted 10-year cumulative VTE recurrence rate in active cancer patients was 28.6% and the cumulative incidence of first VTE recurrence was also higher in patients with active cancer than patients without [51]. Finally, VTE was reported to be the second most common cause of death in cancer patients [46,48]. The efficacy of VKA in reducing the risk of thrombosis in cancer patients is half that of LMWHs, with no improvement in controlling the risk of bleeding [52]. The CLOT study [53] reported no significant difference between dalteparin and VKA in the rates of major bleeding, any bleeding, and mortality at six months. These trends were confirmed in the CATCH study [54] which reported similar recurrent VTE rates, major bleeding, and overall mortality between tinzaparin and VKA. However, in the LITE study [55], cancer patients receiving tinzaparin had less recurrent VTE and haemorrhagic complications compared with VKA. A number of clinical studies have compared the efficacy of different types of ACG treatments in cancer patients. The RECOVER studies [56,57] showed no significant difference between dabigatran and warfarin for cancer patients at baseline. In the AMPLIFY trial [58], recurrent VTE and major bleeding were not statistically different between
306 apixaban and enoxaparin/warfarin. The EINSTEIN studies [59,60] showed similar recurrent VTE and major bleeding for rivaroxaban and warfarin patients [61], and rivaroxaban has been suggested as an acceptable therapy in cancer patients [62]. Additionally, the HOKUZAI trial showed less frequent occurrence of VTE with edoxaban compared to warfarin (4% vs 7%, P = 0.0007), less clinically relevant bleeding (12% vs 19%, P = 0.017), and similar major bleeding rates (3%) [63]. A meta-analysis [61] reported that, comparing DOAC to VKA, the relative risks were non-significantly in favour of DOAC for both recurrent VTE and major bleeding. An indirect comparison of LMWH and DOAC shows that DOAC were not more efficient (recurrent VTE) than LMWH in cancer patients and were not more at risk of major bleeding [61]. The American Society of Clinical Oncology recommends LMWH over UFH for the initial 5 to 10 days of anticoagulation for the cancer patient with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance < 30 mL/min). For long-term anticoagulation, LMWH for at least 6 months is preferred due to improved efficacy over VKA. However, VKA are an acceptable alternative for long-term therapy if LMWH is not available. Anticoagulation with LMWH or VKA beyond the initial 6 months may be considered for select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. The use of DOAC for either prevention or treatment of VTE in cancer patients is not recommended [64]. The International Initiative on Thrombosis and Cancer [65] recommends LMWH for the initial treatment of established VTE (first 10 days) in patients with cancer (grade 1B). They further state that LMWH is easier to use than unfractionated heparin and that once-per-day regimen of LMWH is recommended, unless a twice-per-day regimen is required because of patient characteristics. Fondaparinux and UFH can also be used for the initial treatment of established VTE in patients with cancer, but there is a lower level of evidence (grade 2D), and fondaparinux is easier to use than UFH. For the early maintenance (10 days to 3 months) and long-term treatments (> 3 months), LMWHs are preferred over (grade 1A) and should be used for a minimum of 3 months to treat established VTE in patients with cancer (grade 1A). DOAC can be considered for VTE treatment of patients with stable cancer not receiving systemic anticancer therapy, and in cases where VKA is an acceptable, but not an available, treatment choice (guidance).
Pregnancy Pregnancy is associated with major physiological alterations in the coagulation and fibrinolytic systems that aim to maintain placental function and prevent excessive bleeding at delivery [66,67]. These alterations mostly promote a procoagulant state and thus unfortunately enhance the risk of thromboembolism. There is an estimated 4.5-fold increase in thrombotic risk throughout gestation and the postpartum period [67—69] and 22-fold risk in the 6-week period following delivery [67,70]. Pulmonary embolism remains the leading cause of direct maternal deaths in developed countries and accounts for approximately 20% of pregnancyrelated deaths [67,71].
I. Elalamy et al. Treatment with VKA is not recommended during pregnancy, especially in early pregnancy, given the risk of fetopathy, and in late pregnancy, given the risk of bleeding [72,73]. Finally, evidence-based data presented on the website GPR (www.sitegpr.com), which provides information on the Good Clinical Use of Medicines, reports that warfarin and acenocoumarol are not recommended during pregnancy and that heparins, UFH or LMWH, should be preferably used [74]. Concerning breastfeeding, only warfarin and acenocoumarol are authorized. LMWH is the treatment of choice for VTE management during pregnancy on the basis of observational data or registers, despite the absence of any randomized studies [72]. Both UFH and LMWH do not cross the placenta and are not secreted in breast milk. Advantages of LMWH include superior bioavailability (90% vs 30%) longer half-life, once daily dosing, more predictable and stable anticoagulation, thus avoiding the need for laboratory monitoring, a lower incidence of heparin-induced thrombocytopenia (HIT) and fewer allergic reactions [73,75]. Osteopenia and osteoporosis are of less concern with LMWH [73,76], and prospective data suggest that symptomatic osteoporosis occurs in 0.1% of pregnant patients [77]. Only few data are available about the exposition of pregnant women to DOAC since most of the large clinical trial did not include these women (or breastfeeding women). However, 10 patients became pregnant during the edoxaban clinical trial with exposure occurring in the first trimester and lasting about 6 weeks. There were six live births (two preterm), one first trimester spontaneous abortion and three elective pregnancy terminations [78]. Furthermore, two publications reported few cases of pregnant women exposed to rivaroxaban [78,79]. Because of their small size, DOAC can pass easily through the foetal-placental barrier and get into the milk. Apixaban rapidly crosses the ex vivo term human placenta from maternal-to-fetal circulation. Foetal apixaban levels in vivo are estimated to be 35—90% of the corresponding maternal levels [80]. A study reported that there was a rapid transfer of rivaroxaban across the human placenta in both the maternal-to-foetal and foetal-to-maternal directions, as evidenced by transfer ratios of 0.69 and 0.69, respectively [81]. For dabigatran; another study reported that there was a slower transfer of dabigatran with a median fetal-tomaternal concentration ratio was 0.33. Furthermore, the pro-drug (dabigatran etexilate mesylate) had limited placental transfer as characterized by a foetal-to-maternal ratio of 0.17 [82]. A recent review analysed 233 unique cases of pregnancy women exposed to DOAC. They reported that the risk of embryopathy after DOAC exposure seems to be at least not higher than the approximately 7% rate reported for VKA related embryopathy. Currently, the use of DOAC is not recommended during pregnancy and lactation [72,74].
Conclusion Patient vulnerability is rarely the result of a single clinical condition, but more of several combined factors. In these situations, the management of VTE continues to be a delicate balancing act. A strategic choice must be made by
Anticoagulants in frail patients. Seven situations at risk the physician after a careful analysis of all of these factors, taking into account the benefit/risk balance between giving antithrombotic treatment, the risk of VTE and the risk of bleeding, in order to find the optimal treatment for these particularly vulnerable patients.
Disclosure of interest The authors have not supplied their declaration of competing interest.
References [1] Pépion C, Jacob L, Samama C-M. Insuffisance rénale chronique et thrombose. Sang Thrombose Vaisseaux 2003;15:193—201. [2] Ocak G, Vossen CY, Lijfering WM, et al. Role of hemostatic factors on the risk of venous thrombosis in people with impaired kidney function. Circulation 2014;129:683—91. [3] Pepion C, Jacob L, Samama C-M. Insuffisance rénale chronique et syndrome hémorragique. Sang Thrombose Vaisseaux 2003;15:442—8. [4] Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med 2014;370:847—59. [5] Bottger B, Wehling M, Bauersachs RM, et al. Prevalence of renal insufficiency in hospitalised patients with venous thromboembolic events: a retrospective analysis based on 6,725 VTE patients. Thromb Res 2014;134:1014—9. [6] Parikh AM, Spencer FA, Lessard D, et al. Venous thromboembolism in patients with reduced estimated GFR: a populationbased perspective. Am J Kidney Dis 2011;58:746—55. [7] Janus N, Mahé I, Launay-Vacher V, Laroche JP, Deray G. Renal function and venous thromboembolic diseases. J Mal Vasc 2016;41:389—95. [8] Cook LM, Kahn SR, Goodwin J, et al. Frequency of renal impairment, advanced age, obesity and cancer in venous thromboembolism patients in clinical practice. J Thromb Haemost 2007;5:937—41. [9] Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 2011;80:181—9. [10] Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009;20:912—21. [11] Leven C, Hudier L, Picard S, et al. Prospective study of drug-induced interstitial nephritis in eleven French nephrology units. Presse Med 2014;43:e369—76. [12] Kalaitzidis RG, Duni A, Liapis G, et al. Anticoagulant-related nephropathy: a case report and review of the literature of an increasingly recognized entity. Int Urol Nephrol 2017;49:1401—7. [13] Ryan M, Ware K, Qamri Z, et al. Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats. Nephrol Dial Transplant 2014;29:2228—34. [14] Shafi ST, Negrete H, Roy P, et al. A case of dabigatran-associated acute renal failure. Wmj 2013;112, 173—5; quiz 6. [15] Wendte J, Voss G, VanOverschelde B. Influence of apixaban on antifactor Xa levels in a patient with acute kidney injury. Am J Health Syst Pharm 2016;73:563—7. [16] Chan YH, Yeh YH, See LC, et al. Acute kidney injury in Asians with atrial fibrillation treated with dabigatran or warfarin. J Am Coll Cardiol 2016;68:2272—83.
307 [17] Rey J-B, Launay-Vacher V. Utilisation des héparines de bas poids moléculaire (HBPM) chez le patient insuffisant rénal en milieu hospitalier. J Pharm Clin 2011;30:61—74. [18] Bisio A, Vecchietti D, Citterio L, et al. Structural features of low-molecular-weight heparins affecting their affinity to antithrombin. Thromb Haemost 2009;102:865—73. [19] Chan KE, Thadhani RI, Maddux FW. No difference in bleeding risk between subcutaneous enoxaparin and heparin for thromboprophylaxis in end-stage renal disease. Kidney Int 2013;84:555—61. [20] Lai S, Coppola B. Use of enoxaparin in end-stage renal disease. Kidney Int 2013;84:433—6. [21] Atiq F, van den Bemt PM, Leebeek FW, et al. A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency. Eur J Clin Pharmacol 2015;71: 921—9. [22] Gouin-Thibault I, Pautas E, Siguret V. Safety profile of different low-molecular weight heparins used at therapeutic dose. Drug Saf 2005;28:333—49. [23] Geldhof V, Vandenbriele C, Verhamme P, et al. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J 2014;12:21. [24] Haute Autorité de Santé. Clinical Practice Guidelines. Nutritional support strategy for protein-energy malnutrition in the elderly; 2007. [25] Bauersachs RM. Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups. Eur J Intern Med 2014;25:600—6. [26] Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17: 1467—507. [27] van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968—75. [28] Levin A, Ben-Artzi M, Beckerman P, et al. Factors associated with bleeding in elderly hospitalized patients treated with enoxaparin sodium: a prospective, open-label, observational study. Drugs Aging 2009;26:77—85. [29] Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141, e24S-e43S. [30] ANSM (Agence nationale de sécurité du médicament et des produits de santé). Les anticoagulants en France en 2014 : état des lieux, synthèse et surveillance; 2014. Available from: http://ansm.sante.fr/content/download/61981/795269/ version/2/file/ANSM-rapport NACOs-avril+2014.pdf. [31] Theuwissen E, Teunissen KJ, Spronk HM, et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: doseresponse relationship in healthy volunteers. J Thromb Haemost 2013;11:1085—92. [32] Ford SK, Misita CP, Shilliday BB, et al. Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios. J Thromb Thrombolysis 2007;24:23—7. [33] McGrath ER, Go AS, Chang Y, et al. Use of oral anticoagulant therapy in older adults with atrial fibrillation after acute ischemic stroke. J Am Geriatr Soc 2017;65:241—8. [34] Donze J, Clair C, Hug B, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med 2012;125:773—8. [35] Haute Autorité de Santé. Evaluation and management of elderly patients at risk of falls; 2009.
308 [36] American Geriatrics Society 2015 Updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227—46. [37] Topaloglu O, Arslan MS, Karakose M, et al. Is there any association between thrombosis and tissue factor pathway inhibitor levels in patients with vitamin D deficiency? Clin Appl Thromb Hemost 2015;21:428—33. [38] Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. Bmj 2009;339:b3692. [39] Jacobs LG, Billett HH, Freeman K, et al. Anticoagulation for stroke prevention in elderly patients with atrial fibrillation, including those with falls and/or early-stage dementia: a single-center, retrospective, observational study. Am J Geriatr Pharmacother 2009;7:159—66. [40] Flaker GC, Pogue J, Yusuf S, et al. Cognitive function and anticoagulation control in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2010;3:277—83. [41] de Rotrou J, Battal-Merlet L, Wenisch E, et al. Relevance of 10-min delayed recall in dementia screening. Eur J Neurol 2007;14:144—9. [42] Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37: 2893—962. [43] Armand-Branger S, Rhalimi M, 3 KM. Aging of the French population and its consequences. J Pharm Clin 2011;30: 159—66. [44] Cecile M, Seux V, Pauly V, et al. Adverse drug events in hospitalized elderly patients in a geriatric medicine unit: study of prevalence and risk factors. Rev Med Interne 2009;30: 393—400. [45] Caldeira D, Costa J, Barra M, et al. How safe is acetaminophen use in patients treated with vitamin K antagonists? A systematic review and meta-analysis. Thromb Res 2015;135: 58—61. [46] Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011;117:1334—49. [47] Khalil J, Bensaid B, Elkacemi H, et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J Surg Oncol 2015;13:204. [48] Scotte F, Rey JB, Launay-Vacher V. Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads. Support Care Cancer 2012;20:3033—42. [49] Farge D, Trujillo-Santos J, Debourdeau P, et al. Fatal events in cancer patients receiving anticoagulant therapy for venous thromboembolism. Medicine (Baltimore) 2015;94:e1235. [50] Søgaard M, Thomsen RW, Bossen KS, et al. The impact of comorbidity on cancer survival: a review. Clin Epidemiol 2013;5:3—29. [51] Chee CE, Ashrani AA, Marks RS, et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 2014;123:3972—8. [52] Akl EA, Kahale L, Barba M, et al. Anticoagulation for the longterm treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2014. Cd006650. [53] Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146—53. [54] Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314:677—86.
I. Elalamy et al. [55] Hull RD, Pineo GF, Brant RF, et al. Self-managed long-term lowmolecular-weight heparin therapy: the balance of benefits and harms. Am J Med 2007;120:72—82. [56] Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342—52. [57] Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764—72. [58] Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 2015;13:2187—91. [59] Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287—97. [60] Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499—510. [61] Posch F, Konigsbrugge O, Zielinski C, et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res 2015;136:582—9. [62] Wells PS, Theberge IA, Bowdridge JC, et al. PO-41 - Rivaroxaban is effective therapy for high risk cancer patients with venous thromboembolic disease. Thromb Res 2016;140:S191—2. [63] Raskob GE, van Es N, Segers A, et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016;3:e379—87. [64] Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015;33:654—6. [65] Farge D, Bounameaux H, Brenner B, et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2016;17:e452—66. [66] Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004;114:409—14. [67] Othman M, McLintock C, Kadir R. Thrombosis and hemostasis related issues in women and pregnancy. Semin Thromb Hemost 2016;42:693—5. [68] Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697—706. [69] Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008;6:632—7. [70] Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2012;156:366—73. [71] Panting-Kemp A, Geller SE, Nguyen T, et al. Maternal deaths in an urban perinatal network, 1992-1998. Am J Obstet Gynecol 2000;183:1207—12. [72] Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141, e691S-e736S. [73] Bauersachs RM. Treatment of venous thromboembolism during pregnancy. Thromb Res 2009;123:S45—50. [74] GPR [Internet]. Bon Usage Clinique du Médicament [26 Juin 2018]. Available from: http://www.sitegpr.com/.
Anticoagulants in frail patients. Seven situations at risk [75] Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy–how safe are they? Curr Opin Obstet Gynecol 2007;19:573—7. [76] Rodger MA, Kahn SR, Cranney A, et al. Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J Thromb Haemost 2007;5:1600—6. [77] Bauersachs RM, Dudenhausen J, Faridi A, et al. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007;98:1237—45. [78] Myers B, Neal R, Myers O, et al. Unplanned pregnancy on a direct oral anticoagulant (Rivaroxaban): A warning. Obstet Med 2016;9:40—2.
309 [79] Konigsbrugge O, Langer M, Hayde M, et al. Oral anticoagulation with rivaroxaban during pregnancy: a case report. Thromb Haemost 2014;112:1323—4. [80] Bapat P, Pinto LS, Lubetsky A, et al. Examining the transplacental passage of apixaban using the dually perfused human placenta. J Thromb Haemost 2016;14:1436—41. [81] Bapat P, Pinto LS, Lubetsky A, et al. Rivaroxaban transfer across the dually perfused isolated human placental cotyledon. Am J Obstet Gynecol 2015;213, 710.e1-6. [82] Bapat P, Kedar R, Lubetsky A, et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2014;123:1256—61.