Optimizing the Use of Anticoagulants (Heparins and Oral Anticoagulants) in the Elderly

Drugs Aging (2013) 30:687 699 DOI 10.1007/s40266-013-0101-0 REVIEW ARTICLE Optimizing the Use of Anticoagulants (Heparins and Oral Anticoagulants) in the Elderly Virginie Siguret Isabelle Gouin-Thibault Pascale Gaussem Eric Pautas Published online: 25 July 2013 Ó Springer International Publishing Switzerland 2013 Abstract As longevity constantly increases, the number of elderly patients (75 years and older) who require anticoagulation likewise rises steadily. Managing elderly patients receiving anticoagulants is challenging because those patients are at high risk of both thrombosis and bleeding. Moreover, older patients are commonly frail: they have substantial chronic co-morbid conditions including renal impairment and frequent acute illnesses and are often polymedicated. There remains a clear need to optimize the use of anticoagulant drugs in these patients, especially at full anticoagulant dose. In the last decade, efforts have been made to better understand the interindividual variability in the response of elderly patients to traditional anticoagulants including heparin derivatives (unfractionated heparin, low molecular weight heparins and fondaparinux) and vitamin K antagonists. Moreover, their safety profile has been evaluated in different settings in the elderly, assisting in minimizing risks related to their V. Siguret (&) I. Gouin-Thibault P. Gaussem E. Pautas Université Paris Descartes, Sorbonne Paris Cité, Paris, France e-mail: virginie.siguret@parisdescartes.fr V. Siguret I. Gouin-Thibault P. Gaussem E. Pautas INSERM UMR-S765, 4 avenue de l Observatoire, Paris, France V. Siguret P. Gaussem Service d Hématologie biologique, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France I. Gouin-Thibault Service d Hématologie biologique, Assistance Publique Hôpitaux de Paris, GH Cochin-Hôtel-Dieu, Paris, France E. Pautas Unité de gériatrie aiguë, Assistance Publique Hôpitaux de Paris, GH Pitié-Salpêtrière-Charles Foix, Ivry-sur-Seine, France use. Emergence of new oral anticoagulants (dabigatran, rivaroxaban, apixaban), which appear to be much more convenient, is promising. Even though some elderly patients were included in pivotal clinical trials evaluating these new anticoagulants, the safety of these drugs remains uncertain in real life. 1 Introduction The risk of thromboembolic disease increases with advancing age: annual incidence of venous thromboembolism (VTE) reaches 1 % in patients aged 75 years and above; prevalence of atrial fibrillation (AF) exceeds 10 % in octogenarians [1 3]. In addition, advanced age is associated with a high risk of acute coronary syndromes (ACS) [4]. As populations age, the number of elderly patients (75 years and older) who require anticoagulation rises steadily. Managing elderly patients receiving anticoagulants is challenging because those patients are at high risk of both thrombosis and bleeding [5] and anticoagulants have a narrow therapeutic index. Moreover, older patients are commonly frail: they have substantial chronic comorbid conditions, frequent acute illnesses and, consequently, take numerous medications. Among co-morbid conditions, renal insufficiency is highly prevalent, affecting more than 75 % of patients [75 years, potentially leading to accumulation and overdosage of renally cleared anticoagulant drugs [6]. Cognitive impairment is also common amongst elderly patients, hampering their participation in clinical studies. Because of those impairments and for many other reasons, frail elderly patients have been largely excluded from clinical trials when in fact they are the very population most likely to benefit from these drugs. In epidemiological surveys, anticoagulant drugs still appear as

688 V. Siguret et al. the first cause of drug-related adverse events and advanced age consistently emerges as one of the main determinants of bleeding complications [7]. Thus, there is a clear need to optimize the use of anticoagulant drugs in the frail elderly, and prescribers must be aware of this special concern. In the present paper, we will focus on anticoagulant drugs used at therapeutic dose since bleeding complications are more frequent and severe than those observed at prophylactic dose. Besides traditional anticoagulants including unfractionated heparin (UFH), low molecular weight heparins (LMWH), fondaparinux and vitamin K antagonists (VKA), new oral anticoagulants (NOA) have been recently marketed for the prophylaxis and management of thromboembolic disease in many countries [8]. Even though many elderly patients were included in pivotal clinical trials, the safety of these new drugs remains uncertain in the real life. A search was conducted on MEDLINE between 1998 and 2012 for articles containing the keywords elderly, aging, heparin, LMWH, vitamin K antagonist and oral anticoagulant. Studies published in English that included patients [75 years of age or analysed a subset of patients [75 years of age were selected. 2 Estimation of Renal Function in the Elderly Receiving Anticoagulant Drugs The estimation of renal function is of major importance in the elderly before making decisions on an anticoagulant treatment option, especially including a heparin derivative or an NOA. Moreover, re-evaluating renal function in special situations and at least once a year should be considered since renal function may worsen throughout acute illnesses and improve when the acute episode is over. In addition, many concomitant medications have the potential to be nephrotoxic. Taking into account serum creatinine level alone is unreliable in estimating renal function in the elderly and therefore creatinine clearance (CrCl) is preferred [9]. Different equations assessing estimated glomerular filtration rate have been developed in the last decade. However, none of the commonly used formulas have been validated in patients over 75 years [10 14]. Thus, an important issue is to decide which formula could be the most appropriate for CrCl calculation when initiating anticoagulant drugs in the frail elderly. The Cockcroft Gault formula (CG CrCl) [10] has been consistently used in clinical trials evaluating LMWH or NOA. Patients with severe renal impairment were excluded from clinical trials with LMWH/fondaparinux at therapeutic dose, leading health authorities of some countries to contraindicate the use of LMWH/fondaparinux at therapeutic dose below the CG CrCl threshold of 30 ml/min. More recently, CG CrCl below 30 ml/min has also been an exclusion criterion of most randomized clinical trials evaluating NOA in AF, and CG CrCl was used for dose adjustment of dabigatran, rivaroxaban and apixaban in elderly patients with impaired renal function [15 18]. One must keep in mind that patients with severe renal impairment defined by a CG CrCl below 30 ml/min may represent up to 20 30 % of elderly hospitalized subjects, and those with moderate renal impairment two-thirds of elderly outpatients [6, 13, 14, 19]. In addition, when using the MDRD (Modification of Diet in Renal Disease) Study equation or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-based equation rather than the CG formula to calculate CrCl, prescribers should be aware that CrCl results differ widely in patients over 80 years [6, 13, 14, 19]: CrCl results are consistently higher with MDRD or CKD-EPI as demonstrated in more than 3,000 patients aged over 80 years included in the EPICA study [13]. Finally, CG CrCl has been shown to be a good reflection of frailty in the elderly, taking into account age, serum creatinine and weight [20]. For all these reasons, the CG formula should be preferred to MDRD or CKD-EPI for the prescription of anticoagulants in the elderly. 3 Heparin Derivatives Numerous clinical trials and meta-analyses have confirmed that LMWH and fondaparinux are at least as effective and safe as UFH for initial treatment of acute VTE and in the management of ACS [21, 22]. Thus, in many clinical situations, LMWH have progressively replaced UFH due to a better predictable effect, a longer half-life and as they are easier to use as there is no routine need to monitor the anticoagulant effect. However, one limitation of LMWH use is that they are mainly cleared by the kidneys. There is therefore a risk of overdosing and/or accumulation in elderly patients with severe to moderate renal impairment [23], given that unlike heparin no routine monitoring of anticoagulant effect is necessary. The risk is especially increased when treatment is prolonged, increasing the risk of bleeding [24]. For the synthetic pentasaccharide fondaparinux, excretion is completely renal. So, concerns have been raised about the safety of LMWH and fondaparinux in elderly patients, especially in those with moderate to severe renal impairment. 3.1 Pharmacokinetic/Pharmacodynamic Studies in the Elderly While LMWH were developed in the 1980s, the first pharmacokinetic (PK)/pharmacodynamic (PD) studies

Optimizing the Use of Anticoagulants 689 specifically devoted to the elderly were only conducted in the late 1990s. Studies based on anti-xa activity measurement contributed to show that the PD response, especially the risk of accumulation effect, may differ among LMWH preparations: therefore, LMWH cannot be considered interchangeable (Tables 1, 2) [19, 25 34]. Indeed, high molecular weight (MW) chains are cleared mostly through the reticulo-endothelial system, whereas low MW chains are preferentially cleared by the kidney [24] (Table 2). Thus, the higher proportion of long chains in some LMWH preparations, such as tinzaparin or dalteparin, compared with enoxaparin, bemiparin or nadroparin may account for a lower contribution of the kidney in the elimination process of these compounds, leading to different PK/PD profiles in the elderly/renally impaired (Tables 1, 2). Since fondaparinux is exclusively cleared by the kidney, a bioaccumulation of anti-xa activity has been observed in patients with renal impairment even at low dose [20, 35]. 3.2 Clinical Use of Heparin Derivatives at Therapeutic Dose Numerous clinical observations and observational cohort studies have highlighted factors associated with an increased risk of bleeding in the elderly treated with heparin derivatives in different settings [4, 27, 36 39]: advanced age, degree of renal failure, concomitant use of antiplatelet drugs (aspirin, thienopyridines, non-steroidal anti-inflammatory drugs) or drugs interacting with platelets such as serotonin reuptake inhibitors, very low body weight (\45 kg) and a misuse (dosing errors, absence of recent body weight to calculate the body weight adjusted dose, etc.). Educational interventions to reduce misuse or the concomitant use of interacting drugs may contribute to minimize the bleeding risk of heparin derivatives in the elderly. When the risk of accumulation is a concern, two approaches are considered to optimize the use of LMWH in the elderly: anti-xa monitoring or empiric LMWH dose reduction. In dose-finding studies and in cohort observational studies in ACS patients, it has been demonstrated that very high peak or residual enoxaparin anti-xa activity levels were associated with an increased risk of bleeding [23, 40 43]. However, it is still debated whether there is a clear benefit in anti-xa monitoring regarding LMWH efficacy and safety outcomes, especially in patients with renal impairment [44 46]. In order to detect overdosage at an early stage, some health authorities suggest that LMWH anti-xa activity monitoring be performed in patients who are at risk of accumulation. Similar recommendations have been also proposed by the Ninth Conference of the American College of Chest Physicians (ACCP) in patients with severe renal insufficiency [21]. Of note, if monitoring is considered, appropriate upper thresholds for peak anti- Xa activity levels should be used, unique to each LMWH and on the dose regimen, taking into account the PD profile of each compound [44]. One limitation is that thresholds have not always been validated in terms of clinical outcomes [47]. Alternatively, empirically reducing the dose to 50 % of the recommended dose has also been proposed with a low grade of recommendation for enoxaparin in patients with ACS or VTE with severe renal impairment [21]. However, Montalescot et al. [42] showed that the empirical reduction of the initial enoxaparin dose without systematic monitoring could lead to an anti-xa peak level below 0.5 IU/mL, leading to an increase of the thrombotic risk. No specific recommendations have been made for other LMWH preparations given the lack of sufficient data [21, 23]. In patients with renal insufficiency, the use of UFH is suggested as UFH elimination is less dependent on renal function. However, UFH use is challenging, especially in the elderly. Compared with younger patients, lower UFH Table 1 The chemical and pharmacological characteristics of heparin derivatives UFH Dalteparin Enoxaparin Tinzaparin Nadroparin Bemiparin Fondaparinux Manufacturing process Mean MW [range] (kda) PS side chains [5.4 kda Anti-Xa/anti- IIa activity ratio Extraction from intestine mucosa a Controlled nitrous acid depolymerization a Benzylation followed by alkaline hydrolysis a Controlled heparinase digestion a Controlled nitrous acid depolymerization a Controlled alkaline depolymerization a 15.0 5.8 [5.0 6.0] 4.5 [3.5 5.5] 6.5 [5.8 6.8] 4.5 [4.2 4.8] 3.6 [3.0 4.2] 1.728 Very high Medium Low High Low Very low Null 1.0 2.5 3.6 1.9 3.2 8.1? Chemical synthesis MW molecular weight, PS polysaccharide, UFH unfractionated heparin,? infinity a Heparin is extracted from porcine intestine mucosa

690 V. Siguret et al. Table 2 Pharmocokinetic studies with low molecular weight heparins in the elderly Authors Study type Treatment Subjects Main results LMWH regimen Duration (days) Indication Age (years) [mean ± SD or median (range)] CrCl (ml/min) a [mean ± SD or median (range)] Number Mismetti et al. 1998 [25] Siguret et al. 2000 [26] Pautas et al. 2002 [27] Chow et al. 2003 [28] Tincani et al. 2006 [29] Mahé et al. 2007 [30] Berges et al. 2007 [31] Schmid et al. 2009 [32] Siguret et al. 2011 [33] Dufour et al. 2012 [34] PK, prospective multiple dose PK, prospective Observational cohort Nadroparine 180 IU/kg/24 h Tinzaparin 175 IU/kg/24 h Tinzaparin 175 IU/kg/24 h Prospective Enoxaparin 100 IU/kg/12 h Prospective cohort Dalteparin 2,500 IU/ 24 h or 5,000 IU/ 24 h PK, RCT Enoxaparin 4,000 IU/24 h or tinzaparin 4,500 IU/24 h Population PK Prospective Observational cohort Enoxaparin 4,000 IU/24 h Dalteparin 100 IU/kg/12 h RCT Tinzaparin 175 IU/kg/24 h Cohort Enoxaparin 4,000 IU/24 h 6 10 25 ± 4 (volunteers) 10 VTE Atrial fibrillation 19 ± 10 Venous or arterial TE C2 Venous or arterial TE 65 ± 3 (volunteers) DVT 65 ± 11 (patients) C6 VTE medical prophylaxis C8 VTE medical prophylaxis 7 (mean) VTE prophylaxis C2 Venous or arterial TE 114 ± 15 12 Anti-Xa accumulation: healthy elderly and patients No anti-iia accumulation 62 ± 6 12 Correlation between CrCl and anti-xa activity clearance 71 ± 24 12 87.0 ± 5.9 41 ± 15 30 No increase of the peak anti-xa and anti-iia activities No correlation between peak anti-xa and anti-iia and age, weight or CrCl 85.2 ± 6.9 51 ± 23 200 No correlation between peak anti-xa and CrCl or age 75 (48 89) [60 b 7 Anti-Xa higher in patients with CrCl B30 ml/min 60 31 b 6 than in patients with CrCl [30 ml/min 30 11 b 4 Correlation between anti-xa and CrCl B30 b 1 83 ± 8 \30 12 No evidence of bioaccumulation on day 6 irrespective 30 59 73 of renal function C60 24 87.9 ± 5.5 35 ± 11 55 Anti-Xa accumulation with enoxaparin but not with tinzaparin 82 ± 5 52 ± 17 or 189 Anti-Xa clearance related to body weight and CrCl. No 69 ± 20 b need for anti-xa monitoring at prophylactic dose 73 (58 81) 89 (75 111) 18 Accumulation of dalteparin in severe RI 79 (76 82) 53 (47 57) 9 72 (62 80) 20 (13 25) 5 C5 VTE 83 ± 5 41 (14 59) 87 No peak anti-xa activity accumulation No correlation between the anti-xa accumulation ratio and age, weight or CrCl C2 VTE medical prophylaxis 83.6 ± 7.3 44 ± 19 or 92 Prediction of risk of higher anti-xa levels with 63 ± 23 b Cockcroft Gault but not with MDRD equation CrCl creatinine clearance, DVT deep vein thrombosis, LMWH low molecular weight heparins, MDRD Modification of Diet in Renal Disease, PK pharmacokinetic, RCT randomized controlled trial, RI renal impairment, TE thromboembolism, VTE venous thromboembolism CrCl is calculated using the Cockcroft Gault formula unless otherwise indicated a b CrCl calculated using the MDRD formula

Optimizing the Use of Anticoagulants 691 doses are required to maintain therapeutic levels of anti-xa activity or activated partial thromboplastin time (APTT) [48]. Large intra- and inter-individual variability of the response is observed in elderly patients as a result of binding to acute phase plasma proteins and cellular components. Therefore, at least daily monitoring is mandatory with iterative blood samplings, and frequent dose adjustments are needed to obtain stable anticoagulation (Table 3). Given the numerous drawbacks, LMWH have often been preferred to UFH in the elderly in real life. In the Global Registry of Acute Coronary Events (GRACE) including 6,203 patients aged 75 years and older, a lower utilization of intravenous UFH versus LMWH has been observed in older patients compared with younger patients [4]. The physicians choice has been guided by less frequent monitoring when using LMWH [49, 50]. In the SYNERGY trial, the age subgroup analysis found similar comparative efficacy and safety of enoxaparin and UFH in the oldest subgroup (n = 2,540 with age C75 years) [51]. In elderly patients included in the FAST-MI registry (mean age 82 years), the use of LMWH was found to be associated with less major bleeding and a significantly higher survival compared with the use of UFH [52]. In patients with VTE, the safety profiles of LMWH in the elderly are less well known [27, 37, 38, 53]. The IRIS ( Innohep Ò in Renal Insufficiency Study ) was the first multicentre, randomized controlled trial specifically conducted in elderly patients with moderate-to-severe renal impairment for the initial treatment of acute deep vein thrombosis (DVT) [53]. The primary objective was to compare the safety profile of the full, unadjusted dose of tinzaparin with APTT-adjusted UFH. Based on an imbalance in overall mortality favouring the UFH group in the 350 patients in the interim analysis and a futility consideration, the Data Monitoring Committee recommended that the study should be stopped. The study was closed early, with 539 patients (mean age 83 years) randomized and followed for 90 days as predefined. In summary, there were no differences between the two groups either in the rate of clinically relevant bleedings (11.9 vs. 11.9 %) or in the rate of recurrent VTE (2.6 vs. 1.1 %; p = 0.34). There was a higher rate of deaths in the tinzaparin arm (11.5 vs. 6.3 %; p = 0.035). When the results were adjusted for patient baseline characteristics, mortality was not significantly correlated to treatment group. However, because of the premature termination of the study, the IRIS study remains inconclusive in terms of clinical outcomes [53]. A substudy showed no accumulation of anti-xa activity of tinzaparin at peak level, suggesting no need for systematic anti-xa monitoring in these patients [33]. The high proportion of high MW moieties in tinzaparin may account for its reduced dependence on renal elimination (see Sect. 3.1). No specific data have been published in the very elderly receiving fondaparinux at curative dose [35]. 4 Vitamin K Antagonists In patients older than 75 years, the two main indications for VKA therapy are the treatment of VTE and the prevention of systemic embolism in patients with non-valvular AF: in both indications, a target international normalized ratio (INR) of 2.5 (range 2.0 3.0) is recommended. Although VKA are beneficial in thromboembolic disorders, e.g. with a 68 % relative risk reduction for stroke for patients with AF, they are still underused especially in patients older than 75 years [54, 55]. There are two main reasons for this underuse in this group of age: (1) the management of VKA therapy is complex for both physicians and patients; and (2) major bleeding is a feared adverse effect, especially in frail patients. 4.1 Factors Influencing the Variability of the Response to Vitamin K Antagonists in the Elderly VKA are characterized by a marked inter- and intra-patient variability and many non-genetic and genetic factors have now been identified as influencing the response to VKA, especially assessed by the maintenance dose. First of all, advanced age is associated with a low warfarin maintenance dose, independently of the presence of co-morbid conditions or co-medications. The decrease in the required maintenance dose has been estimated at about 10 % per decade [56, 57]. Indeed, the mean warfarin maintenance dose is around 6 mg in 30-year-old patients versus around 4 mg in 70-year-old patients and &3 mg in octogenarians [58]. Secondly, it has been demonstrated that patients with low body weight, patients with stable co-morbid conditions such as congestive heart failure, liver disease or severe renal failure require lower doses. Furthermore, acute illnesses such as fever, diarrhoea or prolonged fasting may be accompanied by a decrease in the maintenance dose [56, 59]. Thirdly, many medications used in geriatric practice potentiate the VKA dose response: amiodarone, azole antibiotics and antifungal agents, macrolides, quinolones, other antithrombotic agents, non-steroidal anti-inflammatory drugs, including selective cyclo-oxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, and lipid-lowering agents [60]. In surveys conducted in hospitalized patients with a mean age of 85 years, antibiotics, azole antifungal agents and amiodarone were the most often recorded drugs that likely led to the over-anticoagulation [61, 62]. Thus, polypharmacy contributes to the low VKA maintenance dose in these patients and frequent changes in medications make INR results more

692 V. Siguret et al. Table 3 Unfractionated heparin initial regimen in the elderly and laboratory monitoring UFH Initial dose and administration route Time of sampling UFH anti-xa activity (IU/mL) APTT ratio Sodium UFH 400 600 IU/kg/24 h 4 h after the start of infusion 0.3 0.7 1.5 to 3.5 4 according to APTT reagent IV infusion a Calcium UFH 500 IU/kg/24 h Half-course between 2 injections 0.3 0.7 1.5 to 3.5 4 according to APTT reagent 2 or 3 SC injections/24 h a APTT activated partial thromboplastin time, IV intravenous, SC subcutaneous, UFH unfractionated heparin a An initial bolus of 50 IU/kg allows reaching more rapidly efficacious anticoagulation unstable than those observed in younger middle-aged patients [63]. Moreover, when acute illnesses and deterioration in chronic co-morbidities or changes in medication use occur, INR monitoring should be intensified because of the narrow therapeutic index of VKA. The increased sensitivity of older patients to VKA remains poorly understood, not only related to co-morbid conditions or concomitant medications: it could be explained on the basis of age-related PK changes, such as modifications in hepatic drug metabolism, especially due to lower blood flow (which is difficult to evaluate). Changes in body composition with advancing age (relative lipid content increases and total body water and lean body mass decreases) can also affect drug PK parameters [64]. Even though numerous acquired factors contribute to lower the maintenance dose in the elderly, variant alleles of both genes encoding vitamin K epoxide reductase C1 (VKORC1) VKA pharmacological target and genes encoding cytochrome P450 2C9 (CYP2C9) metabolism enzyme of VKA also contribute to the dose response variability [56, 57]. In a cohort of Caucasian inpatients mean aged 87 ± 6 years, we found that in addition to age, genetic variants of VKORC1, CYP2C9 and CYP4F2 were found to be significant predictor variables for the maintenance dose of warfarin, explaining about one-quarter of the dose inter-individual variability [65]. 4.2 Optimizing Vitamin K Antagonist Initiation in the Elderly The induction phase of VKA treatment is challenging and this period is associated with the highest risk of bleeding [65 68]. Various algorithms for the initiation of warfarin have been published in order to minimize the time required to achieve the therapeutic range (TTR) without causing excessive anticoagulation. Many VKA dose regimens were associated with unacceptable dangerous over-anticoagulation during treatment induction in older patients [69]. It is now clear that a single dosing algorithm is unlikely to be effective for all patients. In the elderly, lower initiation doses more approximating the average maintenance dose may be more appropriate [8, 54]. Significantly fewer patients on an age-adjusted regimen had high out-of-range INRs, compared with standard dosing [68, 69]. In a prospective multicentre study, we developed and validated a simple low-dose regimen for starting warfarin therapy in elderly inpatients with a daily dose of 4 mg for the first 3 days [70, 71] (Table 4). The daily maintenance dosage was predicted from the INR measured the day after the third daily intake of 4-mg warfarin (day 3). The physician adjusted the daily dose as needed from day 4 onward based on INR values obtained at least every 2 3 days until determination of the actual maintenance dose. The predicted daily maintenance warfarin dose was closely correlated with the actual maintenance dose (R 2 = 0.84). The mean time needed to achieve a therapeutic INR was 6.7 ± 3.3 days (median 6.0 days). Only a few patients had an INR above 4.0 during this period even among the subset requiring very low maintenance doses (0.5 2 mg) [65, 69]. One question is whether VKORC1 and CYP2C9 genotype information would guide initiation dosing. Before starting warfarin therapy, VKORC1 genotype is the best predictor of the maintenance dose. Once treatment is started using induction doses tailored for elderly patients, the contribution of VKORC1 and CYP2C9 genotypes in dose refinement is negligible compared with two INR values measured during the first week of treatment [71]. Response to a standard dosing algorithm can accurately predict maintenance dose without genotyping. In order to simplify and improve the management of VKA in elderly patients, safe and accurate VKA induction regimens for elderly patients should be introduced into computer-based dosage programmes [72]. 4.3 Optimizing Long-Term Vitamin K Antagonist Treatment in the Elderly In long-term treatment, the indication and the safety should be carefully re-evaluated, at least annually, balancing the risk to benefit ratio for each individual patient. For instance, a fall is a frequent event in an elderly patient. Patients at high risk for falls are presumed to be at increased risk for intracranial haemorrhage (ICH), and high risk for falls is cited as a contraindication to antithrombotic

Optimizing the Use of Anticoagulants 693 Table 4 Warfarin induction dosing algorithm based on the international normalized ratio measured on day 3 and day 6 [70, 72] INR international normalized ratio a This algorithm does not apply to patients who have a pretreatment INR [1.3 Day INR value Warfarin dosage Day 0 Do not measure 4 mg a Day 1 Do not measure 4 mg Day 2 Do not measure 4 mg Day 3 INR \ 1.3 5 mg 1.3 B INR \ 1.5 4 mg 1.5 B INR \ 1.7 3 mg 1.7 B INR \ 1.9 2 mg 1.9 B INR \ 2.5 1 mg INR C2.5 Measure INR daily and omit doses until INR \2.5, then give 1 mg Day 6 ± 1 INR B1.6 Increase by 1 mg/day 1.6 \ INR B 2.5 Maintain the dosage 2.5 \ INR B 3.5 If warfarin dosage C2 mg Reduce by 1 mg/day If warfarin dosage =1 mg Maintain the dosage INR [3.5 Hold warfarin and determine INR daily until INR value B3. Restart at lower dose therapy. Yet Man-Son-Hing et al. [73] calculated that AF patients taking warfarin would need to fall about 295 times in 1 year for warfarin to not be the optimal choice of therapy. Thus, the fall-related bleeding risk is probably over-estimated and over-utilized in not giving eligible patients anticoagulants despite the benefit of VKA treatment. As with the risk of falls, other risk factors depending on patient characteristics should be regularly re-evaluated in order to better detect patients at high risk of bleeding. Another challenge is to avoid over-anticoagulation during long-term treatment with VKA. Indeed, when INR is greater than 4.0, the risk of bleeding increases sharply. Of note, the risk for ICH increases linearly with an increase in INR; the risk for a subdural haematoma increases markedly for INRs greater than 4.0 [8]. Over-anticoagulation is frequent in geriatric practice. Over a 1-year period, at least one INR value C5.0 was found in 25.6 % of 524 patients aged 80 89 years versus \15 % of 333 patients aged 60 years or below (p = 0.003) [63]. These patients need to be monitored carefully as recommended by the Ninth ACCP Conference on Antithrombotic Therapy [8]. Of note, when changes in concomitant drugs occur, and especially when drugs known to potentiate the effect of VKA are added, oral anticoagulation should be closely monitored to allow early detection of excess anticoagulation and thus to minimize potential bleeding complications [62]. Even though managing older outpatients or inpatients on VKA is challenging, those who are monitored by anticoagulation clinics show a good quality of anticoagulation [68, 74, 75]. The median time in the TTR exceeded 60 % in 4,093 outpatients over 80 years followed by Italian centres for anticoagulation [67]. Interestingly, the proportion of patients with mean INR close to 2.5 was strongly associated with a higher percentage of time in the TTR than those with mean INR close to the lower or upper limit of the TTR (2.0 or 3.0) as shown in the VARIA (Veterans AffaiRs study to Improve Anticoagulation) study [75]. In addition, Waterman et al. [76] demonstrated that being older than 80 years was predictive of out-of-range INRs due to non-adherence. Adherence can be improved among older patients by providing pill containers or home health visits, repeating adherence education, and recruiting a family member to oversee medication use. Self-monitoring or self-management in older adults with education has also been shown to be beneficial. In this setting, studies in anticoagulated patients aged 65 years or over reported that the percentage time within the TTR was higher in the self-monitoring patients than in those with usual care [77]. It is noteworthy that patient education alone improves the quality of anticoagulation in the elderly [77, 78]. Interestingly, in 323 patients aged 80 years or above treated with warfarin, Kagansky et al. [78] showed that socioeconomic, cognitive variables and functional impairments were not associated with an increased rate of bleeding; the poor quality of patient education about warfarin was the most significant risk factor for the ineffectiveness of anticoagulation and for bleeding complications. A comprehensive geriatric assessment focused on the risk and/or the cause of falling, the level of cognitive performance, the level of autonomy and anticipated problems with compliance should be systematically conducted in older patients, especially in those discharged from hospital to the community. At home, educated caregivers (family or health

694 V. Siguret et al. professionals) and general practitioners need to manage oral anticoagulant therapy in a coordinated fashion in order to detect adverse effects to VKA early or to make dosing decisions during the treatment course. Risk factors or determinants for bleeding depending on treatment characteristics may be minimized with patient or caregiver education, and an organized system of follow-up. 5 New Oral Anticoagulants The drawbacks with the use of traditional anticoagulants have encouraged the finding of NOA agents that ideally would be safer and easier to use. Two classes of directly active NOA have been developed, selectively targeting either thrombin (dabigatran) or activated coagulation factor X (rivaroxaban, apixaban, edoxaban ) (Table 5) [8]. Their properties are attractive: rapid onset of action, predictable response allowing fixed doses and no regular laboratory monitoring. Several randomized trials have shown that NOA are non-inferior to heparins and VKA for preventing and treating VTE disease, or preventing embolism in AF. Published data in the frail elderly are scarce and no trial has specifically focused on older patients (Table 6). However, some data are available in subgroup analysis of trials, especially comparing VKA and NOA in AF. Dabigatran, an oral direct thrombin inhibitor, was approved in 2010 by the US FDA for the prevention of stroke and systemic embolism in patients with AF [79]. The RELY study compared dabigatran with dose-adjusted warfarin (target INR 2.0 3.0) in patients with AF in a multicentre, randomized, open-label study [15]. Results of this study showed that both doses of dabigatran were non-inferior to warfarin in preventing systemic embolism or stroke. With 150 mg twice daily (bid), the prevention of thromboembolism was greater than that conferred by warfarin, while with 110 mg bid, fewer major bleeding accidents occurred. Overall, there was a lower risk of bleeding (major, lifethreatening, intracranial, and major or minor bleeding) but a higher incidence of dyspepsia and gastrointestinal bleeding compared with warfarin [15, 80, 81]. The RELY trial included 7,528 patients aged 75 years and older (Table 6). A significant interaction between age and treatment assignment was observed in terms of major bleeding complications. In patients aged \75 years, dabigatran 110 mg bid was associated with a lower risk of major bleeding (1.89 vs. 3.04 %; p \ 0.001), whilst the risk was similar in patients aged 75 years and older (4.43 vs. 4.37 %; p = 0.89), and dabigatran 150 mg bid was also associated with a lower risk of major bleeding in patients younger than 75 years (2.12 vs. 3.04 %; p \ 0.001) versus a trend towards more major bleeding complications in Table 5 New oral anticoagulants: pharmacological data Dabigatran etexilate Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Drug/prodrug Prodrug a Drug Drug Bioavailability (%) 6.5 80 100 50 T max (h) 0.5 2 2 4 3 4 Protein binding 35 95 87 (%) Half-life (h) 12 14 b 7 11 a 12 a Drug transporter P-gp P-gp P-gp Metabolism No CYP 3A4 CYP 2J2 CYP 3A4/5 Renal elimination (%) *85 33 (active form), 33 (inactive form) CYP cytochrome P450, P-gp P-glycoprotein, T max time of maximum drug concentration a Dabigatran etexilate is converted into dabigatran by rapid esterasecatalysed hydrolysis b The half-life is prolonged in older patients those above 75 years of age (5.10 vs. 4.37 %; p = 0.07). There was no interaction with age for ICH: the rates of ICH were 0.61, 0.14 and 0.26 % for warfarin, 110- and 150-mg dabigatran, respectively, in patients under 75 years of age, versus 1.00, 0.37 and 0.41 % in patients above 75 years (p values for interaction 0.28 and 0.29, respectively) [81]. An extension of the RELY study, the RELY-ABLE study, is currently ongoing to evaluate the long-term safety of dabigatran. Rivaroxaban, an oral direct factor Xa inhibitor, was approved in 2011 by the FDA in patients with non-valvular AF. The ROCKET trial was a randomized, double-blind, double-dummy trial, comparing rivaroxaban with warfarin in the prevention of stroke and systemic embolism in patients with AF and a history of stroke, TIA, systemic embolism or at least two risk factors for stroke [16]. In this trial, 14,264 patients were randomized to take either rivaroxaban (20 mg/day, or 15 mg in patients with CrCl of 30 49 ml/min) or dose-adjusted warfarin (target INR 2.0 3.0) (Table 6). The rate of primary events (stroke or systemic embolism) was 2.1 %/year in the rivaroxaban group and 2.4 %/year in the warfarin group [hazard ratio (HR) 0.88; 95 % CI 0.74 1.03; p \ 0.001 for non inferiority; p = 0.12 for superiority). The incidence of major and clinically relevant non-major bleeding was not significantly different in the two groups, but ICH (HR 0.67; 95 % CI 0.47 0.93) and fatal bleeding were less common with rivaroxaban, whereas major bleedings from a gastrointestinal site were more common with rivaroxaban. In the ROCKET trial, 18 % of the included patients were aged 80 years and older, and the efficacy as well as the safety of rivaroxaban appears to be consistent irrespective of age, 25

Optimizing the Use of Anticoagulants 695 Table 6 Trials evaluating new oral anticoagulants for the prevention of stroke in patients with atrial fibrillation RELY (dabigatran etexilate) ROCKET AF (rivaroxaban) ARISTOTLE (apixaban) Drug dosage vs. comparator 150 mg 9 2 or 110 mg 9 2 vs. warfarin 20 mg (15 mg if moderate renal impairment) vs. warfarin Patient number 18,113 14,264 18,201 Median age 72 years 73 years 70 years Elderly patients (%) 42 % C75 years 18 % [80 years 31 % C75 years Median CHADS2 2 4 2.1 Patients with previous stroke (%) 20 55 19 5mg9 2 (2.5 mg 9 2if[80 years, weight \60 kg, or creatinine \133 lmol/l) vs. warfarin AF atrial fibrillation, CHADS2 Congestive heart failure, Hypertension, Age 75 years or above, and Diabetes mellitus, and 2 points for prior Stroke/transient ischaemic attack although more detailed analyses on the elderly have not yet been published. Apixaban, another oral direct factor Xa inhibitor, was compared with warfarin in the prevention of stroke and systemic embolism in patients with AF in the ARISTOTLE study, a randomized, double-blind, double-dummy trial [17]. In this trial, 18,201 patients with AF were randomized to take either apixaban (5 mg bid, or 2.5 mg in patients with two or more of the following criteria: age at least 80 years, body weight less than 60 kg, plasma creatinine 1.5 2.5 mg/dl) or dose-adjusted warfarin (target INR 2.0 3.0). The rate of primary events (stroke or systemic embolism) was 1.27 %/year in the apixaban group and 1.60 %/year in the warfarin group (HR 0.79; 95 % CI 0.66 0.95; p \ 0.001 for non inferiority; p = 0.01 for superiority). Haemorrhagic stroke was significantly less common in the apixaban group (HR 0.51; 95 % CI 0.35 0.75; p \ 0.001) as well all cases of stroke. Major bleedings were significantly less frequent in the apixaban group (HR 0.69; 95 % CI 0.60 0.80; p \ 0.001). ICH was also significantly less frequent in the apixaban group (0.33 %/year vs. 0.80 %/year, HR 0.42; 95 % CI 0.30 0.58; p \ 0.001). Of note, 31 % of the included patients were aged 75 and older, and the ARISTOTLE study is the only NOA trial in AF with an age-adjusted dose (Table 6). No interaction with age was observed for the primary endpoint or for major bleeding. NOA that are easier to use and might offer similar or better levels of stroke prevention with a similar or reduced risk of bleeding should lead to an increase in the use of antithrombotic therapy in the management of elderly AF patients. Moreover, the risk of ICH should be considered rather than the risk of all major haemorrhages. In elderly AF patients, ICH is associated with high rates of mortality and morbidity. The incidence of ICH is low, 0.7 % (including haemorrhagic stroke), in elderly patients treated with warfarin in the BAFTA (Birmingham Atrial Fibrillation Treatment of Aged) study [82]. However, ICH does account for almost 90 % of deaths from VKA-associated bleeding and the majority of disability in survivors [83]. However, the suitability of the NOA has not been extensively studied in geriatric patients with multiple morbidities, and some pharmacological specificities of NOA may be underlined in the context of their use in the elderly [84]: Dabigatran etexilate is a prodrug that is quickly converted to the active form dabigatran, with up to 80 % eliminated through the kidneys. The elimination half-life of dabigatran is twice as long and the area under the curve is six times higher in patients with severe renal impairment than in those without renal impairment. [85 87]. A PK model predicted an 11 % increase in dabigatran exposure for every 10 ml/min decrease in CrCl from the second treatment day onwards [88]. Approximately onethird of rivaroxaban and one-quarter of apixaban is excreted unchanged by the kidneys [89, 90]. PK studies indicate that decreased renal function correlates with increased rivaroxaban concentrations [91]. Higher plasma concentrations of NOA may increase the risk of bleeding and may be anticipated during anticoagulation in elderly subjects [24]. Renal function declines with increasing age and moderate renal impairment is reported in more than 50 % of patients with AF who are over the age of 80 years [92]. Only 20 % of patients had moderate renal insufficiency in the ROCKET trial [16]. Furthermore, elderly patients with severe renal impairment were excluded from randomized clinical trials evaluating NOA (CG CrCl \30 ml/min for dabigatran and rivaroxaban,\25 ml/min for apixaban). In the RELY study, less than 20 % of the patients had a CrCl of less than 50 ml/min and 0.02 % had a body weight lower than 50 kg [15, 84]. As seen in Sect. 4.1, warfarin has numerous welldocumented interactions with other drugs and this factor may be problematic in an elderly population likely to require additional medications for concomitant

696 V. Siguret et al. disorders. Advantages of NOA over warfarin clearly include fewer drug interactions. However, since xabans are catabolized by CYP3A4, it is essential for clinicians to be cautious about concomitant use of rivaroxaban and apixaban with CYP3A4 inhibitors and inducers, as the pharmacokinetics of the NOA will be altered in such settings [86]. In addition, all marketed NOA are substrates of P-glycoprotein (P-gp), a drug efflux transporter. The concomitant use of several substrates or inhibitors of P-gp is likely to be frequent in the elderly: Jungbauer et al. [92] estimated that 42 % of patients with AF were treated with at least one P-gp modulator. Such interactions may lead to an increased exposure of patients to NOA, the extent of which is not well known. For example, amiodarone and verapamil, which are P-gp inhibitors, increase dabigatran plasma concentrations [93]. Whether interactions between NOA and P-gp substrates or inhibitors have a significant impact on safety outcomes in the elderly remains poorly documented. The requirement for a twice-daily dosage regimen for dabigatran and apixaban may be problematic for medication adherence. Compliance is important given the relatively short duration of anticoagulant activity. Data are limited on specific agents used to reverse anticoagulant effects in patients receiving NOA. For patients with normal renal function, plasma concentrations of these drugs fall relatively quickly upon discontinuation. Drug discontinuation is usually sufficient to reverse anticoagulant activity. However, rapid reversal may be needed in cases of severe bleeding or emergency surgery, and few treatments are available to antagonize anticoagulant activity induced by NOA. Dialysis, recombinant activated factor VII, oral activated charcoal administration and prothrombin complex concentrates are treatment options, but their clinical effectiveness and safety has yet to be proven, especially in the elderly [93, 94]. Finally, although routine laboratory monitoring is usually not performed, there are a number of situations in which it may be useful to know the degree of anticoagulation induced by NOA. Such situations may include emergency surgery, active bleeding, thrombosis including stroke, worsening renal function, the need for an invasive procedure. Physicians should be aware that NOA, especially dabigatran and rivaroxaban, affect the results of global laboratory coagulation tests, prolonging prothrombin time and APTT. However, the results of these tests are not reliable to determine drug concentrations because these tests lack sensitivity. Specific assays have been developed to provide accurate results (expressed in ng/ml), using specific calibrators and controls. For direct anti-xa NOA, tests are based on the measurement of anti-xa activity, whereas for dabigatran they are based on the measurement of the inhibition of thrombin. However, to date, there are limited data supporting or describing the relationship of these tests for assessing the degree of anticoagulation and whether these test measurements result in improved clinical outcomes, especially in the elderly [24]. Data are lacking regarding the NOA drug concentrations relationship to the bleeding potential, for example, in trauma and surgical patients. In conclusion, a widespread use of NOA is expected among elderly AF patients, but caution seems to be recommended because of the limited experience with the NOA in the frail elderly. Careful consideration should be given to the appropriateness of these agents in patients with fluctuating renal function. For elderly patients currently receiving NOA therapy, it could be recommended to continue monitoring renal function at least annually and more often for those with moderate renal impairment. The risk of overdose is increased in this population, with no routine coagulation test and no antagonist available. Data obtained from specific tests could help in the management of patients in some special situations. Increased vigilance is warranted for bleeding events among elderly patients as NOA gain popularity and more data accumulate via specific clinical trials and registries [84]. Finally, utilization of NOA may also be hampered by cost. Consequently, despite its proven inadequacies and the need for close laboratory supervision, treatment with VKA might continue as the dominant therapy for patients with AF, especially in the setting of limited financial resources. Physicians may also delay using these promising newer agents in their elderly patients as they await safety data in the real world [95]. Conflicts of interest V. Siguret has participated in expert meetings for Poxel, Bayer and BMS-Pfizer. I. Gouin-Thibault has participated in expert meetings for Bayer, BMS and Boehringer Ingelheim. E. Pautas has participated in training sessions for Bayer and Sanofi. P. Gaussem has no conflicts of interest to declare. References 1. Spencer FA, Gore JM, Lessard D, et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost. 2008;100(5):780 8. 2. Stein PD, Hull RD, Kayali F, et al. Venous thromboembolism according to age: the impact of an aging population. Arch Intern Med. 2004;164(20):2260 5. 3. Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J. 2006;27(8):949 53. 4. Avezum A, Makdisse M, Spencer F, GRACE Investigators, et al. 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