Use of anticoagulants in elderly patients

Thrombosis Research 129 (2012) 107–115

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Mini Review

Use of anticoagulants in elderly patients Rupert M. Bauersachs ⁎ Department of Vascular Medicine, Klinikum Darmstadt GmbH, 64283 Darmstadt, Germany

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Article history: Received 30 June 2011 Received in revised form 12 September 2011 Accepted 15 September 2011 Available online 19 October 2011 Keywords: Anticoagulation Apixaban Dabigatran etexilate Elderly patients Rivaroxaban Thromboembolism

a b s t r a c t Thromboembolic disorders are a major cause of morbidity and mortality, and the risk of thromboembolism increases with age. Anticoagulants are recommended for indications including the prevention of venous thromboembolism in surgical and medical patients, treatment of venous thromboembolism and stroke prevention in patients with atrial fibrillation. Traditional anticoagulants that have been used include unfractionated heparin, low molecular weight heparin, fondaparinux and vitamin K antagonists. However, these agents are all associated with drawbacks (i.e. parenteral administration or frequent coagulation monitoring/ dose titration), and it has been particularly challenging to treat elderly patients with anticoagulants. Some specific characteristics of elderly patients may influence the safety of anticoagulant therapy, such as decreased renal function, co-morbidities and the use of multiple medications. The complexity of anticoagulation therapy and the increased risk of bleeding complications in elderly patients may prevent some physicians from prescribing anticoagulants to these patients, which leaves them at risk of thromboembolic events. Thus, safer and more convenient anticoagulants are needed, particularly for elderly patients. New oral anticoagulants have been developed in recent years and have shown promise in clinical studies that included elderly patients. These agents could simplify the management of thromboembolic disorders and improve the safety of anticoagulation. © 2011 Elsevier Ltd. All rights reserved.

Contents Guideline recommendations for the use of anticoagulants in the elderly Traditional anticoagulants – specific concerns in the elderly . . . . . . Heparins and fondaparinux . . . . . . . . . . . . . . . . . . . Warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . New oral anticoagulants . . . . . . . . . . . . . . . . . . . . . . Pharmacological profiles . . . . . . . . . . . . . . . . . . . . . . Rivaroxaban . . . . . . . . . . . . . . . . . . . . . . . . . . Apixaban . . . . . . . . . . . . . . . . . . . . . . . . . . . Dabigatran etexilate . . . . . . . . . . . . . . . . . . . . . . Prevention of VTE after major orthopaedic surgery . . . . . . . . . . Rivaroxaban . . . . . . . . . . . . . . . . . . . . . . . . . . Apixaban . . . . . . . . . . . . . . . . . . . . . . . . . . . Dabigatran etexilate . . . . . . . . . . . . . . . . . . . . . . Prevention of VTE in medically ill patients . . . . . . . . . . . . . . Rivaroxaban . . . . . . . . . . . . . . . . . . . . . . . . . . Apixaban . . . . . . . . . . . . . . . . . . . . . . . . . . . Dabigatran etexilate . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: ACC, American College of Cardiology; ACCP, American College of Chest Physicians; AF, atrial fibrillation; AGS, American Geriatrics Society; AHA, American Heart Association; ASA, acetylsalicylic acid; bid, twice daily; AUC, area under the plasma concentration–time curve; CNS, central nervous system; CrCl, creatinine clearance; DVT, deep vein thrombosis; ESC, European Society of Cardiology; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; LMWH, low molecular weight heparin; od, once daily; PD, pharmacodynamic; PE, pulmonary embolism; PK, pharmacokinetic; RIETE, Registro Informatizado de la Enfermedad TromboEmbolica venosa; THR, total hip replacement; TKR, total knee replacement; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism. ⁎ Tel.: + 49 6151107 4401; fax: + 49 6151107 4499. E-mail address: [email protected]. 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.09.013

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Treatment of VTE . . . . . . . . . . Rivaroxaban . . . . . . . . . . Apixaban . . . . . . . . . . . Dabigatran etexilate . . . . . . Stroke prevention in patients with AF Rivaroxaban . . . . . . . . . . Apixaban. . . . . . . . . . . . Dabigatran etexilate . . . . . . Discussion . . . . . . . . . . . . . Conflict of interest statement . . . . Acknowledgments . . . . . . . . . References . . . . . . . . . . . . .

R.M. Bauersachs / Thrombosis Research 129 (2012) 107–115

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Thromboembolic disorders are a major cause of morbidity and mortality, and the risk of these disorders increases markedly with age. In the community setting, patients aged ≥65 years constitute the majority of cases of venous thromboembolism (VTE) [1]. It is estimated that nearly 60% of patients diagnosed with venous thrombosis are aged ≥70 years [2,3]. Elderly patients are often frail, immobile and have other acute and/or chronic medical conditions. Several studies have identified independent risk factors for VTE in hospitalized medical patients, including age ≥75 years, immobility, history of VTE, acute heart failure, infection or paresis or paralysis of a lower limb [4,5]. Fatal pulmonary embolism (PE) and case–fatality rates are also higher in the elderly than in younger patients [1,6]. The Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry, an international, multicentre, observational registry of consecutive patients with symptomatic acute VTE, identified four clinical factors predicting a fatal PE: patients aged ≥75 years, immobilized for a neurological disease, those with cancer or those with cardiac or respiratory diseases [7]. However, timely diagnosis can be more challenging in the elderly, because elderly patients often present with atypical symptoms. Results from a meta-analysis showed that the Wells clinical probability score (which stratifies patients into groups with high, intermediate and low probability of deep vein thrombosis [DVT]) performed better in patients aged b60 years than in older patients [8]. In addition, D-dimer concentration increases with age, which reduces its clinical value when used as an exclusion test for a suspected venous thromboembolic event. Although the sensitivity is high, D-dimer testing has been reported to have low specificity, particularly in the elderly population [9]. Atrial fibrillation (AF) is the most common cardiac arrhythmia of clinical significance. It affects approximately 1% of the general population and up to 10% of those aged N80 years [10,11]. AF is associated with a four to fivefold increase in the risk of ischaemic stroke [12,13] and this risk increases with age. In the Framingham Heart Study, it was found that up to 36% of strokes were attributable to AF in patients aged N80 years, compared with 21% in those aged 70–79 years and 8% in those aged 60–69 years [12]. As the elderly population increases, the number of individuals with AF is likely to increase substantially in the coming years. It is projected that more than 5.6 million people will be affected by AF in the US alone by 2050, with 36% of those between the age of 65 and 79 years and 53% aged ≥80 years [10]. The rising prevalence of thromboembolic disorders as a result of the increasing age of the population is likely to lead to a growing demand on healthcare resources. The current guidelines recommend the use of anticoagulants for the prevention or treatment of thromboembolic disorders [11,14,15]. However, there are some specific age-related problems that make anticoagulant therapy challenging in the elderly. For example, data from the RIETE registry showed that those aged ≥80 years more often had other underlying medical conditions and co-medication use compared with patients aged b80 years. They more frequently weighed b65 kg, used antiplatelet drugs and had heart failure, chronic respiratory disease or reduced renal function [6] – it is known that the rate of

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glomerular filtration decreases with increasing age [16]. Because of these characteristics of the elderly population, special consideration should be given when prescribing anticoagulants to these patients to ensure the safety, as well as the effectiveness, of these drugs. Despite the increased risk of thromboembolism in the elderly, data from reallife clinical settings indicate that elderly patients are less likely to be treated with anticoagulants, even in situations for which they have been proven efficacious, possibly because of concerns about bleeding risk [17]. Therefore, there is a need for simpler, safer and more convenient anticoagulants for elderly patients. This article will provide an overview of current guidelines and specific issues concerning the use of anticoagulants (as well as their effectiveness) in elderly patients. New oral anticoagulants that are in the most advanced stage of clinical development, such as the direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran etexilate, will be presented and their potential in the management of thromboembolic disorders in the elderly will be discussed. Guideline recommendations for the use of anticoagulants in the elderly A number of guidelines on the use of anticoagulants have been developed for the prevention and treatment of thromboembolic disorders. These guidelines are largely based on the results of clinical trials; however, some high-risk individuals (such as the elderly) are not always included in these trials. Nevertheless, some guidelines have considered elderly patients as a specific subgroup. For the prevention of VTE in surgical or acutely ill, hospitalized patients, the American College of Chest Physicians (ACCP) recommended anticoagulants are: low dose unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or a vitamin K antagonist (VKA; such as warfarin). The ACCP guidelines also recommend that renal function be considered when making decisions about the use and/or the dose of LMWH, fondaparinux and other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients, those with diabetes mellitus and those at high risk of bleeding. In these situations, guidelines suggest using a lower dose of the agent or monitoring the drug level or its anticoagulant effect or avoiding the use of an anticoagulant that bioaccumulates in the presence of renal impairment [14]. In elderly patients or patients who are debilitated or malnourished, have congestive heart failure or liver disease, have had recent major surgery or are taking medications known to increase sensitivity to warfarin, the ACCP guidelines recommend the use of a reduced starting dose with subsequent dosing based on the international normalized ratio (INR) [18]. In patients with AF who have two or more risk factors for future ischaemic stroke, the ACCP guidelines recommend long-term anticoagulation with an oral VKA (such as warfarin), with a targeted INR of 2.5 (range 2.0–3.0). These risk factors include old age (i.e. N75 years), history of hypertension, diabetes mellitus, and moderately or severely

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impaired left ventricular systolic function and/or heart failure. Longterm anticoagulation therapy is also recommended for patients with AF who have just one of the risk factors, such as those aged N75 years [11]. The American Geriatrics Society (AGS) has also set guidelines for managing oral anticoagulation in the elderly (those aged N60 years). These guidelines were abstracted from the 6th ACCP Consensus Conference on Antithrombotic Therapy and adapted for use in elderly patients [19]. Similar to the ACCP guidelines, the AGS guidelines recommend low dose UFH, LMWH or an oral VKA for thromboprophylaxis in surgical or acutely ill, hospitalized patients. The AGS guidelines recommend the use of warfarin for the treatment of VTE (with an initial parenteral anticoagulant) and for stroke prevention in patients with AF who have any high risk factor or more than one moderate risk factor, with a targeted INR of 2.5 (range 2.0–3.0). The initial dose should be an estimate of the average daily dose of warfarin, usually less than 5 mg daily in the elderly because of increased pharmacodynamic (PD) activity [19]. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) guidelines for the management of AF state that older age (≥75 years) is one of the major risk factors for stroke, and patients should be prescribed an oral anticoagulant to prevent thromboembolic events, unless there is a high risk of bleeding. According to the new CHA2DS2-VASc scheme, patients aged ≥75 years are at a greater risk of stroke compared with those aged 65–74 years. It is also noted that age ≥75 years carries a worse prognosis for stroke and mortality than hypertension, diabetes or heart failure [20]. The American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (ACC/AHA/ESC) joint guidelines also recommend chronic oral anticoagulant therapy in patients with AF at high risk of stroke, such as those aged ≥75 years, unless the use of anticoagulants is contraindicated [21]. Traditional anticoagulants – specific concerns in the elderly Heparins and fondaparinux The efficacy and safety of UFH, LMWHs and fondaparinux in the management of thromboembolic disorders have been demonstrated in large numbers of clinical trials in medical and surgical patients. Elderly patients have also been included in some of the clinical trials investigating the efficacy and safety of these agents. For example, an analysis of the PREVENT trial in acutely ill medical patients aged ≥75 years (one-third of the patient population) showed that the reduction in the composite of VTE and sudden death favoured dalteparin (2.77% vs 4.96% in the placebo group). The incidence of major bleeding was low but was higher in the dalteparin group compared with the placebo group (0.49% vs 0.16%) [22]. Similarly, a subgroup analysis of the MEDENOX study assessing enoxaparin for the prevention of VTE in medical patients also demonstrated a significant 78% reduction in VTE in patients aged N75 years who received enoxaparin 40 mg once daily (od) [4]. In the recent EXCLAIM trial evaluating the efficacy and safety of extended-duration enoxaparin for thromboprophylaxis in acutely ill medical patients, enoxaparin was shown to reduce VTE more than it increased major bleeding events in patients aged ≥75 years, women and those with recent immobility [23]. Similar efficacy has also been demonstrated for enoxaparin with UFH in VTE prevention in medical patients with heart failure or severe respiratory disease, in which more than 55% of the patients were aged N70 years [24]. The efficacy of fondaparinux for the prevention of VTE in older, acute medical patients has also been demonstrated in the ARTEMIS trial, in which over 50% of the patients were aged ≥75 years [25]. Although effective, these agents are associated with drawbacks. The parenteral route of administration is inconvenient for long-term or home use, especially in the elderly who may not be able, or willing, to inject themselves, and, therefore, require daily nurse assistance.

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Furthermore, because renal clearance is the primary mode of elimination for UFH, LMWH and fondaparinux, these agents may accumulate and increase the risk of bleeding in patients with reduced renal function (such as in some elderly patients). A recent study in patients with acute VTE enrolled in the RIETE registry, who were aged ≥90 years, showed that 63% of these patients had abnormally elevated creatinine levels [26]. It has been shown that old age was associated with increased risk of bleeding and increased heparin levels after standard heparin doses [27], and a lower UFH dose is required to maintain therapeutic activated partial thromboplastin time [28]. UFH is therapeutically variable as a result of binding to numerous plasma proteins and cellular components; therefore, rigorous and frequent haemostatic monitoring is required to ensure safety. In addition, UFH is also associated with the risk of developing heparin-induced thrombocytopenia (HIT) [29]. Although LMWHs have a more predictable anticoagulant response and a lower risk of HIT, attention should be given to renal function when prescribing LMWHs to elderly patients to avoid accumulation and bleeding complications. An earlier study showed that, after daily administration of the LMWH nadroparin (180 anti-Factor Xa IU/kg per day) for 6–10 days, a significant accumulation of anti-Factor Xa activity was observed in the healthy elderly subjects who had a creatinine clearance [CrCl] of 62 ± 6 ml/min) [30]. Fondaparinux produces a predictable anticoagulant response that precludes the need for routine coagulation monitoring and does not cause HIT [29]. However, fondaparinux is contraindicated in patients with severe renal failure (CrCl b20 ml/min) for the prevention of VTE, and the dose should be reduced to 1.5 mg od in patients with CrCl in the range of 20–50 ml/ min [31]. Warfarin Warfarin has been used in long-term anticoagulant therapy for over 50 years. Although its efficacy in stroke prevention in patients with AF is well established, warfarin therapy carries the risk of major bleeding, particularly intracranial bleeding. The INR target of 2.0–3.0 optimizes the efficacy and safety of warfarin therapy but is difficult to achieve consistently because its effect is modified by diet, drug–drug interactions, co-morbidities and genetic factors. Because of the variable response, frequent coagulation monitoring is required to maintain the INR within the target therapeutic range [18]. In elderly patients, maintaining a safe and stable level of anticoagulation with warfarin therapy is particularly challenging because of the propensity of co-medications for long-term co-morbidities and frequent changes (addition or withdrawal) in co-medications for other acute illnesses. An earlier meta-analysis of sixteen trials showed the efficacy of warfarin in reducing stroke, but the benefit was not offset by the risk of major bleeding [32]. However, it was shown in another meta-analysis of six randomized trials that VKA therapy was more effective than acetylsalicylic acid (ASA) in preventing stroke, but at the cost of a significantly higher rate of major bleeding [33]. The risk of major bleeding during warfarin therapy is believed to be related to patient characteristics and specific co-morbid conditions, with old age being an independent risk factor. In an analysis of bleeding risks with VKA therapy, it was shown that bleeding increased significantly with age, with a 32% increase in all bleeding events and a 46% increase in major bleeding events for every 10-year increase in age, compared with those aged b40 years [34]. In a multicentre study in patients with AF who received warfarin, approximately 5% of patients aged N75 years experienced major bleeding compared with approximately 1% in younger patients [35]. Consistent with these findings, data from the EuroHeart Survey indicate that elderly patients are at an increased risk of bleeding, and a new bleeding risk score system (HAS-BLED) has been derived, in which age N65 years is one of the clinical characteristics for bleeding

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Table 1 Completed and ongoing phase III trials with rivaroxaban, apixaban and dabigatran etexilate.

VTE prevention after total hip or total knee replacement surgery

VTE prevention in medically ill patients Acute treatment/secondary prevention of VTE

Rivaroxaban

Apixaban

Dabigatran etexilate

RECORD1 RECORD2 RECORD3 RECORD4 MAGELLAN EINSTEIN DVT EINSTEIN EXT EINSTEIN PE*

ADVANCE-1 ADVANCE-2 ADVANCE-3

RE-NOVATE RE-NOVATE II RE-MODEL RE-MOBILIZE – RE-COVER RE-COVER II RE-MEDY RE-SONATE RE-LY RELY-ABLE* –

Stroke prevention in AF

ROCKET AF

Secondary prevention in ACS

ATLAS ACS TIMI 51

ADOPT AMPLIFY* AMPLIFY-EXT*

AVERROES ARISTOTLE APPRAISE-2†

*Ongoing trials; †Terminated. ACS, acute coronary syndrome; AF, atrial fibrillation; VTE, venous thromboembolism.

risk [20]. The observed increase of bleeding events in elderly patients may be as a result of the difficulties in the control of anticoagulation with warfarin. Although it has been suggested recently that a low intensity INR (1.5–2.0) may provide adequate protection without increasing bleeding risk in elderly patients (N75 years of age) [36], findings from other studies suggest that INRs b2.0 were not associated with a lower risk of intracranial bleeding compared with INRs of 2.0–3.0 [37]. The concern over bleeding risk may lead some physicians to avoid prescribing anticoagulants, particularly to elderly patients. It has been shown that warfarin use declines with age: 47% in patients aged 69– 79 years, 24% in those aged 80–89 years and only 15% in those aged ≥90 years [17]. A study in elderly patients with AF showed that 26% of patients aged ≥80 years discontinued warfarin therapy within the first year; of these, 81% were as a result of safety issues [38]. A recent study assessing guideline adherence in elderly patients with AF admitted to internal medicine wards also indicated that old age (N80 years) had a significant negative impact on the uptake of VKA therapy [39]. The inconvenience and cost of routine coagulation monitoring may also contribute to the low levels of warfarin use. The underutilization of anticoagulant therapy in elderly patients with AF leaves many of them at a high risk of stroke and related complications. New oral anticoagulants The limitations of the currently available anticoagulants have led to the development of new oral anticoagulants that selectively target a specific step, or factor, in the coagulation pathway, in an attempt to find effective but safer and more convenient agents. Among the new oral agents, the direct Factor Xa inhibitors rivaroxaban and apixaban and the direct thrombin inhibitor dabigatran etexilate are in the most advanced stages of development and have shown promise in large-scale clinical trials (Table 1). The main pharmacological profiles and the results of the phase III studies with rivaroxaban, apixaban and dabigatran etexilate are described below.

Pharmacological profiles Rivaroxaban Rivaroxaban is an oral, direct Factor Xa inhibitor with a terminal half-life of 5–9 hours in young individuals and 11–13 hours in the elderly [40,41]. After oral administration, approximately two-thirds of the administered dose undergoes metabolic degradation in the liver, of which half is excreted via the kidneys and the other half via the hepatobiliary route. The final one-third of the administered dose undergoes renal excretion as unchanged active substance in the urine (Table 2) [42]. In healthy older subjects (60–76 years of age), rivaroxaban was well tolerated, with predictable pharmacokinetics (PK) and PD at doses up to 40 mg [41]. In another study, it was shown that elderly subjects (N75 years of age) had higher area under the plasma concentration–time curve (AUC) values than younger subjects, although the maximum plasma concentration was unaffected [43]. Rivaroxaban has been shown to have no clinically relevant drug–drug interactions with frequently used concomitant medications, such as the non-steroidal anti-inflammatory drug naproxen [44] and ASA [42,45]. Preliminary studies also indicated that there are no clinically relevant interactions of rivaroxaban with clopidogrel [46], digoxin [47] or atorvastatin [48]. Apixaban Apixaban is an oral, direct Factor Xa inhibitor with a mean terminal half-life of 12–15 hours [49,50]. After administration, the majority (~51%) of the recovered dose is in faeces, with urinary excretion of unchanged drug accounting for approximately 22% of the recovered dose (Table 2) [51]. In healthy subjects, age did not affect apixaban maximum plasma concentration, although the AUC was 32% higher in the elderly (≥65 years of age) than in younger subjects (18–40 years of age) [50]. Apixaban did not alter the PK of digoxin, naproxen or

Table 2 Main pharmacological characteristics of traditional and selected new oral anticoagulants [18,42,52,57,86]. VKAs Target Prodrug Dosing Bioavailability (%) Time to peak (hours) Half-life (hours) Renal elimination (%)

Vitamin K-dependent clotting factors (II, VII, IX, X) No Once daily (INR-adjusted) High 1.5 36–42 Predominantly renal

Drug–drug interactions Routine coagulation monitoring

Multiple Yes

Rivaroxaban Factor Xa No Once daily 80–100 2–4 5–13 ~ 33 (unchanged) ~ 33 (inactive metabolites) CYP3A4 and P-gp inhibitors No

*Percentage of the recovered dose; †After an intravenous dose. CYP3A4, cytochrome P450 3A4; INR, international normalized ratio; P-gp, P-glycoprotein; VKAs, vitamin K antagonists.

Apixaban Factor Xa No Twice daily 34–88 1.5–3.5 12–15 ~ 22 (unchanged)* CYP3A4 and P-gp inhibitors No

Dabigatran etexilate Factor IIa Yes Twice daily ~6 1.5–3.0 12–14 ~ 80† P-gp inhibitors No

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atenolol [52]. The effect of concomitant administration of apixaban and statins has not been reported [53]. Dabigatran etexilate Dabigatran etexilate is an oral, direct thrombin inhibitor with a relatively low oral bioavailability (~6%) and a half-life of approximately 12–14 hours (Table 2) [54]. Elimination of dabigatran occurs predominantly via the kidneys, with approximately 80% excreted unchanged in the urine after intravenous administration [55]. In healthy older subjects (≥65 years of age), dabigatran exposure is 40–60% higher than in younger subjects [56,57]. There is no clinically relevant influence of digoxin, diclofenac or atorvastatin on the PK of dabigatran or vice versa [58-60]. Prevention of VTE after major orthopaedic surgery Rivaroxaban The efficacy and safety of rivaroxaban for the prevention of VTE in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery have been investigated in four phase III studies (the RECORD programme) [61-64]. In all these studies, the primary efficacy endpoint was the composite of any DVT, non-fatal PE and all-cause mortality. The primary safety endpoint was major bleeding (which did not include surgical-site bleeding in these studies). The RECORD1 and RECORD3 studies compared rivaroxaban (10 mg od) with enoxaparin 40 mg od, given for 31–39 days after THR (RECORD1) [61], or 10–14 days after TKR (RECORD3) [63]. In both studies, rivaroxaban was significantly more effective than enoxaparin for the prevention of VTE. The incidence of major bleeding was comparable and not significantly different between treatment groups [61,63]. RECORD3 also showed a significant reduction in symptomatic VTE [63]. RECORD2 investigated the efficacy and safety of extended thromboprophylaxis with rivaroxaban (31– 39 days) compared with short-term enoxaparin (10–14 days) followed by placebo, in patients undergoing THR [62]. The results showed that extended prophylaxis with rivaroxaban was superior to short-term prophylaxis with enoxaparin 40 mg od for the prevention of VTE, including symptomatic events [62]. The rate of major bleeding was low and similar between the two treatment groups (b0.1%), despite the fact that rivaroxaban was given for a longer period [62]. In the RECORD4 study in patients undergoing TKR, rivaroxaban was superior to enoxaparin (30 mg twice daily [bid]) for the primary efficacy endpoint, with no significant difference in the rates of major bleeding between the two groups [64]. A prespecified pooled analysis of the four RECORD studies showed that rivaroxaban significantly reduced the incidence of clinically important symptomatic VTE and death compared with enoxaparin regimens at Day 12 ± 2 in the active treatment pool (i.e. during the enoxaparin-controlled period common to all studies). The pooled analysis also showed that there was no significant difference between the rivaroxaban regimens and enoxaparin regimens in the rates of treatment-emergent major bleeding. In the pooled subgroup analyses, rivaroxaban demonstrated consistent reductions in the composite of symptomatic VTE and all-cause mortality, irrespective of patients’ age (b65, 65–75 or N75 years), weight (≤70, N70–90 or N90 kg), gender or renal function (calculated CrCl N80, 50–80 or b50 ml/min at baseline) [65]. Apixaban Apixaban has been evaluated in three phase III studies for the prevention of VTE in patients undergoing THR or TKR. In the ADVANCE-1 study, apixaban (2.5 mg bid) did not meet the prespecified criteria for non-inferiority compared with enoxaparin 30 mg bid (both regimens

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were administered for 10–14 days) [66]. However, the ADVANCE-2 study in patients undergoing TKR demonstrated superior efficacy for apixaban (2.5 mg bid) compared with enoxaparin 40 mg od for the prevention of DVT, non-fatal PE and all-cause mortality. Clinically relevant bleeding (major or non-major clinically relevant) occurred in fewer patients given apixaban, although the differences were not significant [67]. The ADVANCE-3 study assessed prophylaxis with apixaban (2.5 mg bid) versus enoxaparin (40 mg od) in patients undergoing THR, and the results demonstrated superior efficacy for apixaban compared with enoxaparin, with similar rates of major and non-major clinically relevant bleeding [68]. Dabigatran etexilate The efficacy and safety of dabigatran etexilate in the prevention of VTE have been evaluated in patients undergoing THR or TKR [69-71]. Dabigatran etexilate (150 mg or 220 mg od) was compared with enoxaparin. The primary efficacy endpoint was total VTE (a composite of venographically detected or symptomatic DVT and/or symptomatic PE and all-cause mortality). The primary safety endpoint was the occurrence of bleeding events during treatment. In the RE-NOVATE study [69] (patients undergoing THR with a duration of prophylaxis of 28–35 days) and the RE-MODEL trial [70] (patients undergoing TKR with a duration of prophylaxis of 6–10 days), both doses of dabigatran etexilate were non­inferior to enoxaparin 40 mg od for the primary efficacy endpoint. However, in the RE-MOBILIZE study in patients undergoing TKR (duration of prophylaxis 12– 15 days), both doses of dabigatran etexilate failed to meet non-inferiority compared with enoxaparin 30 mg bid for the primary efficacy endpoint [71]. There was no significant difference in the frequency of major bleeding events during treatment between both dabigatran etexilate doses and the enoxaparin regimens in all three studies. Prevention of VTE in medically ill patients Rivaroxaban Rivaroxaban has been evaluated in a phase III study for the prevention of VTE in hospitalized medically ill patients aged between 40 and 105 years (MAGELLAN; NCT00571649). The efficacy and safety of rivaroxaban (10 mg od for up to 14 days or up to 39 days) for VTE prophylaxis were compared with enoxaparin (40 mg od for up to 14 days, followed by oral placebo) in hospitalized acutely ill medical patients [72]. The outcomes of this study were presented at the ACC annual congress in New Orleans, in April 2011. The results confirm that there is a continued risk of VTE beyond the initial period of hospitalization or immobilization in acutely ill patients. In this study, rivaroxaban was non-inferior to enoxaparin at Day 10 and was superior to enoxaparin followed by placebo at Day 35 in reducing the risk of VTE. Overall bleeding rates were low but were significantly higher in the rivaroxaban arm [73]. Apixaban Apixaban is also undergoing a phase III study for the prevention of VTE in hospitalized medically ill patients (ADOPT; NCT00457002). This study is comparing apixaban 2.5 mg bid for 30 days with enoxaparin 40 mg od for 6–14 days followed by placebo for VTE prophylaxis in acutely ill medical patients (aged ≥40 years) during and after hospitalization. This study was completed in May 2011. Dabigatran etexilate Dabigatran etexilate is not under evaluation for VTE prevention in hospitalized medically ill patients to date.

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Treatment of VTE Rivaroxaban The phase III EINSTEIN studies were designed to assess rivaroxaban for the treatment and secondary prevention of VTE. EINSTEIN PE (NCT00439777) is currently ongoing. The EINSTEIN DVT study showed that rivaroxaban (15 mg bid for the first 3 weeks, followed by 20 mg od for 3, 6 or 12 months) was non-inferior to enoxaparin (1.0 mg/kg bid for ≥5 days, plus a VKA titrated to INR 2.0–3.0) for the prevention of recurrent symptomatic VTE with the same rate of major or non-major clinically relevant bleeding events [74]. In the EINSTEIN Extension study in patients who had completed 6–12 months of therapy for acute VTE, rivaroxaban (20 mg od for 6–12 months) was associated with a significant reduction in the rate of recurrent symptomatic VTE compared with the placebo group (a relative risk reduction of 82% with rivaroxaban). Major bleeding did not occur in the placebo group and occurred in four (0.7%, non-significant) rivaroxabantreated patients, although none of these events was fatal or occurred in a critical organ [74]. Subgroup analyses revealed that the results for the primary efficacy and safety outcomes were consistent regardless of age (b65, 65–75 or N75 years), renal function (calculated CrCl N80, 50–80 or b50 ml/min at baseline) or body weight (≤ 70, N70– 90 or N90 kg) [74]. Apixaban The efficacy and safety of apixaban for the treatment and secondary prevention of VTE are being investigated in two phase III studies. The AMPLIFY study is assessing apixaban (10 mg bid for 7 days, followed by 5 mg bid for 6 months) versus conventional treatment (enoxaparin plus warfarin) for the treatment of patients with DVT or PE (NCT00643201). The AMPLIFY-EXT study is evaluating apixaban 2.5 mg or 5.0 mg bid compared with placebo for 12 months in patients with DVT or PE who have completed their intended treatment (NCT00633893). Dabigatran etexilate The efficacy and safety of dabigatran etexilate for the treatment of VTE were evaluated in the phase III RE-COVER study [75]. The results showed that dabigatran etexilate (150 mg bid for 6 months, with initial parenteral anticoagulant treatment for at least 5 days) was as effective as warfarin (target INR of 2.0–3.0, after initial treatment with a parenteral anticoagulant) for the treatment of acute symptomatic VTE, with a similar rate of major bleeding events. The rate of major or non­major clinically relevant bleeding events was significantly lower in patients receiving dabigatran etexilate compared with those receiving warfarin. The rate of treatment discontinuation was higher in the dabigatran etexilate group compared with the warfarin group (P = 0.05). Moreover, there was no significant difference in efficacy in the predefined subgroups such as age (including those aged ≥75 years) and renal function (i.e. CrCl ≥30 ml/min). Additional phase III trials in the treatment (RECOVER II; NCT00680186) and the secondary prevention of VTE (RE-MEDY; NCT00329238, and RE-SONATE; NCT00558259) have also been completed recently. Stroke prevention in patients with AF Rivaroxaban Rivaroxaban has been investigated in a phase III study in patients with non-valvular AF (ROCKET AF; NCT00403767). The efficacy and safety of rivaroxaban (20 mg od, or 15 mg od in patients with CrCl = 30–49 ml/min) were compared with dose-adjusted warfarin

(titrated to a target INR of 2.5 [range 2.0–3.0]) for the prevention of stroke and non-central nervous system (CNS) embolism. Qualifying criteria included prior stroke, transient ischaemic attack or systemic embolism, or two or more of the following risk factors: clinical heart failure and/or left ventricular ejection fraction ≤ 35%, hypertension, age ≥ 75 years or diabetes mellitus [76]. The primary efficacy endpoint was the composite of stroke and non-CNS systemic embolism. The principal safety endpoint was the composite of major and non-major clinically relevant bleeding events. The results showed that rivaroxaban was non-inferior to warfarin in the intention-to-treat study population (including events on and off treatment). During the treatment period, rivaroxaban had a lower risk of stroke and non-CNS systemic embolism versus warfarin. Although there was no significant between-group difference in the risk of major bleeding, both intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Subgroup analyses revealed that the effect of rivaroxaban, as compared with warfarin, was consistent across all prespecified subgroups, including age (b75 years and ≥ 75 years) and renal function (CrCl N80, 50–80 or b50 ml/min at baseline) [76]. Apixaban Apixaban has been evaluated in phase III studies for the prevention of stroke in patients with AF. In the ARISTOTLE study (NCT00412984), patients with AF were randomized to receive either warfarin (target INR 2.0–3.0) or apixaban (5 mg or 2.5 mg bid). The main objective of the study was to determine whether apixaban is non-inferior to warfarin at reducing the combined outcome of stroke (ischaemic or haemorrhagic) and systemic embolism in patients with AF and at least one additional risk factor for stroke [77]. The results of this study were presented at the ESC congress 2011 in Paris. It was shown that apixaban was associated with lower rates of stroke and systemic embolism, major bleeding events and mortality compared with warfarin, and the effects were consistent across all major subgroups. In the AVERROES study, apixaban 5 mg bid (or 2.5 mg bid in selected patients) was compared with ASA (81 mg to 324 mg od) for the prevention of stroke or systemic embolism in patients with AF and at least one risk factor for stroke who are unsuitable for or unwilling to take a VKA. The primary efficacy endpoint was stroke (ischaemic or haemorrhagic) or systemic embolism, and the primary safety endpoint was major bleeding [78]. Overall, the data showed that, compared with ASA, apixaban significantly reduced the risk of stroke or systemic embolism, with no significant increased risk of major bleeding [79]. Dabigatran etexilate Dabigatran etexilate has been investigated in a phase III study for stroke prevention in patients with AF (the RE-LY trial) [80,81]. In this non-inferiority trial, patients who had AF with a risk of stroke were randomized to receive fixed doses of dabigatran, 110 mg or 150 mg bid, or dose-adjusted warfarin. The results showed that dabigatran etexilate 110 mg bid was non­inferior and dabigatran etexilate 150 mg bid was superior to warfarin for the prevention of stroke and systemic embolism. The rate of major bleeding was significantly lower in patients receiving dabigatran etexilate 110 mg bid compared with warfarin. The rate of haemorrhagic stroke was 0.38% in the warfarin group compared with 0.12% with dabigatran etexilate 110 mg bid and 0.10% with dabigatran etexilate 150 mg bid. However, there was a higher rate of treatment discontinuation in the dabigatran etexilate groups (probably because of gastrointestinal adverse effects), and a small non-significant increase in the rate of myocardial infarction [81,82]. Although ~80% of the dabigatran dose is excreted renally, subgroup analysis revealed that there was no significant interaction

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in the treatment effect of dabigatran across levels of the baseline calculated CrCl (i.e. ≥30 ml/min) [80]. Further subgroup analyses showed that both doses of dabigatran etexilate (110 mg and 150 mg bid), compared with warfarin, had lower risks of both intracranial and extracranial bleeding in patients aged b75 years. However, in patients aged N75 years, intracranial bleeding risk was lower but extracranial bleeding risk was similar or higher with both doses of dabigatran etexilate compared with warfarin [83]. Discussion The elderly population is at high risk of thromboembolism, and the incidence of VTE and AF increases markedly with age. Risk factors associated with thromboembolic disorders are more prevalent in the elderly than in younger individuals. Despite the increased risk in the elderly, anticoagulants are underused in these patients, partly because of concerns over bleeding complications; some studies have indicated that bleeding risk is higher in elderly patients. Until recently, VKAs (such as warfarin) have been the only oral anticoagulants available. However, it is challenging to maintain safe and effective anticoagulation with warfarin therapy as a result of its narrow therapeutic window, variable response and multiple drug–drug and food–drug interactions. This is particularly problematic in the elderly because of other underlying medical conditions and the co-administration of other drugs. LMWHs provide a predictable anticoagulant effect across patient populations but require parenteral administration. Because LMWHs are primarily eliminated via the kidneys, elderly patients with moderate or severe renal impairment are potentially at risk of LMWH accumulation and increased exposure. In some countries, UFH is contraindicated in patients with severe renal impairment. The limitations and complications with the use of conventional agents may dissuade physicians from prescribing anticoagulant therapy to the elderly. New oral anticoagulants (such as rivaroxaban, apixaban and dabigatran etexilate) have been found to have predictable PK and PD and minimal drug–drug interactions; thus, routine coagulation monitoring was not conducted in the phase III trials evaluating the efficacy and safety of these agents. Rivaroxaban, dabigatran and most recently apixaban, have already been approved in some countries for specific indications in a wide patient population, including the elderly. Renal function decreases with age; therefore, the clearance of drugs that are eliminated via the kidneys may be affected. A moderate increase in rivaroxaban exposure (i.e. AUC, but not the maximum plasma concentration) was observed in healthy elderly subjects aged N75 years [43]. Because one-third of the administered rivaroxaban dose undergoes renal excretion as unchanged active substance, renal clearance of rivaroxaban decreased with increasing renal impairment [84]. In the subgroup analyses of the phase III studies for the prevention and treatment of VTE and for stroke prevention in patients with AF, patients aged N75 years had similar efficacy and safety outcomes to those of younger patient groups (i.e. b65 years or 65– 75 years). Mild or moderate renal impairment did not influence the efficacy and safety outcomes in these studies, although a reduced daily dose (15 mg instead of 20 mg od) was used in patients with a CrCl of 30–49 ml/min) in the ROCKET AF study [76]. Patients with severe renal impairment (CrCl b30 ml/min) were excluded from these clinical studies. Renal excretion of unchanged apixaban accounts for approximately 22% of the recovered dose after administration [51]. Exposure to apixaban is also affected by age; in healthy elderly subjects (≥65 years of age), there was a moderate increase in apixaban exposure as indicated by the AUC [50]. In the ARISTOTLE study, a reduced dose was used in subjects with two of the following criteria at baseline: age ≥80 years, body weight ≤60 kg and serum creatinine level ≥1.5 mg/dl (133 μmol/l) [77]. Dabigatran is predominantly eliminated via the kidneys, with approximately 80% excreted unchanged in the urine after intravenous administration [55], and both age and renal function appear to affect the

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exposure to dabigatran. In healthy elderly participants [56], dabigatran exposure was increased up to two fold in the elderly compared with younger subjects after dabigatran etexilate 150 mg bid dosing for 6 days. Further analysis of the RE­LY study revealed that the risk of major bleeding was higher in patients aged ≥75 years receiving dabigatran etexilate than that in patients aged b75 years. In addition, a more than twofold higher risk of major bleeding was found in patients receiving either dabigatran etexilate or warfarin who had impaired renal function (measured as CrCl b50 ml/min versus ≥80 ml/min) [83]. Accumulation of dabigatran in two elderly patients (N80 years of age) has been reported recently, including one case of fatal bleeding [85]. Both patients were female, N80 years of age, with low body weights and impaired renal function (CrCl = 32 ml/min and 29 ml/min, respectively) who were taking dabigatran etexilate 75 mg or 110 mg bid for stroke prevention [85]. Fixed-dose, unmonitored therapy with anticoagulants that are predominantly eliminated via the kidneys can lead to drug accumulation and an increased exposure in patients with renal impairment, and this may be a particular concern in the elderly. Therefore, in case of any deterioration of renal function during the treatment period, repeated measurements of renal function could provide reassurance for the safe use of these agents. Most studies showing increased exposure of the new oral anticoagulants have been conducted in healthy elderly participants, and patients with severe renal impairment were excluded from the phase III clinical studies evaluating the efficacy and safety of these new oral agents. In order to optimize both safety and efficacy of the new oral anticoagulants in elderly patients with renal impairment, and to validate guideline recommendations, randomized clinical trials designed specifically for this patient population would be of value. In conclusion, emerging evidence suggests that the new oral agents may provide convenient, safe and effective anticoagulation for elderly patients as well as for the general patient population. However, because of the specific characteristics of elderly patients, special consideration should be given when prescribing anticoagulants to these patients. Nevertheless, the new oral anticoagulants are expected to improve the management of thromboembolic disorders in the elderly. Conflict of interest statement Professor Bauersachs has received honoraria for lectures or consultancies from Novartis, LEO, Bayer, Boehringer-Ingelheim and BMS. Acknowledgments The author would like to acknowledge Yong-Ling Liu who provided editorial support with funding from Bayer HealthCare Pharmaceuticals and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The author is fully responsible for the content and received no financial support related to the development of this manuscript. References [1] Spencer FA, Gore JM, Lessard D, Emery C, Pacifico L, Reed G, et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost 2008;100:780–8. [2] Engbers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost 2010;8:2105–12. [3] Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a populationbased study. J Thromb Haemost 2007;5:692–9. [4] Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Fibrinolysis 2003;14:341–6. [5] Weill-Engerer S, Meaume S, Lahlou A, Piette F, Saint-Jean O, Sachet A, et al. Risk factors for deep vein thrombosis in inpatients aged 65 and older: a case–control multicenter study. J Am Geriatr Soc 2004;52:1299–304.

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