SEARCH

SEARCH BY CITATION

Keywords:

  • anticoagulation;
  • atrial fibrillation;
  • elderly;
  • stroke

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

Sinnaeve PR, Brueckmann M, Clemens A, Oldgren J, Eikelboom J, Healey JS (University Hospitals Leuven, Leuven, Belgium; Global Clinical Development and Medical Affairs, Ingelheim am Rhein, Germany; Uppsala University, Uppsala, Sweden; and Population Health Research Institute, Hamilton, Canada). Stroke prevention in elderly patients with atrial fibrillation: challenges for anticoagulation (Review). J Intern Med 2012; 271: 15–24.

Abstract.  Elderly patients with atrial fibrillation (AF), who constitute almost half of all AF patients, are at increased risk of stroke. Anticoagulant therapies, especially vitamin K antagonists (VKA), reduce the risk of stroke in all patients including the elderly but are frequently under-used in older patients. Failure to initiate VKA in elderly AF patients is related to a number of factors, including the limitations of current therapies and the increased risk for major haemorrhage associated with advanced age and anticoagulation therapy. Of particular concern is the risk of intracranial haemorrhages (ICH), which is associated with high rates of mortality and morbidity. Novel oral anticoagulant agents that are easier to use and might offer similar or better levels of stroke prevention with a similar or reduced risk of bleeding should increase the use of antithrombotic therapy in the management of elderly AF patients. Amongst these new agents, the recently approved direct thrombin inhibitor dabigatran provides effective stroke prevention with a significant reduction of ICH, and enables clinicians to tailor the dose according to age and haemorrhagic risk.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

Atrial fibrillation (AF) is a disease of the elderly: its prevalence increases with advancing age [1], ranging from only 0.1% in subjects under 55 year to >10% in subjects above 80 years of age (Fig. 1). Amongst patients with diagnosed AF, 45% are older than 75 years, and it is even estimated that more than half of patients with AF will be older than 80 by the year 2050 [2]. Thromboembolism, including stroke, is the most feared complication of AF. Its risk depends on comorbidities including diabetes, hypertension, heart failure, vascular disease, previous history of stroke and female gender, but is particularly high in older patients (Fig. 2) [3]. In the Framingham cohort, the proportion of AF-associated strokes increased progressively with age, from 6.7% for ages 50–59 years to 36.2% for ages 80–89 years [4]. In addition, morbidity and mortality are exceedingly high in elderly patients experiencing a stroke [5]. Consequently, with a rapidly ageing population, it is clear that AF and AF-related stroke are an expanding healthcare concern. Vitamin K antagonists (VKA) effectively reduce the risk of stroke in AF, but they are underused and poorly managed, particularly in the elderly, who carry the highest burden of the disease owing to stroke. In this study, we review the challenges faced in preventing AF-related stroke in the elderly.

image

Figure 1.  Prevalence of atrial fibrillation according to age in the Rotterdam study. (adapted from Heeringa et al. [1]).

Download figure to PowerPoint

image

Figure 2.  Rates (annual rate/100) of thromboembolic events per age (adapted from Singer et al. [7]).

Download figure to PowerPoint

Stroke prevention in the elderly

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

Anticoagulation reduces the risk of stroke in the elderly

Long-term VKA are the standard treatment for patients with AF at risk of stroke. VKA decrease the risk of stroke in patients with AF by 64% (95%CI 49–74) [6]. In a large study of 13 559 patients with nonvalvular AF, the net clinical benefit of VKA use was assessed by subtracting the rate of VKA-associated intracranial haemorrhages (ICH) from the rate of prevented ischaemic strokes and systemic emboli, using an impact weight of 1.5 for ICH (Figs 2 and 3) [7]. The adjusted net clinical benefit of VKA was 0.68% per 100 patients per year (95%CI 0.34–0.87) in the overall cohort. Whilst the net benefit was absent in young patients, it was substantial (2.34%, 95%CI 1.29–3.30) in patients above 85 years, a finding diametrically opposed to what many physicians believe to be the case. The extent of the net benefit depended on the CHADS2 score, ranging from almost zero in patients with a CHADS2 score of 0, to 0.19% and 0.97% for scores of 1 or 2, respectively and to 2.22% (95%CI 0.58–3.75) in patients with a score of 4 or greater. Because age is a powerful risk factor for stroke, AF guidelines specifically recommend VKA in the elderly [8–10]. This is reflected by their adoption of the CHADS2 or CHA2DS2-VASc risk scores for stroke, both including age as a predictor [11–13].

image

Figure 3.  Rates (annual rate/100) of intracranial haemorrhages per age (adapted from Singer et al. [7]).

Download figure to PowerPoint

Antiplatelet agents are often preferred in elderly patients because of a perceived lower risk of bleeding [14]. They also decrease the risk of AF-related stroke, but to a much lesser extent (i.e. 20%) than VKA [6]. In addition, a meta-analysis of 12 AF trials suggests that the relative efficacy of antiplatelet therapy to prevent stroke decreases with ageing: hazard ratio for ischaemic stroke at age 50 is 0.40 (95%CI 0.22–72) but gradually increases with advancing age, exceeding 1.0 at age 82 [15]. VKA were directly tested against aspirin in an elderly population (mean age 81.5 years) in the Birmingham atrial fibrillation treatment of the aged (BAFTA) study [16]. Warfarin (target INR 2–3) substantially decreased the risk of stroke, ICH or systemic embolus, compared with 75 mg of aspirin [relative risk, (RR) 0.48; 95%CI, 0.28–0.80; P = 0.003]. Results from ACTIVE-W confirm that oral anticoagulation even remains superior to dual antiplatelet therapy (i.e. aspirin plus clopidogrel) in reducing the incidence of stroke in high-risk AF patients [17]. Dual antiplatelet therapy is superior to aspirin alone in preventing stroke, but there is price to be paid in terms of an increased risk of major bleeding complications [18].

Limitations of current pharmacological stroke prevention strategies in elderly patients with AF

Existing strategies for preventing stroke in AF have inherent limitations that are often particularly relevant to elderly patients (Table 1). The anticoagulant response to VKA is inconsistent and unpredictable in general, but maintaining optimal anticoagulation might be especially challenging in elderly persons. In an individual patient, the level of anticoagulation is influenced by genetic factors, comorbidities, diet, concomitant medication, age and compliance. Several drug-related characteristics limit the practical use of VKA, including its slow onset and offset of action, multiple drug and food interactions. Owing to their narrow therapeutic window, VKA also require frequent anticoagulant monitoring and dose adjustments to avoid both thromboembolic risk owing to a low International Normalized Ratio (INR) and bleeding risk because of a high INR. In particular, elderly patients react slower to changes in VKA dose [19]. They also often take several concomitant medications or have comorbidities that can affect the anticoagulant effect of VKA [19, 20]. Although less potent in preventing stroke, antiplatelet agents increase the risk of gastrointestinal bleeding complications especially in the elderly as well [21].

Table 1.   Possible issues related to vitamin K antagonists (VKA) use and potential advantages of new oral anticoagulant agents in elderly patients with atrial fibrillation
Issues related to VKA in the elderlySpecific advantages of new agents for elderly patients
Narrow therapeutic windowBroader therapeutic window
Unpredictable anticoagulant responseMore predictable and more stable anticoagulant response
Need for frequent monitoringNo need for routine monitoring
Slow onset/offset of actionShorter half-life and faster offset of action
Diet interactionsNo diet interactions
Drug interactionsFewer drug interactions

Underuse and poor control of VKA in the elderly

Despite the strong reason to believe that VKA reduce stroke and improve net clinical benefit in elderly patients, they are used in only one-third of eligible patients over the age of 85 years [22]. In a systematic review of 54 VKA studies in AF from 1998 to 2008, the percentage of patients with a prior stroke who were anticoagulated ranged from 81% to only 19%, whilst only 70% (range, 39–92%) of patients with a CHADS2 score ≥2 received VKA [23]. In addition, in clinical studies, the INR remains in the therapeutic range only during 29–75% of the time, contributing to both stroke and haemorrhagic risk [24]. Results from the Euro Heart Survey indicate that antithrombotic undertreatment of high-risk patients with AF is associated with worse 1-year prognosis; overtreatment did not appear to be associated with a higher bleeding risk [25]. In contrast, excessively high anticoagulation levels were observed in 14.2% of 10 020 patients ≥65 years of age, explaining 25.6% (95%CI 19.4–31.7) of all serious haemorrhages [26]. In the same cohort of senior patients, thromboembolic events were almost seven times higher when the INR was below 2 (RR, 6.9; 95%CI, 4.6–10.3) but also more than twice as high with an INR above 3 (RR, 2.3; 95%CI, 2.3–3.7), than when the INR was held between 2 and 3. These findings clearly illustrate that elderly patients with AF do benefit from VKA, provided that anticoagulation levels can be held within target range. In addition, a retrospective cohort study of 2235 VKA-treated AF patients with regular INR readings clearly demonstrates a graded stroke and mortality reduction with increasing time spent within the therapeutic range (i.e. INR 2–3) [27]; for every 10% increase in time out of target range, the risk of mortality increases with 29% (P < 0.001), underscoring the impact of suboptimal anticoagulation levels [28].

An almost systematic underuse of VKA is particularly worrisome in the elderly. The percentage of hospitalized patients with AF discharged with VKA indeed dramatically falls with advancing age (Table 2) [29]. In the ATRIA cohort, only 62% of high-risk patients with AF between 65 and 75 years of age and without contraindications were treated with VKA [30]. The decision to withhold anticoagulation in the elderly with AF in the absence of formal contraindications is multifactorial, often the result of a combination of underestimating of thromboembolic risk, overestimating of bleeding risk including intracranial haemorrhage (ICH), frailty and risk of falling and the need for monitoring (Table 2) [29, 31–33]. Fear of interactions with concomitant medication might also play a role [20]. Data from a prospective study of hospitalized patients with AF above 65 years, half of which older than 80 years, identified older age, cognitive impairment, history of falling, history of haemorrhage, patient preference and terminal illness as independent baseline predictors of not receiving warfarin at discharge (Table 3) [29]. Cognitive dysfunction, even mild, also appears to be an independent marker of suboptimal anticoagulation in the elderly [34]; at the same time, patients with impaired cognitive dysfunction also have an increased risk of both vascular events and bleeding complications. Vice versa, in a study of patients with known AF who presented with ischaemic stroke and no contraindications for anticoagulation therapy, only 54% were receiving warfarin on admission [35]. Increasing age was associated with a reduced likelihood of receiving warfarin whilst a history of stroke or transient ischaemic attack or congestive heart failure was associated with increased odds of warfarin use. Strikingly, only one of three eligible patients >85 years were receiving warfarin on admission for stroke compared with three of four patients <75 years old [35]. Vice versa, elderly patients with AF might also have formal contraindications for VKA [36], although the proportion of truly ineligible patients is (much) lower than the perceived [37]. The development of novel oral antithrombotic agents, such as direct thrombin inhibitors and factor Xa inhibitors, may provide a safer and more effective alternative for stroke prevention in elderly patients with AF.

Table 2.   Predictors for withholding vitamin K antagonists in patients ≥65 year (from Hylek et al. [29])
Independent predictorsAdjusted OR (95%CI)P-value
Age (per 10 years)1.49 (1.08–2.06)0.015
Female1.56 (0.98–2.47)0.059
Cognitive impairment6.35 (2.74–14.47)<0.001
Hx of falling5.61 (2.50–12.57)<0.001
Hx of haemorrhage3.22 (1.87–5.56)<0.001
Advanced malignancy4.57 (1.82–11.46)0.001
Table 3.   Physician-cited reasons vitamin K antagonists underuse in the elderly (%) (from Hylek et al. [29])
Physician-cited reasons (%)
Haemorrhage (33)
Falls (32)
Patient refused or history of nonadherence (14)
Cognitive impairment (3)
Advanced illness (8)
Alcohol abuse (2)

Balancing stroke prevention against bleeding risk in elderly patients with AF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

Bleeding complications

When prescribing anticoagulant agents in patients with AF, it is essential to optimize the balance between efficacy and safety, regardless of age. Unfortunately, bleeding complications owing to VKA are particularly frequent in elderly patients, especially in the early phase after treatment initiation [16, 38]. In ‘real-world’ consecutive patients, the cumulative incidence of major haemorrhage is 13.1 per 100 patient-years when older than 80 years of age, versus only 4.7 for those below 80 years [39]. As the decision to start VKA is based on balancing risk versus benefit in daily practice, especially in an ageing population, it appears to be reasonable to include risk factors for bleeding complications into a decision model (Table 4). If warfarin is the treatment of choice, avoiding excessive loading doses, good INR control (at least 65% of time in therapeutic range) combined with an effective healthcare infrastructure that helps to achieve INR therapeutic targets is essential [40, 41]. The implementation of hospital guidelines developed from evidence-based recommendations also can improve the appropriateness of warfarin use in elderly patients with AF at hospital discharge, as does the use of nomograms, but it remains unknown whether this translates into a reduced risk of bleeding (Table 4) [42]. To facilitate comparing the risk of haemorrhage in anticoagulated AF trials, bleeding scores have been created, such as the HEMORR2HAGES classification scheme [43]. Of the several proposed schemes, the most recent one, HAS-BLED, appears to be both reasonably predictive and simple to use in patient care [44, 45]. The HAS-BLED score was derived from the SPORTIF III and SPORTIF V trials and incorporates hypertension, abnormal liver or renal function (1 point each), stroke, bleeding history or predisposition, labile INR (<60% in the therapeutic range of INR 2–3), elderly (>75 years), and drugs/alcohol (1 point each; includes antiplatelet agents or NSAIDs). Significant age-specific predictive factors for bleeding complications patients on VKA include insufficient patient education, polypharmacy and INRs above the therapeutic range [46]. Nevertheless, the risk of major bleeding only appears to increases modestly with increasing thromboembolic risk, resulting in a greater absolute net clinical benefit of OAC the older the patient [7, 15].

Table 4.   Measures to improve vitamin K antagonists (VKA) use/control in elderly patients
Possible measures to improve VKA use/control in elderly patients
Improved physician guidance
 Recommendation of risk scores for stroke (CHADS2, CHA2DS2-VASc) [11, 12]
 Recommendation of risk scores for bleeding (e.g. HASBLED) [45]
 Control of additional risk factors for bleeding (e.g. hypertension, aspirin use)
Improved INR monitoring and adherence
 Discharge INR nomograms
 Healthcare infrastructure (e.g. accessible INR testing facilities)
 VKA education

Intracranial haemorrhages

Of particular concern in an ageing population are VKA-associated ICH (Fig. 3). Although the incidence of ICH is low (0.7%, including haemorrhagic stroke, in elderly patients treated with warfarin in the BAFTA study [16]), ICH does account for almost 90% of deaths from VKA-associated bleeding and the majority of disability in survivors [47]. Hence, the risk of intracranial haemorrhage should be considered rather than the risk of all major haemorrhages [47, 48]. The relative odds of ICH increase with age and anticoagulation intensity: its risk is particularly increased in the very elderly and at INRs ≥3.5 [49]. Although elderly patients typically have comorbidities that predispose for ICH, including hypertension or a history of cerebral ischaemia, a relative increase in the annual event rate of major haemorrhage including intracranial of 1.2% per older age category in warfarin-treated patients with AF persists after adjusting for other risk factors [30].

Fear for ICH is a major factor in the widespread underuse of VKA in elderly people. One in four patients above 80 years also stops taking warfarin within the first year of initiation, predominantly because of these safety concerns [39]. A case-base analysis suggests that a perceived higher risk of falls should not prevent VKA treatment in elderly patients with AF, as the benefit in terms of reducing stroke greatly outnumbers the increased risk of fall-related ICH; in fact, it was calculated that a person on warfarin must fall almost 300 times in 1 year to outweigh the benefit of VKA [33, 50]. Improved understanding how to calculate haemorrhagic risk against ischaemic risk is essential to evaluate whether or not to anticoagulate an elderly patient. Keeping the INR ≤3.0, controlling hypertension and avoiding the addition of aspirin to VKA help to reduce the frequency of ICH (Table 4) [51]. Avoiding over-dosing of elderly patients on warfarin certainly also limits the risk of haemorrhage [52]. At least in selected elderly patients with AF, careful INR control targeted at 2.5 (accepted range 1.8–3.3) through an anticoagulant clinic appears to limit the risk of haemorrhage [53]. One strategy to minimize the risk of bleeding complications in daily practice is often to specifically target a low INR in elderly patients with AF. Lowering the INR target from 3–4.5 to 2.5–3.5 was shown to decrease the risk of major haemorrhage, mainly because of a reduction in ICH [54]. A small study even suggests that elderly patients might be better managed on very low-intensity anticoagulation (INR target of 1.5–2.0, median INR 1.86) therapy compared with standard care [55]. Interestingly, the 2008 Japanese AF guidelines do recommend an INR target of 1.6–2.6 in patients above 70 years (Table 4) [56]. In any case, there is no consensus on this strategy particularly because a (very) low target INR is not consistently associated with a lower rate of ICH but with an increased risk of ischaemic stroke [49]; European and North American guidelines do not recommend lower INR levels in the elderly [8–10, 57]. In addition, Hylek et al. [58] demonstrated that an INR above 2 is associated not only with a lower risk of stroke, but also with a lower severity or risk of dying from stroke. On aggregate, subanalyses from VKA studies in patients with AF suggest that lower INR targets or suboptimal controlled INR rates over time are clearly inferior in preventing stroke.

Alternatives for stroke and ICH prevention

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

Although most elderly patients with AF require effective antithrombotic therapy to reduce their risk of stroke, data suggest that a significant proportion of elderly patients with AF are not suitable for warfarin [36]. The adoption of newer, easier to use and safer anticoagulants might lower the threshold to initiate oral anticoagulation therapy in patients with AF, owing to their better safety/benefit profile (Table 1) [59]. The direct thrombin inhibitor ximelagatran appeared to be as effective and safer compared with VKA in elderly patients in the SPORTIF III and SPORTIF V studies, but its development was discontinued because of excessive liver toxicity [60].

In addition, a number of factor Xa inhibitors are being developed for preventing stroke in patients with AF, including rivaroxaban, apixaban and edoxaban. Rivaroxaban (20 mg qd) was noninferior to VKA in preventing stroke or systemic embolism in high-risk patients with AF (mean CHADS2 score 3.5) in the intention-to-treat analysis of the ROCKET-AF trial [61]. Major or clinically relevant bleeding complications were similar in both treatment arms, but the risk of intracranial haemorrhage was significantly reduced with rivaroxaban (HR 0.67, 95%CI 0.47–0.93). The efficacy as well as safety of rivaroxaban appears to be consistent irrespective of age, although more detailed analyses on the elderly have not yet been presented. Apixaban was shown to be superior to VKA in the recent double-blind ARISTOTLE trial [62]. Apixaban 5 mg bid significantly reduced the primary end-point of stroke or systemic embolism by 21% and of major bleeding by 31%. No interaction with age was observed for the primary end-point as well as for major bleeding. In the AVERROES trial, apixaban was also found to be superior to aspirin in preventing stroke whilst not increasing bleeding complications in patients with AF (mean age 70 ± 10 years) for whom VKA were deemed unsuitable [63]. Awaiting more detailed analyses in the elderly, no significant interaction with age was observed in this study as well, indicating that apixaban is a better alternative than aspirin for elderly patients with AF unsuitable for VKA. Finally, edoxaban is currently being compared to VKA in the ENGAGE trial [64]. On aggregate, the factor Xa inhibitors apixaban and rivaroxaban offer advantages over warfarin in terms of stroke prevention and risk of bleeding complications, and are likely to be an alternative treatment option for elderly patients with AF. To date, no oral factor Xa inhibitor has yet been approved for stroke prevention in AF. Hence, in the following paragraphs, we focus on the oral reversible direct thrombin inhibitor dabigatran, the only novel oral anticoagulant currently approved for use in AF and recommended in guidelines as an alternative to warfarin.

Is tailored dosing of dabigatran etexilate the answer for elderly patients with AF?

Dabigatran, the active moiety of dabigatran etexilate, is an oral direct thrombin inhibitor that, in contrast with VKA, has few drug–drug and no drug–food interactions, and is approximately 80% renally excreted, without requirement for routine monitoring. It has already been approved in many countries worldwide as thromboprophylaxis following hip or knee replacement surgery and has been granted approval in North America (US and Canada), Europe, Australia, Japan, Korea and several other countries for stroke prevention in patients with AF at risk of stroke. Two doses, 110 and 150 mg bid, were tested in the 18 113-patient RE-LY study, which included 7528 AF patients aged 75 and older [65]. To be eligible, patients needed to have documented AF at screening or within the previous 6 months and have at least one additional risk factor for stroke, including previous stroke or TIA, LV ejection fraction below 40% or symptomatic heart failure, and an age above 75 years or between 65 and 75 with concomitant diabetes, hypertension or coronary artery disease. Patients within 14 days of a stroke (6 months in case of a severe, disabling stroke) were excluded from RE-LY, as well as those with increased bleeding risk, chronic renal impairment (clearance below 30 mL min−1), severe valvular disease, active liver disease, and recent gastrointestinal (GI) ulcer (<30 days) or bleeding (<1 year). Long-term use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) or concomitant heparin and fibrinolytic agents was discouraged in the RE-LY trial [66]. NSAIDs and antiplatelet agents can be combined with dabigatran if clinically indicated, but may increase the risk of bleeding.

In the overall population, dabigatran 150 mg bid was superior to warfarin for preventing stroke or systemic embolism (RR 0.65, 95%CI 0.52–0.81, < 0.001) whilst both therapies showed similar rates of major bleeding (3.32% vs. 3.57% respectively, = 0.13). In contrast, dabigatran 110 mg bid showed similar efficacy compared with warfarin but a significantly lower rate of major bleeding complications (2.87% vs. 3.57%, < 0.003). Rates of intracranial haemorrhage were significantly lower with both doses of dabigatran (HR 0.30 (95%CI 0.19–0.45, P < 0.0001) and 0.41 (0.28–0.60, P < 0.0001), respectively), which was consistent across all age groups [65, 67]. Haemorrhagic stroke was also significantly lower with both doses of dabigatran when compared to warfarin [65, 67].

A significant interaction between age and treatment assignment was observed in terms of major bleeding complications. In patients aged <75 years, dabigatran 110 mg 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 and older (4.43 vs. 4.37%, = 0.89) [68]. In contrast, 150 mg dabigatran bid also was associated with a lower risk of major bleeding in patients younger than 75 (2.12% vs. 3.04%, < 0.001), versus a trend towards more major bleeding complications in those above 75 years of age (5.10% vs. 4.37%, = 0.07). Although the interaction was significant for extracranial bleeding, 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 (P for interaction 0.28 and 0.29, respectively) (Fig. 4). These analyses imply that all bleeding complications including ICH are consistently lower with both doses of dabigatran compared to VKA in younger patients, whilst in those aged ≥75 years, ICH risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran [68]. Figure 5 also illustrates that the benefit of dabigatran in reducing extracranial bleeding complications attenuates with increasing age, whilst the benefit of dabigatran over warfarin for prevention of stroke/systemic embolism was clear throughout all age categories. One hypothesis that might explain dabigatran’s lower rates of ICH across all ages is that it does not interfere with tissue factor-dependent hemostatic mechanisms in the brain, whereas VKA reduces the formation of factor VIIa and tissue factor complexes. Tissue factor is found in high concentrations in the brain [68].

image

Figure 4.  Annual rates of intracranial haemorrhage (ICH) according to age in RE-LY (RR = relative risk versus VKA; Int P = P-value for interaction).

Download figure to PowerPoint

image

Figure 5.  Annual rates of stroke/non-CNS embolism and major bleeding according to age in RE-LY.

Download figure to PowerPoint

Intuitively, these results from RE-LY trial appear to be especially appealing for stroke prevention in an elderly AF population: the observation that 110 mg dabigatran bid is associated with similar efficacy to warfarin for preventing stroke and systemic emboli and significantly less ICH and haemorrhagic stroke without increasing major bleeding is of particular importance for elderly patients in need of effective anticoagulation. Especially elderly patients with AF now treated with antiplatelet agents or not receiving antithrombotic therapy at all might now be considered for stroke prophylaxis with dabigatran. As renal function gradually declines with advancing age [69], physicians might still hesitate to prescribe dabigatran, which is mostly renally cleared, to older patients. The benefits of dabigatran at doses used in RE-LY appear to be consistent irrespective of renal function, although dabigatran has not been evaluated in patients with a creatinine clearance of <30 mL min−1 [68]. In contrast to VKA treatment, it is essential to consider the renal function to allow for an appropriate dosing decision of dabigatran. Especially in the elderly, suspected changes in renal function should be checked to prevent overexposure to dabigatran. The efficacy and safety of dabigatran have also not been evaluated in elderly patients with AF excluded from the RE-LY study, including those with recent GI bleeding or active ulcer, or those with severe valvular disease or mechanical valves.

In Canada and in the EU, regulatory agencies recommend the use of dabigatran 150 mg BID for patients below 80 years of age and the 110 mg BID dose for patients with an age of 80 years and above. The selected age cut-off was based on a favourable benefit/safety profile of the 110 mg bid dose in the 3016 patients above 80 years in RE-LY: hazard ratio 0.68 (95%CI 0.44–1.05) for stroke and systemic emboli and 1.12 (0.84–1.149) for major bleeding events (unpublished data from RE-LY included in the Canadian label: http://www.boehringer-ingelheim.ca/en/Home/Human_Health/Our_Products/index.htm).

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

Elderly patients with AF, who constitute almost half of all patients with AF, are at significantly increased risk of stroke. Anticoagulant therapies, especially VKA, clearly reduce the risk of stroke in all patients including the elderly but are frequently underused in older patients. Failure to initiate VKA in elderly patients with AF is related to a number of factors, including the limitations of current therapies and the increased risk of major haemorrhage associated with advanced age and anticoagulation therapy. Of particular concern is the risk of ICH, which is associated with high rates of mortality and morbidity. Novel oral anticoagulant agents that are easier to use and might offer similar or better levels of stroke prevention with a similar or reduced risk of bleeding should increase the use of antithrombotic therapy in the management of elderly patients with AF. Amongst these new agents, the recently approved direct thrombin inhibitor dabigatran provides effective stroke prevention with a significant reduction of ICH and enables clinicians to tailor the dose according to age and haemorrhagic risk.

Conflict of interest statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References

PRS reports receiving institutional research grants from Boehringer-Ingelheim, Daiichi-Sankyo, and Bayer; MB and AC are full-time employees of Boehringer-Inghelheim; JO reports receiving institutional research grants, consulting and lecture fees from Boehringer-Ingelheim and consulting and lecture fees from Bayer and Bristol-Myers Squibb; JE & JSH report receiving a research grant from Boehringer-Ingelheim.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Stroke prevention in the elderly
  5. Balancing stroke prevention against bleeding risk in elderly patients with AF
  6. Alternatives for stroke and ICH prevention
  7. Conclusions
  8. Conflict of interest statement
  9. Acknowledgement
  10. References
  • 1
    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: 94953.
  • 2
    Go AS, Hylek EM, Phillips KA et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285: 23705.
  • 3
    Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 9838.
  • 4
    Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987; 147: 15614.
  • 5
    Saposnik G, Black SE, Hakim A, Fang J, Tu JV, Kapral MK. Age disparities in stroke quality of care and delivery of health services. Stroke 2009; 40: 332835.
  • 6
    Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 85767.
  • 7
    Singer DE, Chang Y, Fang MC et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009; 151: 297305.
  • 8
    Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011; 27: 7490.
  • 9
    Camm AJ, Kirchhof P, Lip GY et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369429.
  • 10
    Fuster V, Ryden LE, Cannom DS et al. ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011; 57: e10198.
  • 11
    Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 286470.
  • 12
    Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010; 137: 26372.
  • 13
    Olesen JB, Lip GY, Hansen ML et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011; 342: d124.
  • 14
    Nieuwlaat R, Capucci A, Lip GY et al. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2006; 27: 301826.
  • 15
    van Walraven C, Hart RG, Connolly S et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke 2009; 40: 14106.
  • 16
    Mant J, Hobbs FD, Fletcher K et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493503.
  • 17
    Connolly S, Pogue J, Hart R et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 190312.
  • 18
    Connolly SJ, Pogue J, Hart RG et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360: 206678.
  • 19
    Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001; 135: 393400.
  • 20
    Howard PA, Ellerbeck EF, Engelman KK, Patterson KL. The nature and frequency of potential warfarin drug interactions that increase the risk of bleeding in patients with atrial fibrillation. Pharmacoepidemiol Drug Saf 2002; 11: 56976.
  • 21
    Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 237383.
  • 22
    Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999; 131: 92734.
  • 23
    Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123: 63845 e4.
  • 24
    Wan Y, Heneghan C, Perera R et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ Cardiovasc Qual Outcomes 2008; 1: 8491.
  • 25
    Nieuwlaat R, Olsson SB, Lip GY et al. Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. The Euro Heart Survey on Atrial Fibrillation. Am Heart J 2007; 153: 100612.
  • 26
    van Walraven C, Oake N, Wells PS, Forster AJ. Burden of potentially avoidable anticoagulant-associated hemorrhagic and thromboembolic events in the elderly. Chest 2007; 131: 150815.
  • 27
    Morgan CL, McEwan P, Tukiendorf A, Robinson PA, Clemens A, Plumb JM. Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control. Thromb Res 2009; 124: 3741.
  • 28
    Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 4727.
  • 29
    Hylek EM, D’Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37: 107580.
  • 30
    Fang MC, Go AS, Hylek EM et al. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006; 54: 12316.
  • 31
    Friberg L, Hammar N, Ringh M, Pettersson H, Rosenqvist M. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J 2006; 27: 195464.
  • 32
    Gallagher AM, Rietbrock S, Plumb J, van Staa TP. Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis? J Thromb Haemost 2008; 6: 15006.
  • 33
    Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159: 67785.
  • 34
    Flaker GC, Pogue J, Yusuf S et al. Cognitive function and anticoagulation control in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2010; 3: 27783.
  • 35
    Partington SL, Abid S, Teo K, Oczkowski W, O’Donnell MJ. Pre-admission warfarin use in patients with acute ischemic stroke and atrial fibrillation: The appropriate use and barriers to oral anticoagulant therapy. Thromb Res 2007; 120: 6639.
  • 36
    Carroll K, Majeed A. Comorbidity associated with atrial fibrillation: a general practice-based study. Br J Gen Pract 2001; 51: 8846, 9–91.
  • 37
    Verheugt FW. Who is ineligible for warfarin in atrial fibrillation? Lancet 2009; 374: 5101.
  • 38
    Torn M, Bollen WL, van der Meer FJ, van der Wall EE, Rosendaal FR. Risks of oral anticoagulant therapy with increasing age. Arch Intern Med 2005; 165: 152732.
  • 39
    Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 268996.
  • 40
    Heneghan C, Tyndel S, Bankhead C et al. Optimal loading dose for the initiation of warfarin: a systematic review. BMC Cardiovasc Disord 2010; 10: 18.
  • 41
    Marinigh R, Lip GY, Fiotti N, Giansante C, Lane DA. Age as a risk factor for stroke in atrial fibrillation patients implications for thromboprophylaxis: Implications for thromboprophylaxis. J Am Coll Cardiol 2010; 56: 82737.
  • 42
    Bo S, Valpreda S, Scaglione L et al. Implementing hospital guidelines improves warfarin use in non-valvular atrial fibrillation: a before-after study. BMC Public Health 2007; 7: 203.
  • 43
    Gage BF, Yan Y, Milligan PE et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151: 7139.
  • 44
    Lip GY, Frison L, Halperin JL, Lane D. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2010; 58: 13989.
  • 45
    Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: 1093100.
  • 46
    Kagansky N, Knobler H, Rimon E, Ozer Z, Levy S. Safety of anticoagulation therapy in well-informed older patients. Arch Intern Med 2004; 164: 204450.
  • 47
    Fang MC, Go AS, Chang Y et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120: 7005.
  • 48
    De Caterina R, Connolly SJ, Pogue J et al. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur Heart J 2010; 31: 213340.
  • 49
    Fang MC, Chang Y, Hylek EM et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: 74552.
  • 50
    Gage BF, Birman-Deych E, Kerzner R, Radford MJ, Nilasena DS, Rich MW. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118: 6127.
  • 51
    Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 2005; 36: 158893.
  • 52
    Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005; 127: 204956.
  • 53
    Copland M, Walker ID, Tait RC. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation. Arch Intern Med 2001; 161: 21258.
  • 54
    Torn M, van der Meer FJ, Rosendaal FR. Lowering the intensity of oral anticoagulant therapy: effects on the risk of hemorrhage and thromboembolism. Arch Intern Med 2004; 164: 66873.
  • 55
    Pengo V, Cucchini U, Denas G et al. Lower versus standard intensity oral anticoagulant therapy (OAT) in elderly warfarin-experienced patients with non-valvular atrial fibrillation. Thromb Haemost 2010; 103: 4429.
  • 56
    JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2008): digest version. Circ J 2010; 74: 2479500.
  • 57
    Wann LS, Curtis AB, January CT et al. ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57: 22342.
  • 58
    Hylek EM, Go AS, Chang Y et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349: 101926.
  • 59
    Eckman MH, Singer DE, Rosand J, Greenberg SM. Moving the tipping point: the decision to anticoagulate patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2011; 4: 1421.
  • 60
    Ford GA, Choy AM, Deedwania P et al. Direct thrombin inhibition and stroke prevention in elderly patients with atrial fibrillation: experience from the SPORTIF III and V Trials. Stroke 2007; 38: 296571.
  • 61
    Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 38391.
  • 62
    Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 98192.
  • 63
    Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 80617.
  • 64
    Ruff CT, Giugliano RP, Antman EM et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010; 160: 63541.
  • 65
    Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 113951.
  • 66
    Ezekowitz MD, Connolly S, Parekh A et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 2009; 157: 80510.
  • 67
    Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 18756.
  • 68
    Eikelboom JW, Wallentin L, Connolly SJ et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123: 236372.
  • 69
    Coresh J, Selvin E, Stevens LA et al. Prevalence of chronic kidney disease in the United States. JAMA 2007; 298: 203847.