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 . 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) . 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 .
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 . 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 . 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 . 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 . 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 . 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 . 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, P < 0.001) whilst both therapies showed similar rates of major bleeding (3.32% vs. 3.57% respectively, P = 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%, P < 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%, P = 0.89) . 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%, P < 0.001), versus a trend towards more major bleeding complications in those above 75 years of age (5.10% vs. 4.37%, P = 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 . 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 .
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).
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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 , 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 . 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).