POVZETEK

Prevalenca atrijske fibrilacije (AF), ki je najpogostnejša motnja srčnega ritma, v Evropi enakomerno narašča zaradi staranja populacije. Atrijska fibrilacija povzroči do 30 % ishemičnih možganskih kapi. Z njo povezane možganske kapi so hujše od drugih. Tveganje trombemboličnih dogodkov je mogoče učinkovito zmanjšati s peroralnimi protikoagulacijskimi zdravili. Zdravljenje z zaviralci vitamina K (ZVK) ima pomembne omejitve, tudi zaradi velikega tveganja za znotrajlobanjsko krvavitev in zaradi zahtev o natančnem laboratorijskem spremljanju. Nova oralna protikoagulacijska zdravila (NOP), neposredni zaviralci trombina ali zaviralci faktorja Xa lahko odpravijo omenjene omejitve. Apiksaban, selektivni zaviralec faktorja Xa, je Evropska agencija za medicino pred kratkim odobrila za preprečevanje ishemične možganske kapi pri bolnikih z nevalvularno atrijsko fibrilacijo. V raziskavi ARISTOTLE (the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) je apiksaban po 5 mg 2-krat na dan znatno zmanjšal pojavnost možganske kapi in sistemske embolije, kar so si v raziskavi zastavili za primarni cilj. Poleg tega se je izkazal tudi za varno zdravilo glede pojavnosti večjih krvavitvev. Menimo, da bodo nova oralna protikoagulacijska zdravila povečala uporabo protikoagulacijske zaščite pri bolnikih z atrijsko fibrilacijo, predvsem zaradi njihove večje varnosti in uporabe fiksnega odmerka zdravila. Zaradi pozitivnega razmerja med koristjo in tveganjem je zlasti apiksaban zelo obetavna alternativa zaviralcem vitamina K v zdravljenju ogrožene populacije bolnikov z atrijsko fibrilacijo.

Ključne besede: apiksaban, atrijska fibrilacija, možganska kap, novi peroralni antikoagulanti

SUMMARY

The prevalence of atrial fibrillation (AF), the most common rhythm disturbance, is steadily increasing due to the aging populations in Europe. AF is responsible for up to 30% of ischemic strokes. These AF-related strokes are more severe than other strokes. The risk of thromboembolic events can be efficiently reduced by oral anticoagulation. However, vitamin K antagonists (VKA) have important limitations including a strong increase of risk for intracranial bleeding and the requirement of close laboratory monitoring. New oral anticoagulants (NOAC), either direct thrombin inhibitors or factor Xa inhibitors, may overcome these limitations. Apixaban, a selective factor Xa inhibitor, has been approved recently for non-valvular AF by the European Medical Agency. In the ARISTOTLE (the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial apixaban 5 mg twice daily not only significantly reduced the primary efficacy endpoint of stroke and systemic embolism but also the primary safety endpoint of major bleedings. A significant reduction of all-cause mortality further emphasizes the favorable benefit-risk ratio of apixaban. In conclusion, NOAC may increase the use of anticoagulation in patients with AF due to their greater safety and the use of a fixed dose. Particularly, apixaban, due to its positive benefit-risk ratio, is a very promising alternative to VKA in the vulnerable population of AF patients.

Key words: apixaban, atrial fibrillation, new oral anticoagulants, stroke

INTRODUCTION

The prevalence of atrial fibrillation (AF), the most common rhythm disturbance, is steeply increasing with age (1) and is therefore steadily rising in the aging populations of Europe. AF at least doubles the risk of stroke and is responsible for up to 30% of ischemic strokes (2). AF not only increases the risk of stroke but also causes more severe strokes compared to ischemic strokes of other causes (3). Functional deficits are more severe and the 30 day mortality almost doubled in patients with AF-related stroke (3).

LIMITATIONS OF VITAMIN K ANTAGONISTS FOR PREVENTION OF THROMBOEMBOLIC EVENTS

As shown in a meta-analysis of randomized controlled trials with more than 28,000 patients oral anticoagulation most efficiently reduces the risk of thromboembolic events by 64 % in patients with AF (4). Vitamin K antagonists (VKA), which have been used as oral anticoagulants for several decades, have important limitations. VKA significantly increase the risk of intracranial bleeding, often with a fatal outcome. Moreover, VKA have a narrow therapeutic range which requires a close laboratory monitoring (5). In clinical practice, only about half of the patients are within the therapeutic range (international normalized ratio [INR] 2–3) (5). The risk of intracranial bleeding steeply increases when the INR exceeds 4. Due to these limitations only about half of the patients with an indication for VKA receive a VKA in clinical practice despite their proven benefits (6).

NEW ORAL ANTICOAGULANTS

New oral anticoagulants (NOAC), including the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban, have been introduced recently (7–9). The mean half life of the three drugs ranges between 12 and 15 hours. The renal elimination varies significantly ranging from only about 25 % with abixaban to about 80 % with dabigatran. All NOAC do not require regular laboratory monitoring and have shown to reduce significantly intracranial bleeding in large randomized controlled trials compared to VKA (7–9). Apixaban, a selective factor Xa inhibitor, has been recently approved for non-valvular AF by the European Medical Agency. In the AVERROES trial, patients unsuitable to VKA received either aspirin or apixaban 5 mg twice daily (10). The study was terminated prematurely due to safety concerns as the primary endpoint stroke and systemic embolism was reduced by 55 % in the apixaban arm without increasing the risk of bleeding. In the ARISTOTLE trial apixaban 5 mg twice daily was compared to VKA in more than 18,000 patients (8). Apixaban not only significantly reduced the primary efficacy endpoint of stroke and systemic embolism by 21 % but also the primary safety endpoint of major bleeding by 31 %. Of note, intracranial bleeding was reduced by 58 %. A significant reduction of all-cause mortality further emphasized the favorable benefit-risk ratio of apixaban. Moreover, a subgroup analysis of the ARISTOTLE trial has shown that apixaban may be particularly safe in patients with reduced renal function, a common problem in AF patients.

With regard to patients with previous stroke or transient ischemic attack (TIA) subgroup analyses revealed that the effects of NOAC are consistent in these high-risk patients (11–14). In ARISTOTLE 19 % of patients had a previous stroke or TIA. The absolute risk reduction with apixaban was higher in these patients due to the higher risk of (recurrent) stroke/TIA (14).

CONCLUSIONS

In conclusion, NOAC have been shown to be safe in patients with non-valvular AF and to reduce significantly intracranial bleeding, an often fatal complication of oral anticoagulation. The use of a fixed dose without the requirement of regular laboratory controls facilitates the use of anticoagulation and will hopefully increase the number of patients with non-valvular AF on anticoagulation therapy in daily practice. Particularly, apixaban, which simultaneously improved efficacy and safety, is a very promising alternative to VKA in the vulnerable population of AF patients. A significant reduction of mortality further emphasizes the favorable benefit-risk ratio of apixaban. Consistent effects of new oral anticoagulants can be expected in the high-risk group of patients with AF and previous stroke or TIA.

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