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Next gen anticoagulants for non-valvular atrial fibrillation

The arrival of Dabigatran, an oral direct thrombin inhibitor (Factor II) has changed the treatment landscape for nonvalvular atrial fibrillation (NVAF). It has replaced the vitamin K dependent anti-coagulants.

The approval of Dabigatran in 2010 by the Food And Drug Administration, USA was followed by other newer anticoagulants like rivaroxaban, edoxaban and apixaban, all direct factor Xa (Factor Xa) inhibitors.

In a recently published network meta-analysis study in the BMJ,  23 randomised trials involving 94656 patients were analysed to compare the efficacy, safety and cost effectiveness of newer oral anticoagulants (NOACs) for patients with nonvalvular atrial fibrillation and to find the choice of NOACs for prevention of stroke in patients with NVAF.

The study showed NOACs, as a class, reduce the risk of stroke and all-cause mortality in patients with atrial fibrillation, and are safer with respect to major and intracranial bleeding than warfarin when used at doses to maintain an international normalised ratio (INR) of 2.0-3.0. Cost effectiveness analysis provided evidence that, despite their higher costs, several NOACs are preferable to warfarin and apixaban 5 mg twice daily has the highest expected incremental net benefit, followed by rivaroxaban 20 mg once daily, edoxaban 60 mg once daily, and dabigatran 150 mg twice daily.

Atrial fibrillation (AF) is the most common rhythm disorder of the heart (arrhythmia) and it has been recognised as a major global health burden due to increasing life expectancy and increase in the coronary risk factors with age. The prevalence of atrial fibrillation roughly doubles with each decade of age, rising to almost 9% at 80-90 years. AF leads to ineffective contraction of the atria and is associated with left atrial enlargement. This results in stagnation of blood and increased propensity for clot formation within the left atrium and atrial appendage with subsequent embolization to the brain causing ischaemic stroke.

The recently released Indian state level disease burden study showed stroke as the fifth leading cause of disease burden in 2016 while ischaemic heart disease occupy the first spot. Data on atrial fibrillation from India is however very limited.

Etiologic trends observed from the RELY-AF study which included  patients of AF from Africa, India and the Middle East were on average 10-12 years younger than those from other regions of the world. Similar observations were also noted from the  REALIZE AF and the first Indian registry, the Indian Heart Rhythm Society (IHRS) AF study where the average age of patients with AF in India was 60 years and 54 years respectively (a decade younger than their western counterparts).

The most dreaded complication of AF is stroke/thromboembolic events, the annual incidence of such an event in nonvalvular AF is 4% per year in India as compared to 5% in the western world.

It has also been observed that the time spent in the therapeutic range for oral anticoagulation is significantly lower in countries outside North America and Western Europe as shown in the ROCKET AF trial among closely monitored patients in the warfarin arm, a substantial proportion of participants from different geographical regions had subtherapeutic anticoagulation  international normalised ratio or INR (<2 for >25% of the time) which was 44% in India thereby increasing risk of stroke and other thromboembolic events.The average time spent in the therapeutic range has been observed to be 55-66%.

Vitamin K dependent anticoagulants (eg, warfarin and acenocoumarol) diminish the formation of platelet-rich and thrombotic clots in the left atrium preventing strokes and systemic embolization in patients with underlying AF and have been in use since 1950s and oral anticoagulation with warfarin (goal INR of 2 to 3) has been the mainstay of stroke prevention treatment  in patients with AF.

But they have many limitations like dietary restrictions, several drug interactions, frequent monitoring of prothrombin time and INR, need of bridging due to long half life (20-60 hours) with unfractionated heparin or low molecular weight heparin (LMWH) and narrow therapeutic window (INR 2 to 3). NOACs on the other hand have no dietary restrictions, can be used in fixed dosage (adjusted for age and renal function), rapid onset of action (shorter half life 12-17 hours), wide therapeutic window and do not require routine blood monitoring.

All these factors have lead to the newer anticoagulants such as dabigatran, rivaroxaban, edoxaban and apixaban to  become anticoagulants of choice in the western countries. However, their cost is substantially higher than that of warfarin and will remain so until market exclusivity periods end and generic products become available (indicative dates 2022, 2018, 2023, and 2020 for apixaban, dabigatran, edoxaban, and rivaroxaban respectively).

All the larger phase III trials comparing a NOAC with warfarin (RELY trial with Dabigatran, ROCKET AF trial with  Rivaroxaban, ARISTOTLE trial with Apixaban and ENGAGE AF-TIMI 48 trial with Edoxaban) showed that these novel oral anticoagulants (NOACs) were noninferior to warfarin  with dabigatran (150 mg) and apixaban being superior than the others for prevention of stroke. All NOACs also had lower rates of intracranial haemorrhage (bleeding) when compared to warfarin. However no direct trial comparing the different NOACs is available.

Dr O P Choudhury
Dr O P Choudhury
Dr O P Choudhury is a founding member and the editor of MediBulletin.com. A practising doctor for the last 22 years, he has been working in the neurology department of Indraprastha Apollo Hospitals for more than ten years. You can contact him at: dr.opchoudhury@medibulletin.com
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