Anticoagulation Therapy (NOAC) and Atrial Fibrillation

Anticoagulation therapy in atrial fibrillation (AF) is divided into 2 main groups:

Vitamin K antagonists
NOAC (Novel Oral AntiCoagulants, Non-vitamin K antagonists), also referred to as:

DOAC (Direct Oral AntiCoagulants)

Infographic illustrating atrial fibrillation with a thrombus in the left atrial appendage and the principles of anticoagulation therapy including NOACs and warfarin.

Vitamin K antagonists inhibit coagulation factors (II, VII, IX, X) and include:

Warfarin (USA, Europe)
Acenocoumarol (Europe, Netherlands, Belgium, Spain)
Phenprocoumon (Europe, Germany, Austria, Switzerland)
Fluindione (Europe, France)

Warfarin is the most commonly used vitamin K antagonist.

The main disadvantage of warfarin is the need for regular INR monitoring, which should be maintained between 2–3,

because warfarin has a narrow therapeutic window, significant drug and food interactions,
and INR variability increases the risk of thrombosis (with low INR) or bleeding (with high INR).

In clinical practice, NOAC are used more frequently, as INR monitoring is not required. In clinical trials they demonstrate:

NOAC and warfarin provide comparable anticoagulant efficacy in the prevention of thromboembolism in AF.
NOAC are associated with a 50 % lower risk of intracranial bleeding compared with warfarin.

There are 4 NOAC available; three inhibit coagulation factor Xa and one inhibits factor IIa:

Rivaroxaban (Xa)
Apixaban (Xa)
Edoxaban (Xa)
Dabigatran (IIa)

In patients with body weight >120 kg or BMI >40 kg/m²

Warfarin is preferred over NOAC due to limited data for NOAC in this population.

NOAC (Non-Vitamin K Oral Anticoagulants)
NOAC	Standard dosing	Dose reduction criteria	Reduced dose
Apixaban (Eliquis)	5 mg twice daily	Dose reduction is recommended if at least two of the following are present: Age ≥ 80 years Body weight ≤ 60 kg Creatinine ≥ 133 µmol/L (CrCl < 50 ml/min)	2.5 mg twice daily
Dabigatran (Pradaxa)	150 mg twice daily	Dose reduction is recommended if at least one of the following is present: Age ≥ 80 years Concomitant use of verapamil Dose reduction should be considered if at least one of the following is present: Age 75 – 80 years CrCl 30 – 50 ml/min (creatinine 130 – 200 µmol/L) Gastritis, oesophagitis, GERD Condition associated with increased bleeding risk	110 mg twice daily
Edoxaban (Lixiana, Savaysa)	60 mg once daily	Dose reduction is recommended if at least one of the following is present: CrCl 15 – 50 ml/min (creatinine 130 – 350 µmol/L) Body weight ≤ 60 kg Concomitant use of: cyclosporine, dronedarone, erythromycin, ketoconazole	30 mg once daily
Rivaroxaban (Xarelto)	20 mg once daily	Dose reduction is recommended if: CrCl 15 – 50 ml/min (creatinine 130 – 350 µmol/L)	15 mg once daily

CrCl – creatinine clearance, GERD – gastro-oesophageal reflux disease

Adverse effects of NOAC
Adverse effect	Annual risk (%)
Minor bleeding (epistaxis, bruising)	10 – 15 %
Dyspepsia (especially with dabigatran)	5 – 10 %
Haematuria	1 – 3 %
Anaemia (due to bleeding)	1 – 3 %
Nausea	1 – 3 %
Major bleeding	1 – 2 %
Gastrointestinal bleeding	1 – 2 %
Intracranial bleeding	< 1 %
Elevated liver enzymes	< 1 %
Allergic / hypersensitivity reactions	< 1 %
Renal dysfunction (rarely in dehydration / bleeding)	< 1 %
Thrombocytopenia	< 1 %

Based on clinical trial data, there are 3 clinical situations in which patients with AF should receive anticoagulation irrespective of CHA₂DS₂-VA score:

Valvular AF (warfarin is always indicated):

Mechanical valve
Mitral stenosis (moderate or severe)

Hypertrophic cardiomyopathy (preferably NOAC or warfarin)
Amyloidosis (preferably NOAC or warfarin)

The main reason why warfarin is more effective in valvular AF is:

Warfarin acts on 4 coagulation factors (II, VII, IX, X) in the coagulation cascade
NOAC act on only one factor (IIa or Xa)

Anticoagulation therapy and atrial fibrillation	Class
In valvular atrial fibrillation: mechanical valve, or mitral stenosis (moderate or severe), warfarin (not NOAC) is always recommended as anticoagulation therapy irrespective of CHA₂DS₂-VA score.	I
During warfarin therapy, a target INR of 2–3 is recommended.	I
Switching from warfarin to NOAC is recommended if anticoagulation is inadequate (Time in Therapeutic Range < 70 %).	I
Dose reduction of NOAC is recommended only if dose reduction criteria are fulfilled.	I
In patients with body weight >120 kg or BMI >40 kg/m², warfarin is recommended according to CHA₂DS₂-VA score.	I
In patients with body weight >120 kg or BMI >40 kg/m², NOAC may be considered according to CHA₂DS₂-VA score.	IIb