Use of newer oral anticoagulants in AF

A guide to using novel oral anticoagulants (NOACs) for stroke prevention in non-valvular atrial fibrillation, including the safety and efficacy profiles of newer anticoagulants and how to switch patients from warfarin to NOACs.

Intracerebral haemorrhage: NOACs are lower risk than warfarin
Intracerebral haemorrhage: NOACs are lower risk than warfarin

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. It affects more than 2.3m patients in the US and more than 6m patients in Europe. It affects more than 1m people in the UK, but remains underdiagnosed. Its UK prevalence is estimated at 2.47% in men and 1.56% in women, but this rises significantly with age (see British Heart Foundation Cardiovascular Disease Statistics 2014).

Cerebral thromboembolism is a major complication of AF, causing the most debilitating strokes. AF amplifies stroke risk fivefold and is present in 15-20% of patients diagnosed with an embolic stroke. 

Consequently, the most important goal of AF treatment is to prevent strokes by objectively assessing the stroke risk in all patients, for example, with the CHA2DS2-VASc score (table 1) and therapeutically anticoagulating those at significant risk (CHA2DS2-VASc ≥1 in men and ≥2 in women). 

The stroke risk must be offset against the bleeding risk, as assessed by the HAS-BLED score, where ≥3 indicates a significant risk (table 2).

Table 1: CHA2DS2-VASc score for stroke risk in AF
Feature Score
Congestive heart failure 1
Hypertension  1
Age >75 years  2
Age 65 to 74 years 1
Stroke/TIA/thromboembolism 2
Vascular disease (previous MI, peripheral arterial disease or aortic plaque) 1
Diabetes mellitus  1
Female 1
Table 2 HAS-BLED bleeding risk score (maximum nine points)
H Hypertension  1
A Abnormal renal and liver function (1 point each)  1 or 2
S Stroke  1
B Bleeding  1
L Labile INRs  1
E Elderly (age >65 years)  2
D Drugs or alcohol >8 units/week (1 point each)  1 or 2


The longest experience of anticoagulation in AF has been with the vitamin K antagonist warfarin. This suppresses the synthesis of vitamin K dependent clotting factors (II, VII, IX and X), and proteins C and S by inhibiting vitamin K epoxide reductase. 

Warfarin does not inhibit circulating clotting factors, so therapeutic anticoagulation can take up to five days. This sometimes necessitates bridging with low molecular weight (LMW) heparins. 

Once established, warfarin has a long half-life, although anticoagulation can be rapidly reversed using vitamin K and prothrombin complex concentrates. The intensity of anticoagulation with warfarin must be regularly monitored with the INR of the prothrombin time, necessitating regular blood tests. The recommended INR range in AF is two to three. 

Warfarin exhibits non-linear pharmacokinetics and significant drug, food and metabolic state interactions. This causes considerable INR variations, requiring continuing dose adjustments in most patients. 

Warfarin has a narrow therapeutic window, with exponential increases in stroke risk at INR less than 2 and bleeding risk  at INR greater than 3.5. Despite this, it is highly effective and reduces the risk of all strokes by 64% (95% CI 49-74%), ischaemic strokes by 67% (95% CI 54-77%) and all-cause mortality by 26% (95% CI 3-43%).1 However, difficulties with warfarin have resulted in many patients at high risk of bleeding remaining unanticoagulated.

Furthermore, patients taking warfarin spend only 55-65% of the time within the recommended therapeutic range.2 This has led to the development of the non-vitamin K antagonist drugs or NOACs. 

Novel oral anticoagulants

NOACs were introduced a few years ago, beginning with dabigatran. Their mechanism of anticoagulation is either inhibition of thrombin (factor IIa) or activated factor X (Xa) (table 3). Four major trials comparing the efficacy of NOACs with warfarin for stroke prevention in non-valvular AF have been concluded.3-6

Table 3: Pharmacology of anticoagulant drugs


Synthesis of II, VII, IX, X

IIa (thrombin)




Dose (mg)











Once daily

Twice daily

Once daily

Twice daily

Once daily

Hours to effect

72 to 96 

2.2 to 4.5

1 to 3 

1 to 2 


Half-life (hours)


12 to 14 


(if creatinine <30)

5 to 9 

9 to 13 (elderly)

8 to 15 

10 to 14 

Renal excretion 







* If creatinine clearance 15-49mL/min

** If creatinine clearance 15-29mL/min, or serum creatinine ≥133 micromole/L + age ≥80 years or weight ≤60kg

Safety and efficacy of NOACs 

A safety and efficacy meta-analysis7 of the NOAC trials concluded the following: 

  • Major bleeds were lower with apixaban, dabigatran 110mg, edoxaban 30mg and 60mg compared with warfarin, whereas dabigatran 150mg and rivaroxaban were equivalent.
  • All NOACs had a lower risk of intracranial bleeding compared with warfarin.
  • Only edoxaban 30mg reduced the risk of GI bleeding.
  • Both dabigatran 150mg and apixaban were better than warfarin at reducing all strokes and systemic emboli.
  • Only dabigatran 150mg was better than warfarin at reducing ischaemic strokes.
  • Edoxaban 30mg had the lowest risk for major and GI bleeds, followed by apixaban. Rivaroxaban had the highest risk.
  • Dabigatran 110mg and edoxaban 30mg had the lowest risk for intracranial bleeding, followed by dabigatran 150mg and apixaban. Warfarin had the highest risk.
  • Rivaroxaban had the lowest MI risk, followed by apixaban.
  • Dabigatran 150mg had the best outcomes when measuring a combined outcome of stroke/systemic emboli, all strokes and ischaemic stroke, followed by apixaban, with edoxaban 30mg being the worst. It is noteworthy that the European Society of Cardiology (ESC) guidelines recommend using dabigatran 150mg in patients experiencing ischaemic stroke while on rivaroxaban or apixaban.7  
  • Warfarin has a worse safety/efficacy profile than all newer anticoagulants. The ESC guidelines consider NOACs as the first-line option in non-valvular AF (class IIa recommendation, level of evidence A).8 

These data would suggest apixaban offers a good balance between efficacy and safety. However, NOACs could also be tailored to specific patients. For example, those at high risk for stroke with a low risk of bleeding may benefit more from dabigatran 150mg. 

Conversely, edoxaban 30mg may be more appropriate in patients with a lower risk of stroke but a high risk of bleeding. Dabigatran 110mg, with its low risk of intracranial bleeding, may be more suitable in those with poorly controlled hypertension, previous haemorrhagic stroke, cerebral microhaemorrhages or amyloid.

Practical aspects of NOAC treatment

There is a detailed discussion of various aspects of NOAC treatment in a guide published by the European Heart Rhythm Association (EHRA),8 together with a web page that is constantly updated and an excellent resource.9 The following are useful to consider:

1 Initiating treatment

    • Calculate stroke and bleeding risk using CHA2DS2-VASc and HAS-BLED respectively 
    • Initiate the appropriate NOAC, taking into account age, weight, renal function and potential drug interactions
    • Give the patient an anticoagulant card detailing specifics about their NOAC (a generic version can be found on the EHRA website)
    • Educate the patient about the perils of missing a dose and overdosing
    • Organise regular follow-up
    • No routine tests of anticoagulation are necessary

Drug interactions9

3 Switching from warfarin to a NOAC

    • If INR <2, stop warfarin and start NOAC immediately
    • If INR 2.0 to 2.5, stop warfarin and start NOAC the following day
    • If INR ≥2.5, stop warfarin and recheck INR once it is expected to be 2.0 to 2.5. This will vary, depending on the initial INR 

4 Switching from NOAC to warfarin

    • Start warfarin concomitantly with NOAC. A loading dose is not required
    • Check INR regularly, just before NOAC is due, to minimise effect on INR. Once INR is 2.0 to 2.5, stop NOAC
    • Recheck INR 24 hours after last NOAC dose
    • Monitor INR closely in first four weeks, to ensure it remains within therapeutic range

5 NOAC to LMW heparin

    • Stop NOAC and start LMW heparin when the next NOAC dose would have been due

6 Aspirin or clopidogrel

    • Stop aspirin or clopidogrel and start NOAC immediately, provided there is no indication for combination therapy

7 Managing bleeding complications (covered in great detail here) 

    • If a patient is actively bleeding, urgent referral to secondary care is required. Patients will receive supportive measures, such as platelet transfusion or haemodialysis, until NOACs are out of the system

Dr Mehul Dhinoja is consultant cardiologist and electrophysiologist at BMI The London Independent Hospital

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  1. Hart RG, Pearce LA, Aguilar MI. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med (2007); 147: 590-2
  2. Tajer C, Ceresetto J, Bottaro FJ et al; TERRA Trial investigators. Assessment of the quality of chronic anticoagulation control with time in therapeutic range in atrial fibrillation patients treated with vitamin K antagonists by haemostasis specialists: the TERRA registry. Tiempo en rango en la República Argentina. Clin Appl Thromb Hemost (2016) pii: 1076029615623378. [Epub ahead of print]
  3. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med (2009); 361: 1139-51
  4. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med (2011); 365: 883-91
  5. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med (2011); 365: 981-92
  6. Giugliano RP, Ruff CT, Braunwald E et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med (2013); 369: 2093-104
  7. Camm AJ, Lip GY, De Caterina R et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J (2012); 33: 2719-47
  8. Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace (2015); 17(10): 1467-507 doi: 10.1093/europace/euv309. Epub 2015 Aug 31
  9. EHRA. Novel Oral Anticoagulants for Atrial Fibrillation

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