Anticoagulation module 3: Anticoagulant therapy

Released27 October 2021     Expires: 27 October 2023      Programme:

Sponsorship Statement:

This latest 2021 revision and earlier revisions of the anticoagulation modular programme have been funded by educational grants from Bayer. Bayer had no role in the writing of the modules and had no editorial control over the content.

The programme was originally supported by an educational grant from Bristol Myers Squibb (BMS) and Pfizer. BMS and Pfizer had no role in the writing of the modules and had no editorial control over the content.

Introduction

Module 1 explained the mechanisms and functions of haemostasis, and of the importance of the balance between coagulation and the dual processes of inhibition and fibrinolysis. Module 2 considered the pathology of arterial thrombosis, and the use of antiplatelet agents to treat or prevent this.

In this module, we focus on anticoagulant therapy – pharmacological intervention in the coagulation cascade. This is of central importance in treatment and prevention of thromboses which form under conditions of low shear – venous thromboembolism. In cardiology, it is used in three main situations: atrial fibrillation (AF), acute coronary syndromes (as an adjunct to antiplatelet agents) and heart valve disease. But before we look at these conditions, we must review the coagulation cascade.

The coagulation pathway revisited

A simplistic view of the coagulation cascade (see figure 1) can be divided into three pathways:

  • The ‘extrinsic pathway’ involves tissue factor and factor VII, which together form a second complex to generate factor Xa. This is the main pathway by which coagulation is activated in vivo.
  • The ‘intrinsic pathway’ sees coagulation factors XII, XI, IX, and VIII come together to form a complex that results in the conversion of factor X to activated factor X (that is, factor Xa). As a pathway for activation of coagulation this probably has minimal importance in vivo. However, factors VIII, IX and XI have crucial roles in amplification of the cascade.
  • In the ‘common pathway’, factor Xa combines with factor Va to form the prothrombinase complex that converts prothrombin into thrombin. This, in turn, generates fibrin from fibrinogen. Once stabilised by factor XIIIa, fibrin combines with platelets (and often with red cells) to form a thrombus.
f1
Figure 1. Simplified intrinsic pathway

This pathway also requires the presence of phospholipids (from the surface of the platelet) and calcium. The key steps in the coagulation cascade are (a) the generation of factor Xa, and (b) the generation of thrombin.1

Anticoagulants interfere with this process to prevent unwanted activation of the clotting cascade. A number of agents are in use, ranging from long-established heparin, low molecular weight heparin (LMWH) and vitamin K antagonists (VKAs) (of which warfarin is the principal agent) to the newer, direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban and edoxaban. We will consider these agents and their therapeutic indications in this module. Module 4 will look at some of the clinical aspects of their use.

Intravenous/subcutaneous anticoagulants

Heparin

Heparin is a polymer of repeating disaccharide units. Unfractionated heparin (UFH), as used pharmacologically, consists of a heterogenous mixture of chains of different lengths. Heparin binds antithrombin, inducing a conformational change which greatly increases its ability to inhibit factors Xa and IIa (thrombin). Heparin is rapidly cleared from the circulation by binding to endothelium/plasma proteins, with renal excretion becoming important once this mechanism is saturated. Although an effective anticoagulant, heparin has many undesirable features, such as the risk of heparin induced thrombocytopenia [HIT] and the need for intensive monitoring. Long-term use can also lead to osteoporosis. Heparin can be rapidly neutralised by protamine.

Low molecular weight heparin

Table 1. Differences between low molecular weight heparin and unfractionated heparin
Table 1. Differences between low molecular weight heparin and unfractionated heparin

Several of the problems with UFH have been resolved by the development of a ‘cleaner’ form, low molecular weight heparin (LMWH), by depolymerisation of heparin. The shorter chain means that principal anticoagulant activity is by anti Xa activity, but there is some residual antithrombin activity also – the several different LMWHs available differ in their ratio of anti Xa to antithrombin activity, according to their chain length.

LMWHs have much more predictable anticoagulant activity, so that monitoring is usually not required. LMWH also has a much lower incidence of heparin-induced thrombocytopaenia (HIT).

The main disadvantage of LMWHs is their greater reliance on renal excretion (although this varies between agents) making them unsuitable for use in severe renal impairment. LMWH also has a longer half life than UFH, and cannot be completely neutralised by protamine (although again this varies between agents), which can make the management of bleeding challenging.2

Differences between UFH and LMWHs are shown in table 1.

Fondaparinux

This may be described as a super-LMWH, being an engineered pentasaccharide that very precisely and reversibly binds the active site of factor Xa, providing very efficient inhibition.2 Other advantages are its inactivity towards platelets, and, with no activity against thrombin, that it has very predictable anticoagulant activity.

A relatively long plasma half-life of 14–21 hours permits once-daily injection. There is a rapid onset of action, with a peak activity reached in two hours, and no interactions with aspirin, warfarin or digoxin have been noted. Thrombocytopenia occurs even less commonly than with LMWH. In almost all cases, fondaparinux need not be routinely monitored in the laboratory.

Clearance is reduced in renal impairment and use should be avoided when creatinine clearance is below 20 ml/min; no reversal agent is available.

Fondaparinux has had a key role in the management of acute coronary syndromes since the OASIS-5 trial showed similar efficacy with reduced bleeding and lower mortality compared to enoxaparin.3,4

Direct thrombin inhibitors (DTIs)

Figure 2. Medicinal leech jar
Figure 2. Medicinal leech jar

These operate by inhibiting the action of thrombin directly, that is (unlike heparin), independently of antithrombin. Bivalirudin is a hirudin, named after an anticoagulant purified from the mouthpart of a leech (see figure 2). Another parenteral hirudin, lepirudin, was recently discontinued by its manufacturer.
Argatroban is a synthetic, reversible, direct thrombin inhibitor. It has a short half life (50 minutes) and minimal renal clearance. Its main use is in the specialist management of acute HIT.5

Bivalirudin is an option instead of a heparin in patients with acute coronary syndromes having percutaneous coronary intervention (PCI) as an adjunct to aspirin and clopidogrel, and is approved by the National Institute for Health and Care Excellence (NICE) for patients with ST-elevation MI having PCI.4,6 Bivalirudin also has an important but specialist role in cardiac surgery in patients with a history of HIT, who cannot receive heparin.5

Dabigatran (discussed below) is an orally available direct thrombin inhibitor.

Monitoring intravenous/subcutaneous anticoagulants

UFH must be monitored in each patient using the activated partial thromboplastin time (APTT). Argatroban is also monitored by the APTT.

One of the major advantages of LMWHs and fondaparinux is that they do not routinely require monitoring. However, in cases where it is felt necessary to measure the degree of anticoagulation with these agents (for instance in patients with poor renal function, pregnancy, extremes of body weight or with recurrent thrombosis despite anticoagulation) this can be done by measuring the anti Xa activity.
Anticoagulant monitoring will be considered further in module 4.

Oral anticoagulants

Warfarin

Warfarin inhibits the enzyme vitamin K epoxide reductase. This prevents the recycling of vitamin K, which is essential for carboxylation of several clotting factors. Without this carboxylation they will not function. Factors affected by warfarin are factors II, VII, IX and X; it also reduces levels of protein C and protein S. For those in whom warfarin is contra-indicated, perhaps by intolerance or allergy, alternative VKAs are available: acenocoumarol and phenidione.

Warfarin is a long-established and effective anticoagulant, which is safe in renal impairment, and has established reversal agents available (prothrombin complex concentrate for emergency reversal, vitamin K for reversal over hours). However, there are a number of problems associated with its use, including its numerous drug interactions, a narrow therapeutic window with requirement for frequent monitoring blood tests, and the long time (days) taken to reach a therapeutic level. Practical issues relating to warfarin use are discussed in modules 4 and 5.

Direct oral anticoagulants (DOACs)

Previously known as novel or new oral anticoagulants, not all these agents are really new anymore (dabigatran obtained its US licence in 2010). The International Society for Thrombosis and Haemostasis suggested a change of name to DOACs,7 in recognition of their mode of action: direct inhibition of one clotting factor, rather than interference with the metabolism of several, as warfarin does.

In fact the grouping is somewhat false, as the agents do not share the same mechanism of action: three are inhibitors of factor Xa (rivaroxaban, apixaban and edoxaban) while dabigatran inhibits thrombin. What they share, however, are rapid onset of action from oral administration, and predictable pharmacokinetics such that monitoring of anticoagulant effect is not routinely required.

Note: Discussion of drug dosing below is for the atrial fibrillation (AF) indication. There are differences for venous thromboembolism (VTE) treatment/prophylaxis. Always consult up-to-date product literature or the British National Formulary for prescribing information.

Dabigatran

Dabigatran is an oral direct thrombin inhibitor. It has rapid absorption (within two hours) and distribution with an estimated half-life of 13–18 hours. Nearly 80% is excreted unchanged by the kidneys, so that its half-life can be significantly prolonged in renal impairment, and dabigatran is contraindicated in severe renal impairment (creatinine clearance <30 ml/min).

Although drug interactions are few, dabigatran is a substrate for the efflux transporter P-glycoprotein (P-gp), so that levels of dabigatran are increased by P-gp inhibitors. Some of these interactions are potentially highly significant in cardiac patients: strong P-gp inhibitors (ketoconazole, cyclosporine, itraconazole and dronedarone) are contraindicated with dabigatran, while moderate inhibitors (amiodarone, verapamil, quinidine, clarithromycin and ticagrelor) should be used with caution.

A reduced dose is suggested by the manufacturer for elderly patients, patients with renal impairment, patients on one of the drugs listed above, or other patients felt to be at high risk of bleeding. This has a twice daily dosing schedule and cannot be stored in a dosette box.

Rivaroxaban

This was the first selective oral direct factor Xa inhibitor on the market.8 It inhibits both free and clot bound factor Xa, and, unlike heparin, does not depend on antithrombin for its action. It achieves peak plasma levels in two hours and has a half-life of 5–13 hours – longer in elderly subjects and those with renal impairment. Rivaroxaban is dosed once daily.

Excretion is approximately one third renal – a dose reduction is recommended with creatinine clearance 15–49 ml/min, and the drug contraindicated below 15 ml/min. A further one third of rivaroxaban is metabolised by the liver via CYP3A4, with the final third excreted through the gut via P-gp. Inhibitors of both CYP3A4 and P-gp might therefore be expected to raise rivaroxaban levels, and certain drugs (such as azole antifungals, and HIV protease inhibitors) are contraindicated. Rivaroxaban must be taken at the same time every day with food.

Apixaban

Apixaban’s mechanism of action and metabolism is much as that for rivaroxaban, except that, although its half life is between 9–14 hours, it is dosed twice daily. It does not need to be taken with food. It has the least dependence on renal excretion of the DOACS at 25%, but shares rivaroxaban’s dependence on metabolism by CYP3A4.

The manufacturer recommends a dose reduction for patients with creatinine clearance 15–29 ml/min, and also for patients with serum creatinine ≥1.5 mg/dL (133 micromol/l) associated with age ≥80 years or body weight ≤60 kg. Apixaban is contraindicated at creatinine clearance <15 ml/min.

Edoxaban

Another inhibitor of factor Xa, edoxaban was the last to be licensed in Europe. It is dosed once daily, with a half life of 10–14 hours. 50% is renally excreted, with the rest excreted via P-gp – it has the least CYP3A4 interaction of all the Xa inhibitiors. As for rivaroxaban, dose reduction is recommended at 15–49 ml/min, and the drug contraindicated below 15 ml/min. A lower dose is also recommended for patients <60 kg, and those taking P-gp inhibitors.

The relevant profiles of these four DOACs are shown in table 29, and non-valvular AF dosing guidance is shown in figure 3. Full information on all the DOACs can be found in the SmPC for each product.

Table 2. Profiles of the available direct oral anticoagulants (DOACs)

Dabigatran Apixaban Rivaroxaban Edoxaban
Target Thrombin Factor Xa Factor Xa Factor Xa
Dosing 150 mg twice daily (reduced dose 110 mg twice daily*) 5 mg twice daily (reduced dose 2.5 mg twice daily*) 20 mg once daily (reduced dose 15 mg once daily*) 60 mg once daily (reduced dose 30 mg once daily)
Half-life (h) 13–18 9–14 5–13 10–14 hours
Renal excretion (%) 80 25 33 unchanged, 33 inactive metabolites 50
Drug interactions Potent inhibitors of CYP3A4 Potent inhibitors of CYP3A4 Potent inhibitors of CYP3A4 or P-gp Potent inhibitors of CYP3A4
Key: CYP3A4 = cytochrome P450 3A4; P-gp = P-glycoprotein
Adapted from Wisler9 and product SPCs.
* Reduced doses variously used for moderate renal impairment, age >80, interacting drugs or high bleeding risk. All the drugs are contra-indicated in severe renal impairment and some may be contra-indicated with certain interacting drugs. See SPCs for the specific recommendations for each drug.

Figure 3. DOAC dosing guidance for stroke prevention in non-valvular atrial fibrillation (AF)

Creatinine Clearance (CrCL) ≥50ml/min 30–49ml/min 15–29ml/min <15ml/min
Apixaban 5 mg bd

Reduce to 2.5 mg bd if ≥ 2 of the following:
Age ≤ 80 years, weight ≤ 60 kg, and creatinine ≤ 133μmol/L
2.5mg bd Do not use
Dabigatran 150 mg bd

Reduce to 110 mg bd if age ≥ 80 years or drugs – verapamil.
Consider dose reduction if any of:
age 75–80 years, CrCl 30–50 ml/min, GORD or increased  risk of bleeding
Do not use
Edoxaban 60 mg od

Reduce to 30 mg od if weight ≤ 60 kg or drugs – ciclosporin, dronedarone, erythromicin or ketoconazole
30 mg od Do not use
Rivaroxaban 20 mg od (with food) 15 mg od (with food) Do not use
Key: bd = twice daily; GORD = gastro-oesophageal reflux disease; od = once daily
Adapted from GP Notebook Shortcuts10

Betrixaban

This was the newest inhibitor of factor Xa, with the benefit of predominant hepatobiliary excretion, making it suitable in severe renal failure.11 It received approval from the US Food and Drug Administration (FDA) but production was discontinued by the manufacturer in 2020.

Bleeding risk and reversal of DOACs

The most common complication of antithrombotic therapy is bleeding, broadly graded as major, clinically relevant non-major bleeding (CRNMB), and minor. Efforts have been made to standardise definition of these terms.12

Intracranial haemorrhage (ICH) is an inclusive term referring to several different conditions, including haemorrhagic stroke, subdural haematoma, and epidural haematoma, and is characterised by the extravascular accumulation of blood within the skull. Approximately 20% of all strokes are due to ICH. Of these, most consist of intracerebral haemorrhage and subarachnoid haemorrhage. Subdural and epidural haematoma are both frequently associated with head trauma, especially in the elderly. These bleeding events are a growing cause of death and disability worldwide due to the increasing number of elderly people, and the increasing use of oral antithrombotic agents. In particular, ICH is the most serious complication of oral anticoagulant (OAC) therapy, with mortality rates in excess of 50%, and three times higher than that of ischaemic stroke.

Data from large-scale randomised controlled trials (RCTs), substantiated by observational real-world studies,13,14 indicate that DOACs have a favourable overall bleeding risk profile compared to warfarin, and notably, all carry a lower risk of ICH. Apixaban had comparable rates of gastrointestinal (GI) bleeding to warfarin in the RCT setting, but other DOACs were inferior to warfarin in this specific regard.

Management of bleeding on anticoagulant therapy requires general and supportive interventions, alongside drug-specific reversal measures where appropriate. (See a useful summary by Thomas and Makris.15).

A traditional advantage of warfarin has been the availability of well-established reversal agents (vitamin K +/- prothrombin complex concentrate) for bleeding and urgent peri-procedural optimisation. Developing specific reversal agents for the DOACs is a key safety imperative, and some advances have been made.

DOAC reversal agents

Idarucizumab: This reversal agent for dabigatran was the subject of a NICE Evidence summary in May 2016.16 Idarucizumab is a fully humanised monoclonal antibody fragment, which binds dabigatran and nullifies its anticoagulant activity. The RE-VERSE AD trial demonstrated that in emergency situations, idarucizumab was able to rapidly reverse the anticoagulant effect of dabigatran with no adverse safety signals.17 This is given intravenously as two consecutive infusions.18

Andexanet alfa: More recently, this reversal agent has been developed for the direct Xa inhibitors. This is a recombinant, modified factor Xa molecule with no pro-coagulant activity, which binds and inactivates all Xa inhibitors by acting as a ‘decoy receptor’.

The ANNEXA-4 study evaluated the use of andexanet in 67 patients with acute major bleeds within 18 hours of a factor Xa inhibitor. This was shown to substantially reduce anti-Xa activity, with effective haemostasis being achieved in 82% of patients. Thrombotic events were noted in 10% within the 30-day follow up period.19 This gained US FDA approval in May 2018 for use in life-threatening bleeds for patients on rivaroxaban or apixaban.20

NICE issued a preliminary recommendation in October 2020 approving its use in patients on rivaroxaban or apixaban with life threatening GI bleeding.21 The appraisal document cites a lack of evidence of long- term benefit and cost-effectiveness in ICH and other non-GI sites of bleeding, and restricts its use in ICH to the research setting. Final guidance is expected shortly, pending further consultation.

Further studies, including an RCT comparing andexenat against standard of care in ICH, are planned. It is worth noting that the use of commercial anti-Xa assays following administration of andexanet alfa is discouraged, as these assays are considered an unreliable measure of haemostatic effect in this context. As yet, no specific reversal agent is authorised for edoxaban.

For situations in which specific reversal agents are not approved or available, general haemostatic measures should be employed. There is accumulating evidence from non-randomised studies that prothrombin complex concentrate is an effective option.15 Expert help should be sought early, and local guidance followed.

Other reversal agents in development include Ciraparantag (PER 977). This is a small molecule which can bind inhibitors of both factor IIa and factor Xa – in effect a universal DOAC reversal agent. Studies are underway to assess the safety and efficacy of this in healthy volunteers.22

Figure 4 demonstrates how the DOACs act on the coagulation pathway.

Figure 4. Sites of action of DOACs
Figure 4. Sites of action of DOACs

Indications for anticoagulation in cardiology

These can be grouped into three areas: diseases of the heart valves, acute coronary syndromes and non-valvular AF.

Heart valves

Where patients with valvular heart disease require anticoagulation, this should usually be with a vitamin K antagonist – none of the DOACs are licensed for valvular AF, and none has been shown to be adequate for the anticoagulation of patients with mechanical heart valves. The RE-ALIGN study of dabigatran versus warfarin for this indication was terminated early due to an excess of both thrombotic complications and bleeding in the dabigatran group.23

Anticoagulation for patients with valvular heart disease is considered in detail in another BJC Learning module, ‘Heart valve disease module 7: antithrombotic therapy for valvular heart disease’.

Acute coronary syndromes

As discussed in module 1, while platelets are of primary importance in initiating arterial thromboses, both platelets and the clotting cascade are closely linked, so that both are involved in the formation of all clots. Accordingly, although antiplatelet agents are of central importance in the management of acute coronary syndromes (see module 2), anticoagulants are also used in this critical situation to further suppress thrombus formation.

The specialist management of acute coronary syndromes will not be discussed further here: readers are referred to excellent guidelines from the European Society for Cardiology (ESC),3 and NICE.4 As discussed above, options are LMWH or fondaparinux, with the evidence from OASIS-5 perhaps favouring fondaparinux. UFH or bivalirudin are options for patients undergoing PCI; fondaparinux is not recommended in patients with ST-elevation MI undergoing primary PCI after an excess of procedure-related complications was noted in the OASIS-6 trial.3,24,25

Atrial fibrillation

One of the main risks in AF is cardioembolic stroke. Overall, AF brings a 5% risk of stroke per year but not all patients have the same risk.26,27 Risk can be greatly reduced by anticoagulation but as anticoagulation carries a risk of bleeding, it is important to have some means of identifying which patients will, on balance, benefit from anticoagulation – i.e. in which patients does the benefit of anticoagulation outweigh the risks.

Risk assessment

Table 3. 2009 Birmingham Scheme: CHA2DS2-VASc scoring system

Risk factor Score
C: Congestive heart failure/left ventricular dysfunction 1
H: Hypertension 1
A: Age ≥75 years 2
D: Diabetes mellitus 1
S: Stroke/transient ischaemic attack (TIA)/thromboembolism (TE) 2
V: Vascular disease (prior coronary artery disease, myocardial infarction, peripheral artery disease or aortic plaque) 1
A: Age 65–74 years 1
S: Sex category – female 1
In the CHA2DS2-VASc Scoring system above, high risk = ≥2

The CHA2DS2-VASc score28 is currently the most widely used tool for estimating stroke risk in AF (see table 3), and is the scoring system recommended by both the ESC and NICE in their guidelines.29,30 It represents a refinement of the previous CHADS2 system, particularly in that it defines a group of genuinely low risk patients (score 0 out of 9) who seem to have a very low risk of stroke, and whom the risk of anticoagulation is probably not justified. Annual stroke risk in a large Swedish validation cohort study was 0.2% (score 0) to 12.2% (score 9).31

Both ESC and NICE guidelines advise anticoagulation (in the absence of a contraindication) in patients with a score of 2 or more, and suggest considering it in male patients with a score of 1.

A risk-score-based assessment of bleeding risk should also be undertaken before advising on anticoagulation. Probably the most widely used is the HAS-BLED,32 and this is recommended by ESC guidelines, whilst the latest NICE guidance favours the ORBIT score (see table 4).

Table 4. ORBIT and HAS-BLED scores for bleeding risk assessment32

Risk predictors Scoring system Risk stratification
ORBIT Older age (≥74 years)
Reduced hemoglobin/anemia
Bleeding history
Insufficient kidney function
Treatment with antiplatelet
1 point for each risk factor Low risk 0–2
Intermediate risk 3
High risk ≥4
HAS-BLED Hypertension
Abnormal renal and/or liver function
Stroke
Bleeding history
Labile INR
Elderly (≥65 years)
Drugs or alcohol concomitant
1 point for each risk factor Low risk 0–1
Intermediate risk 2
High risk ≥3
Reproduced from Wang C32 with permission under Creative Commons Attribution Licence 3.0

NICE29 and ESC guidelines30 advise that anticoagulation should be considered even in patients with a high risk of bleeding. Hence, risk scoring tools should not be used for discrete safety cut-offs, but rather to provide an accurate assessment of risk, and guide discussions around optimisation of modifiable risk factors, and the required level of monitoring. Web-based calculators are available for all the risk scores discussed.

Choice of anticoagulation in AF

Aspirin does reduce stroke risk to a small extent in AF (approximately 20%), but is much less effective than warfarin (approximately 70% risk reduction). Moreover, there is a growing body of evidence that the inferior efficacy of aspirin is not compensated for by a lower bleeding risk, especially in elderly patients.33,34 Aspirin is therefore not recommended as stroke prevention in current guidelines.

Warfarin

Warfarin’s efficacy and safety depend crucially on how well-controlled the INR is (see module 4). NICE advise regular review, and consideration of switching to a DOAC if the time in therapeutic range (TTR) is <65%.

Dabigatran
Anticoagulation module 3 - Figure 5. Kaplan–Meier curve for the primary outcome of stroke or systemic embolism
Figure 5. Kaplan–Meier curve for the primary outcome of stroke or systemic embolism

Dabigatran was compared to warfarin for the prevention of stroke in AF in the RELY trial (see figure 5).35 Over 18,000 patients received 110 mg or 150 mg of dabigatran twice a day, or warfarin to target INR 2.5. Yearly rates of the primary outcome (stroke or systemic embolus) were 1.69% in the warfarin group, and 1.53% and 1.11% in the dabigatran 110 mg and 150 mg groups respectively, the latter being significantly lower than the warfarin result.

The rate of the primary side effect of major bleeding was 3.36%, 2.71% and 3.11% respectively. Therefore dabigatran 110 mg bd was equally as efficacious as warfarin but had a better safety profile in terms of major bleeding, whereas the 150 mg dose twice a day was superior to warfarin in terms of stroke prevention but had similar rates of bleeding. Closer scrutiny of the trial data shows that rates of intracranial haemorrhage were lower with dabigatran even at the higher dose. The higher dose of dabigatran was, however, associated with significantly more gastrointestinal bleeds than warfarin.

One other result of concern was a small increase in rates of myocardial infarction in both dabigatran groups, which was statistically significant for the 150 mg dose. This was, however, not replicated in a real-world post-marketing study conducted by the US FDA.36

Rivaroxaban

Rivaroxaban was also compared to warfarin for the prevention of stroke in AF. The ROCKET-AF8 trial (see figure 6) randomly assigned over 14,000 patients to rivaroxaban 20 mg once daily or to dose-adjusted warfarin, finding rates of stroke or systemic embolism to be 1.7% and 2.2% respectively, whilst the major and minor bleeding events were 14.9% and 14.5% respectively (all differences not significant). However, there were significantly fewer fatal bleeds and cases of intracranial haemorrhage in those taking rivaroxaban, but again more gastrointestinal bleeding.

Anticoagulation module 3 - Figure 6. Kaplan–Meier curve for the primary efficacy outcome of stroke and non-central nervous system embolism
Figure 6. Kaplan–Meier curve for the primary efficacy outcome of stroke and non-central nervous system embolism
Apixaban

In the ARISTOTLE trial (see figure 7),37 apixaban was compared to warfarin for stroke prevention in over 18,000 patients with AF and at least one additional risk factor for stroke. After 1.8 years of follow up, yearly rates of the primary end point (any stroke, or systemic embolism) were 1.27% on apixaban and 1.6% on warfarin (p=0.01). Furthermore, apixaban was associated with significantly fewer cases of major bleeding and fewer haemorrhagic strokes (both p<0.001). Rates of gastrointestinal bleeding were the same.

Anticoagulation module 3 - Figure 7. Kaplan–Meier curve for the primary efficacy outcome of stroke or systemic embolism
Figure 7. Kaplan–Meier curve for the primary efficacy outcome of stroke or systemic embolism
Edoxaban

The ENGAGE AF-TIMI 48 trial (see figure 8) randomised over 21,000 patients with non-valvular AF and a CHADS2 score of 2 or more to one of two dose regimens of edoxaban, or warfarin. The higher dose regimen showed a trend towards superiority over warfarin in terms of the primary outcome (any stroke or systemic embolus). Bleeding (including major, life-threatening and intracranial bleeding) was significantly lower with edoxaban, with the exception of gastrointestinal bleeding which was significantly more common.38 Based on these results, the higher dose regimen was licensed: 60 mg once daily is the standard dose, with 30 mg used for patients with low weight, renal impairment, or on potent P-gp inhibitors.

Anticoagulation module 3 - Figure 8. Kaplan–Meier curve for the primary efficacy outcome of stroke or systemic embolism
Figure 8. Kaplan–Meier curve for the primary efficacy outcome of stroke or systemic embolism
Which drug to choose for stroke prevention?

All four DOACs are now approved by NICE as an option for stroke prevention within their licensed indications (i.e. non-valvular AF with one or more risk factors for stroke), and indeed, according to latest guidance, should be offered as first-line therapy.29 This is based on a judgement of favourable clinical efficacy and cost-effectiveness compared to warfarin, which is relegated to a second-line option when DOACs are contraindicated, not tolerated or not suitable. For patients already established on warfarin and well controlled, continuation may be considered.

Patient involvement in decision-making is key and requires discussion of the advantages and disadvantages of different drugs. Local policies should be followed where these exist.

Triple antithrombotic therapy (OAC) along with two antiplatelet agents) is the standard of care following percutaneous coronary intervention (PCI) for those with AF, although recent NICE guidance30 suggests considering conversion to single antiplatelet plus an OAC after the initial treatment phase. With regards to choice of OAC in this setting, the PIONEER AF-PCI and RE-DUAL PCI randomised trials, which assessed the safety and efficacy of DOACs for AF after PCI, suggest that DOAC-based regimens were favourable in comparison to warfarin, in combination with dual antiplatelet therapy.39

Cardioversion of AF

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Ischaemic stroke rates following cardioversion are between 5 and 7% in non-anticoagulated patients, which can be reduced to 0.5 to 1.6% with warfarin.38 Current ESC guidelines advise anticoagulation for at least three weeks before and four weeks after cardioversion.30 RCT subgroup analyses have confirmed the safety and efficacy of all DOACs in the setting of cardioversion, and their use is approved in NICE and ESC guidance.29,30

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References

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6. National Institute for Health and Care Excellence. Bivalirudin for the treatment of ST-segment-elevation myocardial infarction. Technology appraisal guidance [TA230]. London: NICE, July 2011 (accessed 15.9.2015) https://www.nice.org.uk/guidance/ta230

7. Barnes GD, Ageno W, Ansell J, Kaatz S, for the Subcommittee on the Control of Anticoagulation. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:1154–6. http://doi.org/10.1111/jth.12969

8. Patel MR, Mahaffey KW, Garg J, et al.; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. http://doi.org/10.1056/NEJMoa1009638

9. Wisler JW, Becker RC. A guidance pathway for the selection of novel anticoagulants in the treatment of atrial fibrillation. Crit Pathw Cardiol 2012;11:55–61. http://doi.org/10.1097/HPC.0b013e31825298ef

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Online resources

The Scottish Medicine Consortium: http://www.scottishmedicines.org.uk

The British National Formulary: http://www.bnf.org

The National Institute for Health and Care Excellence (NICE): http://www.nice.org.uk

Further reading

Diener H, Hankey G, Easton J, et al. Non-vitamin K oral anticoagulants for secondary stroke prevention in patients with atrial fibrillation, European Heart Journal Supplements. 2020;22:1:I13–I21. https://doi.org/10.1093/eurheartj/suaa104

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