Anticoagulation module 3: anticoagulant therapy

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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, non-VKA oral anticoagulants (NOACs) 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 inihibit 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 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; 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.

Direct thrombin inhibitors (DTIs)

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.

Figure 3. Medicinal leech jar
Figure 2. Medicinal leech jar

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.4

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.5 Bivalirudin also has an important but specialist role in cardiac surgery in patients with a history of HIT, who cannot receive heparin.4

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, 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.

Non-vitamin K antagonist oral anticoagulants (NOACs)

Previously known as novel or new oral anticoagulants, not all these agents are really new anymore (dabigatran obtained its US licence in 2010). This has led to them being renamed, e.g. by NICE as non-vitamin K antagonist oral anticoagulants. The International Society for Thrombosis and Haemostasis, however, recently suggested a change of name to DOACs,6 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.

Discussion of drug dosing below is for the atrial fibrillation indication. 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 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.

Rivaroxaban

This was the first selective oral direct factor Xa inhibitor on the market.7 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 contrainidicated. Full information can be found in the rivaroxaban SPC.

Apixaban

Apixaban’s mechanism of action and metabolism is much as for rivaroxaban, except that, although its half life is between 9–14 hours it is dosed twice daily. It has the least dependence on renal excretion of the NOACS 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 – see SPC for further details.

Edoxaban

Another inhibitor of factor Xa, Edoxaban is newly licensed in Europe, but has been licensed in Japan since 2012. 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 NOACs are shown in table 2.8

Table 3. Profiles of the available novel oral anticoagulants (NOACs)
Table 2. Profiles of the available non-vitamin K antagonist oral anticoagulants (NOACs)

Reversal of NOACs

A reversal agent for dabigatran – idarucizumab – is now licensed in the US and Europe. For the Xa inhibitors, reversal agents are in the late stages of development, and can be expected to be available soon.

Idarucizumab is a fully humanised monoclonal antibody fragment, which binds dabigatran and nullifies its anticoagulant activity. The RE-VERSE AD trial, a phase 3 trial of efficacy of idarucizumab, is still ongoing, but interim results were published recently which showed impressive correction rates of both laboratory parameters and bleeding.9

Andexanet alfa is a recombinant, modified factor Xa molecule with no pro-coagulant activity, which binds and inactivates all Xa inhibitors. Phase 2 trials have yielded promising results, and phase 3 trials are underway. This agent may also be useful in the reversal of low molecular weight heparins (as discussed above, these mostly target factor Xa, and are incompletely reversed by the available antidote, protamine).

Andexanet’s manufacturer, Portola Pharmaceuticals, has provided a video illustrating its mechanism of action:
https://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/

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 NOAC reversal agent.

Pending licensing of these agents, the British Committee for Standards in Haematology have issued guidance on the management of bleeding in patients on all anticoagulants, including NOACs.10 In an emergency, prothrombin complex concentrate is suggested based on limited data from animal and human studies. Expert help should be sought early, and local guidance followed.

Figure 3 demonstrates how the NOACs act on the coagulation pathway.

Figure 4. Sites of action of NOACs
Figure 3. Sites of action of NOACs

Indications for anticoagulation in cardiology

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

Heart valves

Where patients with valvular heart disease require anticoagulation, this should usually be with a vitamin K antagonist – none of the NOACs is 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.11

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.

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

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), and NICE. As discussed above, options are low molecular weight heparin 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.3,12,13

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. 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

The CHA2DS2-VASc score14 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 recent guidelines.15,16 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).17

Table 4. HAS-BLED scoring system
Table 4. HAS-BLED scoring system18

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 even in patients with a score of 1 (unless the only risk factor is female sex).

An assessment of bleeding risk should also be undertaken before advising on anticoagulation. Probably the most widely used is the HAS-BLED score (see table 4) – this is recommended by both NICE and ESC guidelines, but it is worth remembering that it was designed, and validated, using cohorts of patients taking vitamin K antagonists:

ESC guidelines advise caution with anticoagulation with a score of 3 or more (bleeding risk approximately 3.7 per 100 patient years). However, each case should be considered individually, with a full discussion of risks and benefits, and taking into account each patient’s perspective. Importantly, several of these factors are correctable, and attention should be paid to this to ensure anticoagulation can be offered more safely.

Web-based calculators are available which can be used to calculate both CHA2DS2-VASc and HAS-BLED scores.

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.19,20 Aspirin is therefore not recommended as stroke prevention in current guidelines, except in patients who refuse anticoagulation.

Figure 5. Kaplan–Meier curve for the primary outcome of stroke or systemic embolism
Figure 4. Kaplan–Meier curve for the primary outcome of stroke or systemic embolism

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

Dabigatran was compared to warfarin for the prevention of stroke in AF in the RELY trial (see figure 4).21 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.

Figure 6. Kaplan–Meier curve for the primary efficacy outcome of stroke and non-central nervous system embolism
Figure 5. Kaplan–Meier curve for the primary efficacy outcome of stroke and non-central nervous system embolism

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.22

Rivaroxaban

Figure 7. Kaplan–Meier curve for the primary efficacy outcome of stroke or systemic embolism
Figure 6. Kaplan–Meier curve for the primary efficacy outcome of stroke or systemic embolism

Rivaroxaban was also compared to warfarin for the prevention of stroke in AF. The ROCKET-AF7 trial (see figure 5) 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.

Apixaban

In the ARISTOTLE trial (see figure 6),23 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.

Edoxaban

Figure 8. 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

The ENGAGE AF-TIMI 48 trial (see figure 7) 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.24 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.

Which drug to choose for stroke prevention?

Based on this data, all four NOACs 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). Given their equivalent or superior efficacy, with apparently superior safety, ESC guidelines advise choosing a NOAC first line, in the absence of contraindication (see figure 8). NICE have suggested that a NOAC might be preferred if a patient’s time in therapeutic range on warfarin is <65%.

Trial data will only be a part of the decision-making process. Patients should be involved; some will not wish to switch, or be nervous of new medications. Financial considerations will also play a part. In the UK, some Clinical Commissioning Groups (CCGs) have sought to limit use of NOACs to reduce cost.25 While NOACs are considerably more expensive than warfarin, it is likely that this cost will be at least partially offset by the improved efficacy and safety (with consequently reduced costs of stroke care/management of bleeding), and by reduced monitoring costs. NICE have undertaken a number of costing analyses:
http://www.nice.org.uk/guidance/ta249/resources/ta249-atrial-fibrillation-dabigatran-etexilate-costing-template2

Economic analyses have also been undertaken in other healthcare settings.26 NOACs have not been directly compared in head-to-head trials, and direct comparison between trials is difficult, as the risk profile of patients in each trial was different (for example the mean CHADS2 score of patients in the RE-LY study was 2.1, compared to 3.47 in the ROCKET-AF trial).

Other issues which should be considered are the twice-daily dosing of dabigatran and apixaban; the greater reliance on renal excretion of dabigatran; and drug interactions (as discussed above). Local policies should be followed where these exist.

Figure 9: Oral anticoagulation for stroke prevention
Figure 8. Oral anticoagulation for stroke prevention

Cardioversion of AF

ispIschaemic 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.24 Current ESC guidelines advise anticoagulation with an INR of 2–3 for at least three weeks before and four weeks after cardioversion.16 Based on analysis of data on over 1,200 patients who underwent cardioversion during the RE-LY trial, dabigatran appears to be as safe and effective as warfarin, and is approved by ESC as an option.16

Since these guidelines were published, a similar analysis of data from the ARISTOTLE trial (apixaban) has been performed,27 and a randomised trial of rivaroxaban versus warfarin for cardioversion published (EX-VeRT28). Again this shows similar efficacy and safety to warfarin, including in the context of early cardioversion with the use of transoesophageal echocardiography to exclude thrombus.

Strict compliance with treatment is crucial if NOACs are to be used pre-cardioversion, as adequacy of anticoagulation cannot be confirmed by measurement of INR, as it can with warfarin. However, it is likely that local protocols will begin to adopt NOACs for this indication.

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References

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http://dx.doi.org/10.1111/jth.12969

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26. Deitelzweig S, Amin A, Jing Y, Makenbaeva D, Wiederkehr D, Lin J, Graham J. Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials. J Med Econ 2012;15:776–85. http://dx.doi.org/10.3111/13696998.2012.680555

27. Flaker G, Lopes RD, Al-Khatib SM et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014;63: 1082–7. http://dx.doi.org/10.1016/j.jacc.2013.09.062

28. Cappato R, Ezekowitz MD, Klein AL et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346–55.
http://dx.doi.org/10.1093/eurheartj/ehu367

All available from http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443 (accessed 14/02/13)

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 Clinical Excellence (NICE): http://www.nice.org.uk

Further reading

Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 2016;3:e000279. http://dx.doi.org/10.1136/openhrt-2015-000279

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