Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation

Review

Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation Mark J Alberts, John W Eikelboom, Graeme J Hankey Lancet Neurol 2012; 11: 1066–81 Northwestern University Feinberg School of Medicine, Chicago, IL, USA (Prof M J Alberts MD); Stroke Program, Northwestern Memorial Hospital, Chicago, IL, USA (M J Alberts); Department of Medicine, McMaster University, Hamilton, ON, Canada (J W Eikelboom FRACP); Department of Neurology, Royal Perth Hospital, Perth, WA, Australia (Prof G J Hankey MD); and School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia (G J Hankey) Correspondence to: Prof Graeme J Hankey, Department of Neurology, Royal Perth Hospital, 197 Wellington Street, Perth, WA 6001, Australia [email protected]

The world faces an epidemic of atrial fibrillation and atrial fibrillation-related stroke. An individual’s risk of atrial fibrillation-related stroke can be estimated with the CHADS2 or CHA2DS2VASc scores, and reduced by two-thirds with effective anticoagulation. Vitamin K antagonists, such as warfarin, are underused and often poorly managed. The direct thrombin inhibitor dabigatran etexilate and factor Xa inhibitors rivaroxaban and apixaban are new oral anticoagulants that are at least as efficacious and safe as warfarin. Their advantages are predictable anticoagulant effects, low propensity for drug interactions, and lower rates of intracranial haemorrhage than with warfarin. A disadvantage is the continuing need to develop and validate rapidly effective antidotes for major bleeding and standardised tests that accurately measure plasma concentrations and anticoagulant effects, together with the disadvantage of possible higher rates of gastrointestinal haemorrhage and greater expense than with warfarin. The new oral anticoagulants should increase the number of patients with atrial fibrillation at risk of stroke who are optimally anticoagulated, and reduce the burden of atrial fibrillation-related stroke.

Introduction Ischaemic stroke and transient ischaemic attacks of the brain (TIA) are caused by embolism from the heart in about 15% of patients. The most common cardiac source of embolism is the left atrium and its appendage, and the most common underlying disorder is non-valvular atrial fibrillation.1 The results of four large clinical trials of three new oral anticoagulants compared with warfarin or aspirin for prevention of stroke in patients with atrial fibrillation have been published in the past 3 years.2–6 In this Review, we discuss these results in the context of best practice and examine how they might affect the prophylactic antithrombotic management of patients with atrial fibrillation who are at risk of stroke.

Epidemiology of atrial fibrillation Prevalence, incidence, and prognosis About 1% of adults have atrial fibrillation.7 The prevalence of atrial fibrillation increases with age, and is higher in men than in women.7,8 Hypertension is the most common risk factor for atrial fibrillation, followed by ischaemic heart disease; valvular heart disease can account for up to 22% of cases of atrial fibrillation.7 The prevalence of atrial fibrillation is projected to increase a further 2·5 times by 2050.9,10 The age-adjusted and sex-adjusted yearly incidence of atrial fibrillation is about 2 (ranging from 1 to 4) per 1000 person-years and is increasing by about 6% per decade.7,11 Atrial fibrillation is associated with a five-fold increased risk of stroke, a two-fold increase in mortality (due to increased stroke and heart failure), and an increase in vascular cognitive impairment (due to stroke and hypertensive small vessel disease) compared with age-matched controls.12–16

Atrial fibrillation-related stroke Strokes caused by atrial fibrillation are more disabling and fatal than strokes due to other causes, partly because 1066

they are caused by embolism of large thrombi that occlude large cerebral arteries, and partly because patients with atrial fibrillation-related stroke tend to be older than other patients with stroke, with more comorbidities.16 The attributable risk of stroke for patients with atrial fibrillation increases progressively with age, ranging from 1·5% in individuals aged 50–59 years to 23·5% in those aged 80–89 years.12 The incidence of atrial fibrillation-related stroke decreased between 1980 and 2000 in Olmsted County, MN, USA, by 3·4% per year, concurrent with an increase in oral anticoagulant use and reduction of systolic blood pressure.17,18 However, the rising prevalence7 and incidence11 of atrial fibrillation is likely to contribute to a projected increase in the burden of stroke from 38 million disability-adjusted life-years (DALYs) in 1990 to 60 million DALYs by 2020.19 Strategies are needed to optimise the prevention of atrial fibrillation and the prevention of often fatal or disabling embolic ischaemic stroke caused by atrial fibrillation. This Review addresses the latter.

Assessment of stroke risk The yearly risk of stroke in individuals with atrial fibrillation is a continuum and varies widely from 0·2% in individuals with atrial fibrillation alone20,21 to more than 10% in individuals with a plethora of risk factors. The major risk factors for stroke in individuals with atrial fibrillation are previous stroke or TIA (relative risk [RR] 2·5, 95% CI 1·9–3·3), advancing age (RR 1·4, 1·3–1·6 per decade), history of hypertension (RR 1·9, 1·5–2·4), systolic blood pressure >160 mm Hg (RR 1·4, 1·2–1·6 for a 30 mm Hg difference), and diabetes (RR 1·7, 1·5–2·1).22 A caveat of these findings is that they were based largely on non-warfarin groups within historical trial cohorts that included few screened patients, and many risk factors (eg, vascular disease) were not adequately or consistently defined or available. Nevertheless, these and other risk factors have been used to derive more than a dozen models for calculation www.thelancet.com/neurology Vol 11 December 2012

Review

of stroke risk.23–25 The most important objective of the models is to accurately discriminate patients at low risk of stroke, for whom oral anticoagulation is unlikely to be beneficial, from those at higher risk, for whom the benefits of oral anticoagulation are likely to offset the bleeding risks. Discrimination is measured by the concordance statistic (C-statistic or C-index), which is the chance that, when assessing any two randomly selected individuals (eg, with atrial fibrillation), one of whom will ultimately develop the event of interest (eg, stroke) and one of whom will remain event free, the prediction model will correctly assign a higher probability of an event to the individual who goes on to have that event.26,27 The most widely used model for stratification of stroke risk in patients with atrial fibrillation is the CHADS2 scheme, which was derived by amalgamating risk stratification schema from clinical trials, and was validated in a cohort of patients with atrial fibrillation who were admitted to hospital and had an overall yearly stroke rate of 4·4% (table 1).28 The C-statistic of the CHADS2 score in this cohort was 0·82. The advantages of the CHADS2 risk-prediction index are that it is externally valid and simple. Its main limitation is that it does not reliably discriminate between patients with low risk, who do not need anticoagulation, and patients at intermediate risk, who do.29–37 This has prompted the development—and external validation in several cohorts—of the CHA2DS2VASc score, which includes several newly recognised risk factors for stroke in atrial fibrillation (table 1).38–43 The CHA2DS2VASc score improves stroke risk stratification in patients with atrial fibrillation who are deemed to be at low or intermediate risk of stroke using the CHADS2 scheme.39–42 For example, in patients discharged from Danish hospitals with atrial fibrillation and a CHADS2 score of 0 who did not receive anticoagulants, the rates of stroke and thromboembolism at 1 year ranged from 0·8% (for those with a CHA2DS2VASc score of 0) to 3·2% (CHA2DS2VASc score of 3; table 2).40 Thus, some patients deemed to be at low risk by a CHADS2 score of 0 are really at intermediate risk.

Assessment of bleeding risk Ideally, the risk of bleeding should be accurately quantified without and with anticoagulation, and balanced against the risk of stroke without and with anticoagulation. The HEMORR2HAGES scheme was derived by adaptation of risk factors for bleeding from three bleeding risk models into a new model for predicting bleeding risk.44 Risk is scored by allocation of two points for rebleeding and one point each for hepatic or renal disease, ethanol abuse, malignancy, older age (>75 years), reduced platelet count or function, hypertension (uncontrolled), anaemia, genetic factors (CYP2C9), excessive fall risk, and stroke. Of 1604 patients with atrial fibrillation who were prescribed warfarin, the rate of major www.thelancet.com/neurology Vol 11 December 2012

bleeding per 100 patient-years increased from 1·9% for a score of 0, to 2·5% for a score of 1, 5·3% for 2, 8·4% for 3, 10·4% for 4, and 12·3% for 5. The C-statistic for patients prescribed warfarin was 0·67.44 Subsequently, the HAS-BLED score was derived from 3456 patients with atrial fibrillation who had 53 major bleeds during 1 year follow-up.45 It is scored by allocation of one point each for uncontrolled hypertension, abnormal renal function, abnormal liver function, stroke, bleeding history or predisposition, labile international normalised ratio (INR; time in therapeutic range [TTR] <60%), elderly age (>65 years), drugs (antiplatelet or nonsteroidal anti-inflammatory drugs), and excessive intake of alcohol. The yearly bleeding rate increased with increasing risk factors, from 1·13% for a score of 0 to 1·88% for a score of 2, 3·74% for 3, 8·7% for 4, and 12·5% for a score of 5. The C-statistic was 0·72 (95% CI 0·65–0·79) in all patients and 0·69 (0·59–0·80) in the 1722 patients who were given oral anticoagulation. The HAS-BLED score has been validated in other anticoagulated cohorts and correlates with risk of intracranial bleeding.42,46–48 A HAS-BLED score of more than 3 identifies patients with atrial fibrillation at high bleeding risk, warranting special caution, control of modifiable risk factors for bleeding, and close monitoring.49,50 It does not necessarily mean that oral anticoagulation should be stopped. This is because the risk of ischaemic stroke without anticoagulation is often higher than the risk of intracranial bleeding with anticoagulation, and a net positive clinical benefit is often noted when prevention of ischaemic stroke is balanced against the risk of intracranial haemorrhage.51,52 Score CHADS2 Congestive heart failure

1

Hypertension

1

Age ≥75 years

1

Diabetes mellitus

1

Stroke, transient ischaemic attack, or thromboembolism

2

Maximum score

6

CHA2DS2VASc Congestive heart failure/LV dysfunction

1

Hypertension

1

Age ≥75 years

2

Diabetes mellitus

1

Stroke, transient ischaemic attack, or thromboembolism

2

Vascular disease (previous MI, PAD, or aortic plaque)

1

Age 65–74 years

1

Sex category (female sex)

1

Maximum score

9

LV=left ventricular. MI=myocardial infarction. PAD=peripheral artery disease.

Table 1: Definitions and scores for CHADS2 and CHA2DS2VASc risk stratification methods

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CHADS2

CHA2DS2VASc

Proportion Stroke rate at of patients 1 year (95% CI) with score

Proportion Stroke rate at of patients 1 year (95% CI) with score

0

22%

1·7% (1·5–1·9)

8%

0·8% (0·6–1·0)

1

31%

4·7% (4·4–5·1)

12%

2·0% (1·7–2·4)

2

23%

7·3% (6·9–7·8)

18%

3·7% (3·3–4·1)

3

15%

15·5% (14·6–16·3)

23%

5·9% (5·5–6·3)

4

7%

21·5% (20·0–23·2)

19%

9·3% (8·7–9·9)

5

2%

19·7% (16·9–22·9)

12%

15·3% (14·3–16·2)

6

0·2%

22·4% (14·6–34·3)

6%

19·7% (18·2–21·4)

7

··

··

2%

21·5% (18·7–24·6)

Aspirin and clopidogrel versus aspirin

8

··

··

0·4%

22·4% (16·3–30·8)

9

··

··

0·1%

23·6% (10·6–52·6)

Data for 73 538 patients with non-valvular atrial fibrillation who were at low or medium risk of stroke at baseline according to CHADS2, not anticoagulated, discharged from hospital in Denmark, and followed up for 1 year.39 The C-statistics at 1 year follow-up, when patients were classified into low-risk (score of 0), intermediate-risk (score of 1), and high-risk (score of ≥2) groups, were 0·72 (95% CI 0·69–0·75) for the CHADS2 score and 0·85 (0·83–0·90) for the CHA2DS2VASc score.39

Aspirin plus clopidogrel 75 mg daily reduces the risk of stroke by a quarter compared with aspirin alone in patients with atrial fibrillation (2·4% per year with aspirin plus clopidogrel vs 3·3% with aspirin; RR 0·72, 95% CI 0·62–0·83).68 Despite an increase in major bleeding (2·0% vs 1·3% per year; RR 1·57, 1·29–1·92), the addition of clopidogrel to aspirin leads to a slight net benefit in patients for whom warfarin is unsuitable.51

Table 2: Score at baseline and stroke rate at 1 year according to CHADS2 and CHA2DS2VASc scores

Warfarin versus control

Difficulty arises in clinical practice when patients have key risk factors for both ischaemic stroke and major bleeding (eg, age, hypertension, or previous stroke).53,54 Of the shared risk factors, increasing age and previous stroke are associated more with ischaemic stroke than with intracerebral haemorrhage, whereas a history of hypertension, diabetes mellitus, renal impairment, and alcohol intake are not more strongly associated with either.54 Research aims to show whether other possible risk factors for bleeding with anticoagulation will improve the predictive accuracy of the HEMORR2HAGES and HASBLED scores, such as ethnicity,55–57 chronic renal disease,58 leukoaraiosis,59 and cerebral microbleeds detected by turbo spin-weighted gradient-recalled echo MRI.60,61

Evidence for thromboprophylaxis in atrial fibrillation Heparin versus control Anticoagulant therapy with unfractionated heparin, low molecular weight heparin, or heparinoids within 48 h of cardioembolic ischaemic stroke does not have a net benefit because it significantly increases symptomatic intracranial bleeding over the next 7–14 days (2·5% of patients who received heparin had intercranial bleeding vs 0·7% of controls; odds ratio [OR] 2·89, 95% CI 1·19–7·01) without significantly reducing early recurrent ischaemic stroke, mortality, or disability.62

Aspirin versus control In individuals with atrial fibrillation, aspirin is associated with a non-significant reduction in the relative risk of stroke by about a fifth compared with placebo (5·2% per 1068

year with aspirin vs 6·3% with placebo; RR 0·81, 95% CI 0·65–1·01) without any significant excess of intracranial haemorrhage (0·16% vs 0·13% per year) or major extracranial bleeding (0·5% vs 0·6% per year).63–65 For individuals with atrial fibrillation and previous ischaemic stroke or TIA, aspirin (300 mg per day) is not associated with a significant reduction in risk of recurrent stroke compared with placebo (10% per year with aspirin vs 12% with placebo; hazard ratio [HR] 0·86, 95% CI 0·64–1·15) nor an increase in major bleeding (0·9% vs 0·7% per year; HR 1·29, 0·36–4·56).66,67

Adjusted-dose warfarin (INR 2·0–3·0) reduces the relative risk of first-ever stroke in individuals with atrial fibrillation by about two-thirds compared with placebo (4·6% per year with warfarin vs 1·8% with placebo; RR 0·36, 95% CI 0·26–0·51) without a statistically significant increase in intracranial haemorrhage (0·4% vs 0·2%) or major extracranial bleeding (2·1% vs 1·2% per year; RR 1·66, 0·82–2·35).65,69 The lack of excess bleeding with warfarin is most likely explained by the inclusion of very highly selected patients in the historical warfarin trials and low statistical power; subsequent trials comparing warfarin with dual antiplatelet therapy or new anticoagulants have shown an excess of intracranial bleeding (see following text). For individuals with atrial fibrillation and previous ischaemic stroke or TIA, adjusted-dose warfarin (INR 2·0–3·0) also reduces the risk of recurrent stroke by about two-thirds compared with placebo (3·9% per year with warfarin vs 12·3% with placebo; HR 0·34, 95% CI 0·20–0·57) and is associated with a non-significant increase in major bleeding (2·8% vs 0·7% per year; HR 3·20, 0·91–11·3).65,66,70

Warfarin versus aspirin Adjusted-dose warfarin is significantly more effective than aspirin for prevention of first-ever stroke (RR 0·62, 95% CI 0·48–0·82)65,71 and recurrent stroke (HR 0·38, 0·23–0·64)66,72 in patients with atrial fibrillation. Although earlier trials reported a higher risk of extracranial bleeding with warfarin (OR 5·16, 95% CI 2·08–12·83),65,72 the more recent Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial, undertaken in selected patients aged 75 years or older, reported no significant difference in the yearly risk of extracranial www.thelancet.com/neurology Vol 11 December 2012

Review

haemorrhage (1·4% with warfarin vs 1·6% with aspirin; RR 0·87, 95% CI 0·43–1·73) or major intracranial or extracranial haemorrhage (1·9% vs 2·0%; RR 0·96, 0·53–1·75).71

monitoring redundant. Disadvantages include twice daily administration for dabigatran etexilate and apixaban; underdeveloped methods of coagulation monitoring; potential for drug toxicity in patients with renal insufficiency; and absence of an antidote.

Warfarin versus aspirin and clopidogrel Adjusted-dose warfarin (target INR 2·0–3·0) is significantly more effective than the combination of clopidogrel (75 mg daily) and aspirin (75–100 mg daily) in patients with atrial fibrillation for prevention of stroke (1·40% per year with warfarin vs 2·39% with clopidogrel plus aspirin; RR 0·58, 95% CI 0·42–0·81) and does not cause more major bleeding (2·21% vs 2·42% per year; RR 0·91, 0·69–1·20).73 However, warfarin is associated with a two-fold excess of intracranial bleeding (0·6% vs 0·3% per year) and might be no more effective than dual antiplatelet therapy when INR control is suboptimal.74 For individuals with atrial fibrillation and previous stroke or TIA, adjusted-dose warfarin is significantly more effective for prevention of stroke than the combination of clopidogrel plus aspirin (2·99% per year with warfarin vs 6·22% with clopidogrel plus aspirin; RR 0·47, 95% CI 0·25–0·81).75

New oral anticoagulants Despite the effectiveness of vitamin K antagonists such as warfarin for prevention of ischaemic stroke in atrial fibrillation, these drugs have several limitations.69 Warfarin has a slow onset of action and variable dose requirements that are due in part to genetic variability of vitamin K epoxide reductase complex 1, which is involved in γ-carboxylation of vitamin-K-dependent clotting factors, and cytochrome P450 enzymes (eg, CYP2C9), which are involved in the metabolism of warfarin.69 Fluctuations in dietary intake of vitamin K and alcohol, and several drug– drug interactions, further contribute to interindividual and intraindividual variability in anticoagulant effects of warfarin. Consequently, despite close monitoring of coagulation to maintain the INR in the therapeutic range, this ratio is frequently outside the therapeutic range, limiting the effectiveness of warfarin in up to 60% of patients with atrial fibrillation, and increasing the risk of bleeding.76–78 This limitation has prompted the development and assessment of several new oral anticoagulants.

Pharmacology The new oral anticoagulants target thrombin or factor Xa (figure 1).79,80 Thrombin has a pivotal role in blood coagulation by converting fibrinogen to fibrin, activating factors V, VIII, and XI, and activating platelets. The pharmacological characteristics of the new anticoagulants are summarised in table 3.79–87 Advantages of the new oral anticoagulants include a rapid onset of action; low propensity for interactions with food, alcohol, and drugs; and a predictable anticoagulant effect that makes routine coagulation www.thelancet.com/neurology Vol 11 December 2012

Dabigatran etexilate Dabigatran etexilate is a prodrug of dabigatran that directly inhibits thrombin.82 Absorption from the gut depends on an acid environment, achieved with tartaric acid pellets coated with dabigatran etexilate. Despite this, bioavailability is only 6–7%. After oral administration, dabigatran etexilate is converted rapidly to dabigatran by hepatic and plasma esterases, and peak plasma concentrations are reached within 2 h.81 Dabigatran is 80% renally cleared. The drug half-life is 12–14 h in patients with normal renal function, 18 h if creatinine clearance is 30–50 mL/min, and more than 24 h if creatinine clearance is less than 30 mL/min. Dabigatran etexilate is a substrate for the P-glycoprotein transporter. P-glycoprotein is an ATPbinding cassette efflux transporter that extrudes specific hydrophobic substances, such as toxins, out of cells into the gut, bile, and urine, and out of the brain and other organs. Since P-glycoproteins block absorption from the gut, coadministration of potent P-glycoprotein inhibitors (eg, ketoconazole), which increase plasma concentrations of dabigatran, and coadministration of potent P-glycoprotein inducers (eg, rifampicin), which reduce plasma concentrations of dabigatran, are contraindicated.82 Steps in coagulation

Coagulation pathway

Drugs

TF/Vlla

Initiation X

IX IXa

Vlla

Va Prothrombinase complex Xa

Propagation

Rivaroxaban Apixaban Edoxaban

Prothrombin (II)

Thrombin (IIa)

Fibrin formation Fibrinogen

Dabigatran etexilate

Fibrin

Figure 1: Sites of action of new oral anticoagulants Factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) block the conversion of prothrombin (factor II) to thrombin (factor IIa) by factor Xa incorporated within the prothrombinase complex (the complex of factor Xa and factor Va bound to the activated platelet surface). Thrombin inhibitors (eg, dabigatran etexilate) block thrombin-mediated conversion of fibrinogen to fibrin. These drugs also block thrombin-mediated feedback activation of factors V and VIII. Coagulation factors are indicated by Roman numerals; lowercase a shows an active form. TF/VIIa=tissue factor and factor VIIa complex. Adapted from Eriksson and colleagues,79 by permission of Annual Reviews.

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Dabigatran etexilate Apixaban

Rivaroxaban

Coagulation target

Thrombin

Factor Xa

Factor Xa

Prodrug

Yes

No

No

Bioavailability Plasma protein binding Dosing in atrial fibrillation

6%

60%

66%

RE-LY

35%

87%

95%

The RE-LY (Randomised Evaluation of Long-term anticoagulant therapY) trial was a three-armed trial that compared two doses of dabigatran (110 mg twice a day or 150 mg twice a day) to standard dose-adjusted warfarin (target INR 2·0–3·0).2,3 Although health-care providers and patients were blinded to dabigatran dose, warfarin was open label. All outcome events were independently adjudicated by two panel members blinded to treatment allocation. Patients were excluded if they had poor renal function (creatinine clearance of <30 mL/min), active liver disease, or a stroke within 14 days of randomisation, or were considered at high risk for bleeding. 20% of patients had a history of stroke or TIA. Low-dose aspirin was taken by about a third of all patients. The lower dose of dabigatran etexilate (110 mg twice a day) was non-inferior to warfarin in reducing the rate of stroke or systemic embolism (p<0·001 for noninferiority) and the higher dose (150 mg twice a day) was superior (p<0·001 for superiority; table 5).2,3 The higher dose also significantly reduced the rate of ischaemic stroke compared with warfarin (RR 0·76, 95% CI 0·59–0·97; p=0·03). Both doses of dabigatran significantly reduced major bleeding compared with warfarin in patients younger than 75 years; however, in elderly patients (>75 years), the lower dose was associated with a similar rate and the higher dose with an increased rate of major bleeding.89 The higher dose increased major gastrointestinal haemorrhage in all patients (1·56% per year with dabigatran vs 1·15% with warfarin; RR 1·48, 95% CI 1·18–1·85). Both doses of dabigatran significantly reduced haemorrhagic stroke and intracerebral haemorrhage compared with warfarin. The case fatality rate of intracerebral haemorrhage, which averaged 52%, was not significantly different in participants assigned dabigatran or warfarin.90 Dabigatran caused higher rates of dyspepsia than did warfarin (11·8% with dabigatran 110 mg twice a day and 11·3% with dabigatran 150 mg twice a day vs 5·8% with warfarin), presumably related to the tartaric acid content of the dabigatran etexilate capsule. A numerical increase in myocardial infarction was reported with both doses of dabigatran compared with warfarin. A meta-analysis of all trials of dabigatran, including RE-LY, suggests that the absolute increase in myocardial infarction is slight (0·14–0·17% per year), not statistically significant, and outweighed by the reduction in stroke and systemic embolism (0·6% per year).91,92 The relative effects of dabigatran versus warfarin in the 3623 patients with previous stroke or TIA were consistent

110 mg twice a day or 150 mg twice a day

5 mg twice a day

20 mg once a day

Onset of action

0·5–2 h

3–4 h

3–4 h

Duration of peak plasma concentration

0·5–2 h

3–4 h

2·5–4 h

Half-life*

12–14 h

12 h

Renal clearance

80%

25%

7–11 h 66% (half unchanged, half inactive metabolites)

Routine monitoring

No

No

No

Drug interactions

P-glycoprotein inhibitors†

P-glycoprotein inhibitors†; CYP3A4‡

P-glycoprotein inhibitors†; CYP3A4‡

*In patients with normal renal function. †P-glycoprotein inhibitors include azole antifungals (eg, ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors (eg, ritonavir). ‡Cytochrome p450 isoenzyme inhibitors include azole antifungals, protease inhibitors (eg, atazanavir), and macrolide antibiotics (eg, clarithromycin).

Table 3: Pharmacological properties of new oral anticoagulants

Rivaroxaban Rivaroxaban is a direct-acting factor Xa inhibitor with a half-life of 7–11 h.83–85 The 20 mg dose has a bioavailability of about 66% in the fasted state and the 10 mg dose has a bioavailability of about 80–100%; coadministration with food increases the bioavailability. A third of rivaroxaban is excreted unchanged via the kidneys and the remainder is broken down via CYP3A4-dependent and CYP3A4independent pathways in the liver and excreted as inactive metabolites in the urine and faeces. Rivaroxaban is also a substrate for P-glycoprotein. Coadministration of potent inhibitors of both P-glycoprotein and CYP3A4 (eg, ketoconazole) results in higher drug concentrations and is contraindicated.

Apixaban Apixaban is a direct-acting factor Xa inhibitor with similar pharmacological properties to those of rivaroxaban.86,87 It is partly broken down via CYP3A4 and excreted via several pathways. A quarter is excreted via the kidneys and the half-life is 12 h. Coadministration of potent P-glycoprotein and CYP3A4 inhibitors is contraindicated.

Clinical trials of new oral anticoagulants The efficacy and safety of dabigatran, rivaroxaban, and apixaban have been compared with warfarin in three large phase 3 clinical trials: RE-LY,2,3 ROCKET-AF,4 and ARISTOTLE.5 Apixaban has been compared with aspirin in the AVERROES trial.6 A large phase 3 trial of the factor Xa inhibitor edoxaban is in progress and results are expected in 2013.88 The characteristics of the published trials are summarised in table 4 and the results are presented in table 5. All were randomised controlled trials in patients with 1070

non-valvular atrial fibrillation at risk of stroke. The primary efficacy outcome in all trials was stroke (ischaemic or haemorrhagic) or systemic embolism.

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with the effects of dabigatran versus warfarin in the 14 490 patients without previous stroke or TIA for stroke or systemic embolism and major bleeding93 (table 6, figures 2, 3).

ROCKET-AF The oral factor Xa inhibitor rivaroxaban was compared with warfarin in ROCKET-AF (Rivaroxaban—Once daily oral direct factor Xa inhibition Compared with vitamin K

RE-LY2,3

ROCKET-AF4

ARISTOTLE5

AVERROES6

Study design

PROBE (dabigatran dose blinded)

Double-blind, double-dummy

Double-blind, double-dummy

Double-blind

Experimental treatment

Dabigatran 110 mg twice a day or 150 mg twice a day

Rivaroxaban 20 mg once a day (15 mg once a day if creatinine clearance 30–49 mL/min)

Apixaban 5 mg twice a day (2·5 mg twice a day in selected patients)

Apixaban 5 mg twice a day (2·5 mg twice a day in selected patients)

Control

Warfarin (INR 2·0–3·0)

Warfarin (INR 2·0–3·0)

Warfarin (INR 2·0–3·0)

Aspirin 81–324 mg once a day

Number of patients

18 113

14 264

18 201

5599

Age (years)

71·5 (mean)

Follow-up (years) Acute stroke exclusion time

73 (median)

2·0 (median) ≤2 weeks; severe stroke ≤6 months

CHADS2 score

70 (median)

1·8 (median)

TIA ≤3 days; non-disabling stroke ≤2 weeks; severe disabling stroke (modified Rankin score 4–5) ≤3 months

2·1 (mean)

Previous stroke or TIA

70 (median)

1·9 (median)

3·5 (mean); 3·0 (median)

20%

55%

Taking aspirin at baseline

39–40%

36–37%

Centre TTR

64% (mean); 67% (median)

55% (mean); 58% (median)

1·1 (mean)

≤7 days

≤10 days

2·1 (mean)

2·0 (mean)

19%

14%

31%

76%

62% (mean); 66% (median)

N/A

RE-LY=Randomised Evaluation of Long-term Anticoagulant Therapy trial.2,3 ROCKET-AF=Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation.4 ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation.5 AVERROES=Apixaban Versus Aspirin to Prevent Stroke.6 PROBE=Prospective, Randomised, Open-label, Blinded Endpoint. INR=international normalised ratio. TIA=transient ischaemic attack. TTR=% time in therapeutic range (refers to INR 2·0–3·0 for patients given warfarin). N/A=not applicable.

Table 4: Completed phase 3 studies of new oral anticoagulants for stroke prevention in patients with atrial fibrillation

RE-LY2,3

ROCKET-AF4

ARISTOTLE5

AVERROES6

Dabigatran Dabigatran Warfarin* RR (95% CI) (n=6022) 150 mg 110 mg (n=6076) (n=6015)

Rivaroxaban Warfarin* HR (95% CI) (n=7131) (n=7133)

Apixaban Warfarin* (n=9120) (n=9081)

HR (95% CI)

Apixaban Aspirin HR (95% CI) (n=2808) (n=2791)

Stroke or systemic embolism

1·54%

1·11%

1·71%

110 mg vs warfarin, 0·90 (0·74–1·10); 150 mg vs warfarin, 0·65 (0·50–0·81)

2·1

2·4

PPOT, 0·79 (0·66–0·96); ITT, 0·88 (0·75–1·03)

1·27%

1·60%

0·79 (0·66–0·95)

1·6%

3·7%

0·45 (0·32–0·62)

Haemorrhagic stroke

0·12%

0·10%

0·38%

110 mg vs warfarin, 0·31 (0·17–0·56); 150 mg vs warfarin, 0·26 (0·14–0·49)

0·26

0·44

0·59 (0·37–0·93)

0·24%

0·47%

0·51 (0·35–0·75)

0·2%

0·3%

0·67 (0·24–1·88)

Intracranial haemorrhage

0·23%

0·32%

0·76%

110 mg vs warfarin, 0·30 (0·19–0·45); 150 mg vs warfarin, 0·41 (0·28–0·60)

0·49

0·74

0·67 (0·47–0·93)

0·33%

0·80%

0·42 (0·30–0·58)

0·4%

0·4%

0·85 (0·38–1·90)

Fatal or disabling stroke

0·94%

0·66%

1·01%

110 mg vs warfarin, 0·93 (0·72–1·21); 150 mg vs warfarin, 0·66 (0·50–0·87)

1·28

1·75

··

0·50%

0·71%

··

1·0%

2·3%

0·43 (0·28–0·65)

All deaths

3·75%

3·64%

4·13%

110 mg vs warfarin, 0·91 (0·80–1·03); 150 mg vs warfarin, 0·88 (0·77–1·00)

4·5

4·9

0·92 (0·82–1·03)

3·52%

3·94%

0·89 (0·80–0·998)

3·5%

4·4%

0·79 (0·62–1·02)

Major bleed

2·87%

3·32%

3·57%

110 mg vs warfarin, 0·80 (0·70–0·93); 150 mg vs warfarin, 0·93 (0·81–1·07)

3·6

3·4

1·04 (0·90–1·20)

2·13%

3·09%

0·69 (0·60–0·80)

1·4%

1·2%

1·13 (0·74–1·75)

Data are number of patients with outcome, expressed as % per year (RE-LY, ARISTOTLE, and AVERROES), or number of patients with outcome per 100 patient-years (ROCKET-AF). RE-LY=Randomised Evaluation of Long-term Anticoagulant Therapy trial.2,3 ROCKET-AF=Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation.4 ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation.5 AVERROES=Apixaban Versus Aspirin to Prevent Stroke.6 RR=relative risk. HR=hazard ratio. PPOT=per-protocol, on-treatment analysis. ITT=intention-to-treat analysis. *Target INR of 2·0–3·0.

Table 5: Outcomes for patients with atrial fibrillation in the major phase 3 studies of new oral anticoagulants for stroke prevention

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RE-LY93

ROCKET-AF94

ARISTOTLE95*

AVERROES96

Dabigatran Dabigatran Warfarin RR (95% CI) (n=1195) 150 mg 110 mg (n=1233) (n=1195)

Rivaroxaban Warfarin HR (95% CI) (n=3754) (n=3714)

Apixaban Warfarin HR (95% CI) (n=1748) (n=1790)

Apixaban Aspirin HR (95% CI) (n=390) (n=374)

Stroke or systemic embolism

2·32%

2·07%

2·78%

110 mg vs warfarin, 0·84 (0·58–1·20); 150 mg vs warfarin, 0·75 (0·52–1·08)

2·79

2·96

0·94 (0·77–1·16)

2·46%

3·24%

0·76 (0·56–1·03)

2·39%

9·16%

0·29 (0·15–0·60)

Major bleed

2·74%

4·15%

4·15%

110 mg vs warfarin, 0·66 (0·48–0·90); 150 mg vs warfarin, 1·01 (0·77–1·34)

3·13

3·22

0·97 (0·79–1·19)

2·84%

3·91%

0·73 (0·55–0·98)

4·10%

2·89%

1·28 (0·58–2·82)

Haemorrhagic stroke

0·08%

0·20%

0·77%

110 mg vs warfarin, 0·11 (0·03–0·47); 150 mg vs warfarin, 0·27 (0·10–0·72)

0·34

0·46

0·73 (0·42–1·26)

0·55†

1·49†

0·37 (0·21–0·67)

0·27%

1·07%

0·25 (0·03–2·25)

Data are number of patients with outcome, expressed as % per year (RE-LY, ARISTOTLE, and AVERROES), or number of patients with outcome per 100 patient-years (ROCKET-AF); therefore, the results depicted are only crude interstudy comparisons and might not depict absolute benefits or harm. RE-LY=Randomised Evaluation of Long-term Anticoagulant Therapy trial.2,3 ROCKET-AF=Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation.4 ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation.5 AVERROES=Apixaban Versus Aspirin to Prevent Stroke.6 *Patients had had a previous stroke or transient ischaemic attack or systemic embolism. †Intracranial bleeding (ie, not just haemorrhagic stroke).

Table 6: Outcomes for subgroup of patients with atrial fibrillation and previous stroke or transient ischaemic attack in the major phase 3 studies of new oral anticoagulants for stroke prevention

Study drug % per year

Warfarin % per year

HR or RR (95% CI)

p for interaction

0·62

RE-LY (dabigatran 110 mg) No previous stroke or TIA

1·34

1·45

RR 0·93 (0·73–1·18)

Previous stroke or TIA

2·32

2·78

RR 0·84 (0·58–1·20)

No previous stroke or TIA

0·87

1·45

RR 0·60 (0·45–0·78)

Previous stroke or TIA

2·07

2·78

RR 0·75 (0·52–1·08)

No previous stroke or TIA

1·44

1·88

HR 0·77 (0·58–1·01)

Previous stroke or TIA

2·79

2·96

HR 0.94 (0·77–1·16)

No previous stroke or TIA

1·01

1·23

HR 0·82 (0·65–1·03)

Previous stroke or TIA

2·46

3·24

HR 0·76 (0·56–1·03)

RE-LY (dabigatran 150 mg) 0·34

ROCKET-AF (rivaroxaban) 0·23

ARISTOTLE (apixaban)

0

1·0

0·71

2·0

Favours study drug Favours warfarin

Figure 2: Risk of stroke (ischaemic and haemorrhagic) or systemic embolism according to previous stroke or transient ischaemic attack Summary of the results of the three large phase 3 warfarin-controlled trials of the new oral anticoagulants for the primary efficacy outcome of stroke or systemic embolism according to whether or not participants had a history of stroke or transient ischaemic attack at the time of randomisation.93–95 RE-LY=Randomised Evaluation of Long-term Anticoagulant Therapy trial.93 HR=hazard ratio. TIA=transient ischaemic attack. ROCKET-AF=Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation.94 ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation.95

antagonism [target INR 2·0–3·0] for prevention of stroke and Embolism Trial in Atrial Fibrillation).4 The study population in ROCKET-AF was at high risk of stroke; 55% of patients had a previous stroke or TIA, and 90% had either a previous stroke or TIA, or three or more risk factors for stroke (table 4). Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism in the primary per-protocol, on-treatment analysis (p<0·001 for noninferiority), but was not better than warfarin according to 1072

the intention-to-treat analysis (p=0·117 for superiority; table 5). The rates of major and clinically relevant non-major bleeding were similar with rivaroxaban (14∙91% per year) and warfarin (14·52% per year; HR 1·03, 95% CI 0·96–1·11; p=0·44). However, rivaroxaban was associated with lower rates of intracranial haemorrhage (p=0·019) and fatal bleeding (0·24% per year with rivaroxaban vs 0·48% with warfarin; HR 0·50, 0·31–0·79), but higher rates of major gastrointestinal bleeding (3·15% vs 2·16% www.thelancet.com/neurology Vol 11 December 2012

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Study drug % per year

Warfarin % per year

HR or RR (95% CI)

p for interaction

0·15

RE-LY (dabigatran 110 mg) No previous stroke or TIA

2·91

3·43

RR 0·85 (0·72–0·99)

Previous stroke or TIA

2·74

4·15

RR 0·66 (0·48–0·90)

No previous stroke or TIA

3·10

3·43

RR 0·91 (0·77–1·06)

Previous stroke or TIA

4·15

4·15

RR 1·01 (0·77–1·34)

No previous stroke or TIA

4·10

3·69

HR 1·11 (0·92–1·34)

Previous stroke or TIA

3·13

3·22

HR 0.97 (0·79–1·19)

No previous stroke or TIA

1·98

2·91

HR 0·68 (0·58–0·80)

Previous stroke or TIA

2·84

3·91

HR 0·73 (0·55–0·98)

RE-LY (dabigatran 150 mg) 0·51

ROCKET-AF (rivaroxaban) 0·36

ARISTOTLE (apixaban)

0

1·0 Favours study drug

0·69

2·0 Favours warfarin

Figure 3: Risk of major bleeding (as defined in each study) according to previous stroke or transient ischaemic attack Summary of the results of the three large phase 3 warfarin-controlled trials of the new oral anticoagulants for the safety outcome of major bleeding according to whether or not participants had a history of stroke or transient ischaemic attack at the time of randomisation.93–95 RE-LY=Randomised Evaluation of Long-term Anticoagulant Therapy trial.93 RR=relative risk. HR=hazard ratio. TIA=transient ischaemic attack. ROCKET-AF=Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation.94 ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation.95

per year; p<0·001). The occurrence of myocardial infarction was similar in both groups. Towards the end of the ROCKET-AF trial, after sites were notified to end study treatment, 92% of patients in both groups still receiving the assigned study drug were transitioned to open-label therapy with vitamin K antagonists. The median time to reach a therapeutic INR was longer (13 days) for those previously assigned rivaroxaban than for those previously assigned warfarin (3 days). The number of primary outcome events (stroke or systemic embolism) in the first month after cessation of randomised treatment was greater in patients transitioning from rivaroxaban than in those transitioning from warfarin (22 vs 7; p=0∙008). The excess events are probably associated with a period of inadequate anticoagulation during transition from rivaroxaban to vitamin K antagonist therapy. A rebound phenomenon was not clearly evident. These data emphasise the importance of the maintenance of adequate anticoagulation in patients at high risk. The relative effects of rivaroxaban versus warfarin in the 7468 patients with previous stroke or TIA were consistent with the effects of rivaroxaban versus warfarin in the 6796 patients without previous stroke or TIA for stroke or systemic embolism (p for interaction=0·23) and major bleeding (p for interaction=0·36;94 table 6, figures 2, 3).

ARISTOTLE The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial www.thelancet.com/neurology Vol 11 December 2012

compared apixaban with warfarin (target INR 2·0–3·0).5 Patients with impaired renal function (serum creatinine >2·5 mg/dL [221 μmol/L] or creatinine clearance <25 mL/min) were excluded. Patients who were elderly (80 years or older), had low bodyweight (60 kg or lighter), or a serum creatinine of 133 μmol/L (1·5 mg/dL) or greater received a lower dose of apixaban (2·5 mg twice a day) than did other patients (5 mg twice a day). Apixaban was better than warfarin in reducing the rate of stroke or systemic embolism (p=0·01 for superiority; table 5).5 Apixaban was also associated with significantly less major bleeding (p<0·001), less intracranial haemorrhage (p<0·001), and lower mortality (p=0·047). The occurrence of gastrointestinal haemorrhage and myocardial infarction was similar in both groups. The relative effects of apixaban versus warfarin in the 3436 patients with previous stroke or TIA were consistent with the effects of apixaban versus warfarin in the 14 765 patients without previous stroke or TIA for stroke or systemic embolism (p for interaction=0·71) and major bleeding (p for interaction=0·69;95 table 6, figures 2, 3).

Meta-analyses of warfarin-controlled trials of the new anticoagulants Indirect comparisons suggest that the relative effects of each of the new oral anticoagulants compared with warfarin were consistent for stroke and systemic embolism (summary OR 0·92, 95% CI 0∙83–1∙02; I²=22%; p value for heterogeneity=0∙28), haemorrhagic stroke 1073

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(OR 0∙43, 0∙34–0∙55; I²=48%; p for heterogeneity=0∙12), and mortality (OR 0∙90, 0∙84–0∙96; I²=0%; p for heterogeneity=0∙73), but not for extracranial major bleeding (OR 0∙98, 0∙91–1∙07; I²=73%; p for heterogeneity=0∙01) and myocardial infarction (OR 1∙03, 0∙89–1∙20; I²=73%; p for heterogeneity=0∙01).97–103 The effects of apixaban versus warfarin on major and gastrointestinal bleeding seemed more favourable than for dabigatran or rivaroxaban versus warfarin. However, indirect comparisons of the new anticoagulants should be interpreted cautiously because the trials had different designs, participants, and interventions (eg, TTR in those assigned warfarin differed between the trials). The PRoFESS trial emphasised the potential flaws of indirectly comparing antiplatelet agents.104

AVERROES The AVERROES (Apixaban Versus Aspirin to Reduce the Risk of Stroke) study investigated apixaban (5 mg twice daily) versus aspirin (81–324 mg per day) in patients with atrial fibrillation who were thought to be unsuitable or unwilling to receive a vitamin K antagonist.6 The reasons for unsuitability for a vitamin K antagonist varied, but most (>70%) were related to issues with INR monitoring, INR instability, and patient refusal to take vitamin K antagonists. The rate of stroke and systemic embolism was significantly lower with apixaban than with aspirin (p<0·001), whereas the rates of major bleeding (p=0·57), intracranial haemorrhage (p=0·69), gastrointestinal bleeding (p=0·71), and myocardial infarction (p=0·59) were similar in both groups (table 5).6 The relative effects of apixaban versus aspirin in the 764 patients with previous stroke or TIA were consistent with the effects of apixaban versus aspirin in the 4832 patients without previous stroke or TIA for stroke or systemic embolism (p for interaction=0·17) and major bleeding (p for interaction=0·73;96 table 6).

Approval of new oral anticoagulants Dabigatran and rivaroxaban have been approved in many countries for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation, whereas apixaban has not been approved for this indication. The European Committee for Medicinal Products for Human Use has recommended approval for apixaban for atrial fibrillation. Different countries have approved different dosing options for dabigatran. The US Food and Drug Administration (FDA) approved the 150 mg twice daily dose and, on the basis of pharmacokinetic and pharmacodynamic modelling, a 75 mg twice daily dose for patients with creatinine clearance 15–30 mL/min.105 The 75 mg twice daily dose of dabigatran can also be considered in patients with creatinine clearance 31–49 mL/min who are also receiving P-glycoprotein inhibitors such as dronedarone or systemic ketoconazole.106 The reason the 1074

FDA did not approve the 110 mg twice daily dose was that the agency was unable to identify any subgroup (including elderly people and patients with renal impairment and previous bleeding) in which the 110 mg dose would offer an advantage over the 150 mg strength.105 Much of the rest of the world has approved the 150 mg twice daily and 110 mg twice daily dose. Since dabigatran’s approval, several reports about an increased risk of serious bleeding events and death have been published. These findings are difficult to interpret without knowing how many people have been exposed to dabigatran (the denominator), how many people, including unreported cases, have had bleeding (the numerator), and how many people would have had bleeding or died if they had been given warfarin instead of dabigatran.107 These uncertainties emphasise the importance of vigilant phase 4 surveillance when new drugs are marketed.

Patients likely to benefit from new oral anticoagulants Patients with non-valvular atrial fibrillation and sound renal function who are otherwise similar to the type of patients enrolled in the major clinical trials of the new oral anticoagulants2–6 are likely to benefit from these drugs. This group includes not only patients previously untreated or poorly treated with warfarin, but also patients treated with warfarin and achieving good INR control, because the lower rate of intracranial bleeding with the new anticoagulants compared with warfarin seems consistent, irrespective of the quality of INR control in patients assigned warfarin. Warfarin will remain the anticoagulant of choice for some patients with atrial fibrillation, such as those with severe renal impairment and atrial fibrillation due to prosthetic or haemodynamically significant valvular heart disease. Warfarin will also remain the anticoagulant of choice for patients who cannot afford the new anticoagulants, and perhaps those who have concerns about compliance with twice daily doses of dabigatran and apixaban (eg, patients taking several medications, and patients who are poorly motivated and forgetful), because the risks of embolic stroke are likely to increase substantially with poor adherence to shorter-acting new oral anticoagulants. Warfarin might be preferred for patients who have a possible need for quick reversal of the anticoagulant effect and who might be at greater risk of gastrointestinal bleeding with dabigatran and rivaroxaban than with warfarin. The safety of the new anticoagulants is likely to be optimised by careful patient selection, use of the lower dose in patients at highest risk of bleeding (eg, those with renal impairment), and serial assessment of renal function.

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Hence, patients with severe renal dysfunction were excluded from the clinical trials, and patients with moderate renal dysfunction were assigned a reduced dose of rivaroxaban (15 mg/day) and apixaban (2·5 mg/day).4–6 Because the proportion of trial patients who received the lower dose regimens was small, data about the safety and efficacy of the new anticoagulants in patients with severe and moderate renal dysfunction are limited and studies of very low doses or perhaps intermittent administration in patients with severe renal dysfunction are needed. For patients with mild and moderate renal impairment, the new anticoagulants can be used, but renal function should be monitored every 4–6 months because it might decline, causing increased plasma concentrations of the new anticoagulants.

Patients with previous stroke or TIA who have atrial fibrillation The proportion of patients with atrial fibrillation who were enrolled in trials of the new oral anticoagulants and had a previous stroke or TIA varied between 14% and 20%, with the exception of ROCKET-AF, in which 55% of patients had had a previous stroke or TIA. In each trial, the absolute rate of stroke or systemic embolism was higher in patients with previous stroke or TIA than in those without previous stroke or TIA, but the relative effect of each new anticoagulant compared with warfarin in the prevention of stroke or systemic embolism was consistent among patients with and without a previous stroke or TIA (table 6, figure 2). By contrast, the absolute rate of major bleeding was not consistently higher in patients who had had a previous stroke or TIA than in those who had not, but the relative effect of each new anticoagulant compared with warfarin on major bleeding was still consistent among patients with and without a previous stroke or TIA (figure 3). In view of the consistently higher absolute risk of stroke, but not consistently higher absolute risk of major bleeding, in patients with previous stroke or TIA, the absolute benefits of anticoagulation are likely to be greater in patients who have had a previous stroke or TIA than in those who have not.

Use of new anticoagulants in other disorders Although the new oral anticoagulants could be considered for other, so-called niche diseases such as cervical arterial dissections, cerebral venous thrombosis, and hypercoagulable states causing strokes or TIAs, evidence of their efficacy and safety in these settings is not reliable. Additionally, evidence from clinical trials for patients with valvular atrial fibrillation or mechanical heart valves is not available. The RE-ALIGN trial is a phase 2 trial that aims to compare dabigatran etexilate with warfarin in patients with mechanical heart valves.108

of administration. For those who are switching from warfarin to a new oral anticoagulant, warfarin should be stopped for 2–3 days before starting the new anticoagulant to allow the INR to fall to 2·0 or less. Patients who have overdosed on a new anticoagulant within the preceding few hours could be candidates for gastric lavage and oral administration of activated charcoal to minimise drug absorption.

When to start or restart anticoagulation after acute cardioembolic ischaemic stroke After an acute cardioembolic stroke due to non-valvular atrial fibrillation, warfarin or a new oral anticoagulant should be started (or restarted) after about 2 weeks have elapsed because the risks of haemorrhagic transformation of the fresh brain infarct in the first 2 weeks seem to offset any benefits from reduction of recurrent embolic ischaemic stroke (see preceding text).62 Patients with small ischaemic strokes, controlled blood pressure, and perhaps no evidence of microbleeding on gradient echo or susceptibility-weighted MRI sequences might be considered for earlier initiation of anticoagulant therapy if they are at high risk of recurrent stroke.60,61,109 Patients with no residual brain infarction, such as those with TIA, should be safe to start anticoagulation immediately.

Follow-up for adherence and safety After initiation of a new anticoagulant, patients should be followed up at 3 months and every 6–12 months thereafter to verify treatment compliance and adherence and to check renal function, particularly in patients with moderate renal impairment and those at increased risk of developing renal impairment (eg, elderly people or those with heart failure). Compliance and adherence to treatment is crucial because the new anticoagulants have a relatively short half-life, and missing more than one dose is likely to result in inadequate anticoagulation. Treatment compliance can be maintained by education of patients and relatives about the new anticoagulant, and regular follow-up.110,111

Interaction of new oral anticoagulants with antiplatelet therapy Coadministration of the new anticoagulants with aspirin, or other non-steroidal anti-inflammatory drugs, roughly doubles the risk of bleeding, and the risk is even greater with dual antiplatelet therapy.89 Because dual antiplatelet therapy is needed after carotid stenting, patients with atrial fibrillation and recently symptomatic severe carotid stenosis should be considered for carotid endarterectomy instead, unless other overriding factors are present.112

Administration and monitoring effects of new oral anticoagulants

Monitoring of anticoagulant effects of the new oral anticoagulants

For patients starting a new oral anticoagulant, the onset of the anticoagulant effect is rapid, within a few hours

One of the advantages of the new drugs is that routine monitoring of their anticoagulant effect is unnecessary

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because most patients taking a standard dose will have a therapeutic anticoagulant effect. However, the effect of an anticoagulant is sometimes useful to establish (eg, to assess adherence, confirm dose adequacy, detect toxicity or drug interactions, plan urgent surgery or thrombolysis, ascertain the cause of bleeding or ischaemic stroke, and reassure patients that the treatment is active). Qualitative tests for identification of the presence or absence of an anticoagulant effect of dabigatran include the activated partial thromboplastin time (aPTT) and thrombin time (TT), and for rivaroxaban the prothrombin time (PT), measured with neoplastin (but not the INR because this ratio is only calibrated and validated for coumarins). These assays are not accurate quantitative measures of the drug plasma concentrations, however, and are dependent on the reagent and laboratory instrument used.113–117 The ecarin clotting time and Hemoclot thrombin inhibitor assay are more sensitive tests for detection of an anticoagulant effect of dabigatran and correlate with drug concentrations. However, they have not been shown to correlate with bleeding risk. Further, the ecarin clotting time is not generally available and commercial kits have not been validated for dabigatran. The Hemoclot direct thrombin inhibitor assay is a sensitised TT test that has direct linear correlation with dabigatran concentrations at all doses, and could become the gold standard for measuring and monitoring the anticoagulant effect of dabigatran.118,119 The anti-FXa assay is a sensitive test for detection of an anticoagulant effect of rivaroxaban and apixaban and it shows a linear relation with their plasma concentrations.120–123 However, calibrated anti-FXa assays are yet to be correlated with bleeding risk.

Management of acute ischaemic stroke in patients taking new oral anticoagulants About 1% of individuals per year taking the new oral anticoagulants for atrial fibrillation are likely to have an ischaemic stroke.2–5 Guidelines recommend against using intravenous alteplase in anticoagulated patients with an acute ischaemic stroke because of a presumed higher risk of haemorrhagic transformation of any infarcted brain.124 Therefore, if a patient is known to be taking one of the new oral anticoagulants, they should not be considered for thrombolysis unless their clinical history and a laboratory test reliably suggest absence of an anticoagulant effect (eg, a normal aPTT, thrombin clotting time, or Hemoclot in patients taking dabigatran, or a normal PT or anti-Xa assay in patients taking rivaroxaban or apixaban) or until at least four half-lives have elapsed since the last dose.125–127 Reversal of any coagulopathy (eg, with prothrombin complex concentrates [PCC]) before initiation of thrombolytic therapy is untested and might produce prothrombotic risks that outweigh any increased risks of haemorrhagic transformation of the brain infarct. 1076

Endovascular therapy could be an alternative approach in patients with acute stroke who are ineligible for thrombolytic therapy, but this approach has not been properly assessed by randomised controlled trials.128 For patients with acute stroke with dysphagia who have to be fed via a nasogastric or percutaneous gastrostomy tube, opening or crushing dabigatran is not recommended due to increased absorption when the capsule is disturbed. Whether rivaroxaban or apixaban can be administered via a feeding tube is unclear. Studies are underway to establish whether the crushed pill or capsule ingredients adhere to the various feeding tube materials and how this might affect absorption, blood concentrations, and anticoagulant effects.

Management of bleeding in patients taking new oral anticoagulants For serious bleeding, the first steps are to stop the anticoagulant, identify and compress the source of bleeding, administer fluids to assist diuresis and renal excretion of the drug, and consider red blood cell transfusion.117,129 Laboratory coagulation tests, renal function, and complete blood count should be measured to later help to establish the cause and extent of the bleeding. For non-compressible major haemorrhage or emergency surgery, no antidote has been proven to immediately reverse the effect of the new anticoagulants. By contrast, the effects of warfarin can be reversed with four-factor PCC or fresh frozen plasma in conjunction with vitamin K.129 Haemodialysis can be used to remove the two-thirds of circulating dabigatran that is not protein-bound. However, the time to obtain vascular access in patients who are anticoagulated and bleeding might be longer than the half-life of the drug, except in patients with impaired renal function (for whom dialysis might be practical and worthwhile). Dialysis is not effective for rivaroxaban and apixaban because these drugs are mainly protein-bound. PCCs consist of four-factor concentrates (which contain coagulation factors II, VII, IX, and X) and threefactor concentrates (which contain II, IX, and X). Four-factor PCCs are available in activated or nonactivated clotting factor formulations. PCC stimulates thrombin formation and bypasses the anticoagulant effect of thrombin and factor Xa antagonists.129 An experimental study in a murine model of intracerebral haemorrhage associated with dabigatran showed that non-activated PCC and, less consistently, fresh frozen plasma prevented excess intracerebral haematoma expansion.130 A small study in human beings showed that non-activated four-factor PCC, given intravenously as one fixed dose of 50 units per kg of bodyweight, immediately and completely normalised the PT in healthy controls taking rivaroxaban, but not the aPTT in controls taking dabigatran.131 Findings from another study of healthy volunteers given either rivaroxaban or www.thelancet.com/neurology Vol 11 December 2012

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dabigatran showed that activated four-component PCC corrected rivaroxaban-induced impaired thrombin generation in a dose-dependent fashion and had a less pronounced effect on reduced thrombin generation after administration of dabigatran.132 The crucial unknown question, however, is whether PCC stops pathological bleeding. In a study in animals, PCC and recombinant activated factor VII (rFVIIa) both did not fully reverse bleeding induced by rivaroxaban overdose, despite correction of several laboratory measures of coagulation.133 This is a salutary message that laboratory assays are not necessarily valid surrogate measures of the in-vivo effects of reversal agents. If clinicians decide to use PCC to reverse bleeding related to these new agents, activated clotting factors (ie, activated PCC) should theoretically lead to better haemostasis than with unactivated clotting factors (ie, non-activated PCCs), but at the potential risk of more thromboembolic complications. The effect of rFVIIa in reversing the anticoagulant effect of the new anticoagulants is uncertain, but rFVIIa is probably not as effective as PCC. Furthermore, in individuals without haemophilia, it increases arterial thrombosis.134 Human fresh frozen plasma is not likely to overcome the direct effect of the new anticoagulant drugs on thrombin or factor Xa, and it cannot be administered rapidly in many cases. Research is needed to test the effect of PCC on bleeding in patients taking the new anticoagulants. Research is also underway to develop and test specific reversal agents targeted at the active sites of these new agents. An engineered monoclonal antibody (clone 22) is a potent and specific inhibitor of dabigatran activity both in vitro and in vivo.135

Economic analyses Although the immediate cost of the new oral anticoagulants is likely to exceed the costs of warfarin and regular INR monitoring, the long-term benefits of the new anticoagulants compared with those of warfarin are likely to be greater in many patients. Formal economic analyses suggest that the incremental benefit of the new anticoagulants is likely to exceed the incremental costs in many patients, and that the new drugs are likely to be cost effective for these patients.136–141 The most influential variables in the economic analyses are the absolute risk of stroke and haemorrhage (eg, the starting age of the patients), the average TTR for patients receiving warfarin, the relative risk of stroke with the new anticoagulant compared with warfarin, the cost of the new anticoagulant, the monthly cost of combined or recurrent stroke or intracerebral haemorrhage, and the utility of mild ischaemic stroke (ie, the perceived quality of life of the individual after a stroke).136–141

Conclusions Atrial fibrillation is an increasingly common cause of stroke. Stroke due to atrial fibrillation is particularly www.thelancet.com/neurology Vol 11 December 2012

Search strategy and selection criteria We identified references for this Review by searches of PubMed from January, 1966, until August, 2012, with the terms “transient isch(a)emic attack”, “ischaemic stroke”, “antithrombotic drugs”, “anticoagulant(s)”, “antiplatelet drugs”, “aspirin”, clopidogrel”, vitamin K antagonists”, “warfarin”, “dabigatran”, “rivaroxaban”, “apixaban”, “edoxaban”, “stroke”, “stroke prevention”, “randomised controlled trial(s)”, “systematic review”, and “meta-analysis”. We also identified articles through searches of reference lists and our own files. We reviewed only articles published in English.

debilitating and problematic to successfully treat in the acute setting. Warfarin is highly efficacious for the long-term prevention of ischaemic stroke in atrial fibrillation, but has substantial limitations including haemorrhagic stroke and other bleeding complications, interactions with several foods and drugs, the need for frequent INR monitoring, and patient and physician reluctance. The RE-LY,2,3 ROCKET-AF,4 ARISTOTLE,5 and AVERROES6 trials all achieved their primary aim of, respectively, showing non-inferiority of dabigatran, rivaroxaban, and apixaban compared with warfarin, and superiority of apixaban compared with aspirin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and adequate renal function. Dabigatran (150 mg twice a day) and apixaban were also better than warfarin for prevention of stroke and systemic embolism. Intracranial haemorrhage rates were significantly lower with each new anticoagulant, but major gastrointestinal haemorrhage rates were higher with dabigatran and rivaroxaban compared with warfarin. The AVERROES trial showed that in patients unwilling or unable to take a vitamin K antagonist, apixaban was more effective than aspirin for prevention of embolic events, and it was as safe as aspirin with respect to major and intracranial bleeding. We anticipate that the addition of these new drugs to the anticoagulant armamentarium will increase the number of individuals with atrial fibrillation who are appropriately and effectively anticoagulated and thereby reduce the incidence and burden of atrial fibrillationrelated stroke. Research and surveillance is needed to provide valid and reliable measures of the anticoagulant effects of the new agents, rapidly accessible and effective antidotes for major non-compressible bleeding or urgent surgery, comprehensive information about observed, expected, and long-term adverse events in the population, and valid economic analyses of overall cost-effectiveness of the new anticoagulants. Contributors MJA, JWE, and GJH all contributed equally to the manuscript. GJH wrote the first draft of the section comprising the introduction,

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epidemiology, and evidence for thromboprophylaxis in atrial fibrillation; JWE wrote the first draft of the section on new oral anticoagulants, and MJA wrote the first draft of the final section, from clinical trials of new oral anticoagulants to the conclusions. All authors reviewed, commented on, and made suggestions and changes to all sections of subsequent drafts.

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Conflicts of interest MJA participated in the ARISTOTLE study. He has received speaking and consultant honoraria from Boehringer Ingelheim and Janssen, and consulting honoraria from Bristol-Myers Squibb and Pfizer. He received honoraria as a member of the Steering Committee for the TRA 2°P TIMI 50 trial and received research funds as the local principal investigator for that study. JWE has received honoraria or research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Portola, and Sanofi-Aventis. GJH has received honoraria for serving on the executive committee of the AMADEUS trial (Sanofi-Aventis), ROCKET-AF trial (Johnson & Johnson), and the BOREALIS trial (Sanofi-Aventis), the steering committee of the TRA 2°P TIMI 50 trial, and the stroke outcome adjudication committee of the RE-LY and AVERROES trials. GJH has also received honoraria from Bayer, Boehringer Ingelheim, and Pfizer Australia for speaking at sponsored scientific symposia and consulting on advisory boards.

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