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Keywords:

  • atrial fibrillation;
  • guidelines;
  • prevention;
  • risk factors;
  • stroke

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

Although warfarin is superior to aspirin in reducing the risk of stroke in patients with atrial fibrillation, it can increase major bleeds. Hence, physicians stratify patients according to stroke risk to ensure a net benefit. In this review, the CHA2DS2-VASc stratification scheme used in the latest European Society of Cardiology (2010/12) guidelines will be explained. The greater sensitivity of this scheme, compared to the previous CHADS2, more closely delineates patients for whom warfarin is appropriate. The review also anticipates that there will be a wider range of patients who may benefit from the new oral anticoagulants, which show similar or superior efficacy and/or safety to warfarin with a significant reduction in intracranial haemorrhage and do not require routine coagulation monitoring. The role of conventional and new anticoagulant options will also be discussed.


Abbreviations
AF

atrial fibrillation

bid

twice daily

INR

international normalized ratio

ICH

intracranial haemorrhage

RR

relative risk

TTR

time in therapeutic range

VKA

vitamin K antagonist

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

In 2010, the European Society of Cardiology published updated guidelines for the management of patients with atrial fibrillation (AF) [1], and these have been followed by a further focused update in 2012 [2]. In this review, the risk stratification and antithrombotic recommendations for stroke prevention in patients with AF reflected in these guidelines will be considered, as well as the clinical implications of the strong dependence of warfarin therapy on the quality of international normalized ratio (INR) control. In addition, new data emerging since the publication of the 2010 guidelines will be examined, including evidence for the potential role of new oral anticoagulants in stroke prevention.

Search strategy and selection criteria

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

Data for this review were identified by searching PubMed for stroke and bleeding risk stratification schemes included in, and subsequent to, the 2010 European Society of Cardiology guidelines on management of AF, on usage, efficacy and safety of vitamin K antagonist (VKA) and antiplatelet therapy pertinent to the implementation of the guidelines, and on Phase III clinical trials of the new oral anticoagulants dabigatran etexilate, rivaroxaban and apixaban for stroke prevention. Only those abstracts from cardiology meetings that illustrated potential new directions from recent research were included.

Overview of the current status of stroke prevention in AF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

Epidemiology

Atrial fibrillation is the most common cardiac arrhythmia with approximately 1% of the general population being diagnosed with the disease; however, significant under-diagnosis is likely [3]. The risk of developing AF increases with age, and there is a 1 : 4 lifetime risk of the development of AF in men and women over 40 years of age [3-5]. Significantly, results from the Framingham study demonstrated that AF increases the risk of stroke approximately fivefold [4].

Options for stroke prevention

Evidence-based guidelines recommend the use of oral anticoagulant or antiplatelet therapy to reduce the incidence of stroke in patients with AF, regardless of the approach used to manage the arrhythmia [1, 6-8]. Pooled results from clinical trials show that warfarin reduces the risk of stroke in these patients by 64%, whilst aspirin, an antiplatelet agent, reduces this risk by 19% [9]. Warfarin is also superior to dual antiplatelet therapy with aspirin and clopidogrel for the prevention of vascular events in patients with AF [10].

Although warfarin is clearly superior to antiplatelet agents, it has a relatively narrow therapeutic window and interacts with a variety of medications, foods and herbal products [11]; in addition, there are pharmacogenetic differences in response between patients [12]. Due to these and other factors, responses to warfarin can vary widely between individuals, and therefore, routine monitoring and dose adjustment are required [13].

Even amongst patients who are eligible for warfarin therapy according to guidelines, the drug is under-used. In addition, those receiving warfarin spend a significant proportion of time with levels of anticoagulation too low or too high for optimal efficacy and safety. Variable INR values can lead to an excess of either stroke or bleeding events. Overall, whilst warfarin is superior to aspirin for stroke prevention, it is associated with a higher rate of the most significant types of bleeding, such as intracranial haemorrhage (ICH). Thus, the net benefit of warfarin relative to aspirin is reduced in patients with few additional risk factors for stroke. For this reason, guidelines for choosing aspirin rather than warfarin as antithrombotic therapy are based on risk stratification. It is interesting that in the era of new oral anticoagulants, this means that choosing aspirin becomes largely invalid, as discussed below.

Risk stratification for warfarin use, and the recent European Society of Cardiology guidelines

To assess an individual's risk of stroke, a risk stratification scheme is employed. The cardiac failure, hypertension, age, diabetes, stroke (doubled) (CHADS2) scheme [14] has been used primarily in recent years. However, with this scheme, a substantial proportion of subjects are categorized as having a ‘moderate risk’ of stroke (score of 1), for which there is no clear guidance on whether patients should receive a VKA (such as warfarin) or aspirin [1].

Refinements to this scheme have been made because evidence shows that some patients categorized as ‘moderate risk’ in the CHADS2 system clearly derive more benefit from an oral anticoagulant than from aspirin. For example, in patients with AF and a CHADS2 score of 1, warfarin was more effective than aspirin at reducing the incidence of ischaemic stroke without increasing the risk of major haemorrhage (although minor bleeding was more common with warfarin) [15]. Similar results have been found in elderly (≥75 years) patients with AF at risk of stroke [16]. Furthermore, the original CHADS2 scheme does not include additional known stroke risk factors, such as vascular disease.

The European Society of Cardiology 2010 guidelines for management of AF recommend use of the more comprehensive CHA2DS2-VASc scheme [17], which doubles the value assigned to older age as a risk factor and includes three additional moderate risk factors: vascular disease, age 65–74 years and sex category (female) (Table 1). For patients with a CHA2DS2-VASc score of ≥2, oral anticoagulant therapy with a VKA is recommended. For those with a CHA2DS2-VASc score of 1, oral anticoagulation with either a VKA or 75–325 mg aspirin daily is recommended; however, oral anticoagulant is preferred. For patients with no additional risk factors, 75–325 mg aspirin or no antithrombotic treatment is recommended; the latter is preferred (Table 2) [1]. Provisional recommendations for the use of new oral anticoagulants are included in the guidelines; these are expected to evolve and are discussed below.

Table 1. Risk factors for stroke and thromboembolism in nonvalvular AF using the CHA2DS2-VASc scheme expressed as a point-based scoring system [1]
Risk factorScore
  1. LV, left ventricular; LVEF, left ventricular ejection fraction (as assessed by echocardiography, radionuclide ventriculography, cardiac catheterization or cardiac magnetic resonance imaging); TIA, transient ischaemic attack; AF, atrial fibrillation.

  2. CHA2DS2-VASc scheme (acronym underlined): ‘major’ risk factors score two points each and ‘clinically relevant nonmajor’ risk factors score 1 point.

  3. a

    Prior myocardial infarction, peripheral artery disease or aortic plaque.

Congestive heart failure or moderate to severe LV dysfunction (e.g. LVEF ≤ 40%)1
Hypertension1
Age ≥ 75 years2
Diabetes mellitus1
Stroke/TIA/thromboembolism2
Vascular diseasea1
Age 65–74 years1
Female sex category1
Maximum score9
Table 2. Recommendations for thromboprophylaxis in patients with AF [1]
Risk categoryCHA2DS2-VASc scoreRecommended antithrombotic therapy
  1. AF, atrial fibrillation; INR, international normalized ratio; VKA, vitamin K antagonist.

  2. aSuch as a VKA (INR = 2.0–3.0). If approved, dabigatran etexilate should also be considered: 150 mg bid for patients with low bleeding risk (HAS-BLED score 0–2) and 110 mg bid for those with a higher risk of bleeding (HAS-BLED score ≥ 3). bSuch as a VKA (INR = 2.0–3.0). If approved, dabigatran etexilate 110 mg bid should be considered.

One ‘major’ risk factor or ≥2 ‘clinically relevant nonmajor’ risk factors≥2Oral anticoagulanta
One ‘clinically relevant nonmajor’ risk factor1

Either oral anticoagulantb or aspirin 75–325 mg daily

Preferred: oral anticoagulant

No risk factors0

Either aspirin 75 mg daily or no antithrombotic therapy

Preferred: no antithrombotic therapy

The CHA2DS2-VASc scheme helps to clarify treatment decisions as it results in a ‘low-risk’ category that is truly low risk, reduces the proportion of patients who were previously categorized as moderate risk and identifies the majority of patients who can expect a net benefit from oral anticoagulant therapy, as shown in Fig. 1 [17].

image

Figure 1. The proportion of patients in the Euro Heart Survey assigned to different stroke risk categories by CHADS2 (revised) score compared with CHA2DS2-VASc score amongst those who did not receive anticoagulation at baseline, and the corresponding incidence of thromboembolic events (TE; i.e. stroke, pulmonary embolism or peripheral embolism) [16] and treatment recommendations [1]. OAC, oral anticoagulant.

Download figure to PowerPoint

A large, registry-based cohort study evaluating the individual risk factors comprising the CHADS2 and CHA2DS2-VASc scores in patients admitted to hospital with AF and not treated with VKAs has supported the original validation of CHA2DS2-VASc.

It confirmed that the CHA2DS2-VASc performed better than CHADS2 in stratifying stroke risk. The rate of thromboembolism at 1-year follow-up was 1.67 per 100 person-years in patients with a CHADS2 score of 0, compared to only 0.78 per 100 person-years in those with a CHA2DS2-VASc score of 0; in intermediate-risk patients with CHADS2 versus CHA2DS2-VASc scores of 1, the rates were 4.75 vs. 2.01 per 100 person-years, respectively. In general, similar rates of events persisted at 5- and 10-year follow-ups [18].

Nevertheless, the importance of some individual risk factors has been debated. The 2006 American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the management of patients with AF [6] included age 65–74 years, coronary artery disease, female gender and thyrotoxicosis as less well validated or weaker risk factors. By contrast, in the development of the CHA2DS2-VASc scheme based on patients in the Euro Heart Survey on Atrial Fibrillation [17], the first three of these were found to be significant risk factors. However, in the large cohort study mentioned above, female sex alone (CHA2DS2-VASc score = 1) was a statistically significant risk factor for hospitalization or death due to thromboembolism at 1-year follow-up (1.24 events per 100 person-years) but was not significant at 5 and 10 years. On the other hand, women with hypertension had a higher stroke risk. If female sex is considered equivalent to a score of 0, appropriate treatment would be no therapy or aspirin; by contrast, female sex plus hypertension would provide a clear indication for oral anticoagulant therapy, corresponding to a score of 2 (of note, either an oral anticoagulant or aspirin would be recommended if these factors represented a score of 1).

Future trials may further refine these schemes. There is current interest in the role of biomarkers that can easily be tested as indicators of stroke risk. For example, in a large clinical trial population of patients with AF randomly assigned to warfarin or dabigatran etexilate, elevated cardiac troponin I levels were associated with an increased risk of stroke and systemic embolism as well as death [19]. Furthermore, elevated levels of N-terminal pro-B-type natriuretic peptide were related to increased risks of stroke, cardiovascular death and major bleeding, even after the adjustment for CHADS2 risk factors [20].

Of note, use of stroke risk schemes to guide therapy needs to be balanced by a full appreciation of the bleeding risk. The European Society of Cardiology 2010 guidelines state that the recently introduced hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (age > 65 years), drugs/alcohol concomitantly (HAS-BLED) scheme [21] is appropriate for assessing bleeding risk in patients with AF receiving a VKA [1]. HAS-BLED produces similar results to an older scheme, HEMORR(2)HAGES, but is easier to use in everyday practice [22]. A five-factor risk score based on patients taking warfarin in the ATRIA study has also recently been published incorporating anaemia, severe renal disease (three points each), age ≥ 75 years (two points), prior bleeding and hypertension (one point each) [23].

The concept of net clinical benefit (ischaemic stroke versus ICH) has been used to compare VKA therapy or aspirin alone, VKA therapy plus aspirin and no treatment. Patients with AF in a large real-world cohort were evaluated for stroke and bleeding risks using CHADS2, CHA2DS2-VASc and HAS-BLED. VKA treatment consistently lowered the risk of thromboembolism compared with aspirin or no treatment, whereas VKA plus aspirin provided no additional benefit. The risk of bleeding was higher in all risk groups compared with no treatment, but overall, there was a positive net clinical benefit of VKAs alone in patients with CHADS2 score ≥1 or CHA2DS2-VASc score ≥2 and a neutral or positive net clinical benefit in patients with CHADS2 score ≥0 or CHA2DS2-VASc score ≥1 [24].

Warfarin and the importance of INR control

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

Time in therapeutic range and the efficacy and safety of warfarin

Amongst patients receiving a VKA, there is a large variation in time in therapeutic range (TTR; INR 2.0–3.0) achieved in different centres and in different countries [25-27]. In a study of 101 community-based practices, following patients for up to 1 year, the mean TTR was 66.5%; TTR was above 75% in 37% of patients and below 60% in 34% [25]. In a retrospective cohort study, it was found that half of patients with a high risk of stroke (CHADS2 ≥2) were outside the therapeutic range for 50% or more of the time for the duration of their warfarin treatment [28]. The TTR of warfarin users was 63% in a UK General Practice Research Database study [29].

In at-risk patients with AF, sub-therapeutic INRs increase stroke susceptibility, stroke severity and total mortality [30-32]. Indeed, in a recent study, 75% of patients with AF admitted to hospital due to stroke had a sub-therapeutic INR (≤2.0). Only 10% of patients who were admitted with acute stroke had a therapeutic INR of ≥2.0 [31]. Furthermore, patients with an INR < 2.0 at admission had a higher risk of severe stroke and of death within 30 days than those with an INR > 2.0 [30]. In the General Practice Research Database study, patients with at least 70% TTR had a 79% reduced risk of stroke and significantly reduced mortality compared to those with TTR of ≤30% [29].

Intracranial haemorrhage is the most serious manifestation of bleeding complications in patients receiving warfarin. With the increasing use of warfarin, the incidence of ICH has risen significantly [33], although rates may have fallen to some extent in recent years [34]. The 30-day case fatality rate is threefold higher for ICH than for ischaemic stroke [35]. Approximately 90% of deaths from warfarin-associated haemorrhages are due to ICH, whilst 76% of patients with ICH die or are severely disabled at hospital discharge [36].

The risk of ICH is highest if the INR is outside the target range of 2.0–3.0 [37, 38]. Risk of ICH increased in patients with an INR > 3.5 but was low at an INR < 3.6, without significant further reductions at <2.0. Overall, the risk of thromboembolic events was low at INR levels >1.8, but increased markedly below this level. These patterns were not substantially affected by age, CHADS2 score or history of stroke. These findings confirm that the standard target INR range of 2.0–3.0 is optimal for a net benefit, regardless of stroke risk factors [[37-40]].

The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W) trial was designed to compare clopidogrel plus aspirin with VKA therapy in patients with AF. VKA therapy was superior for the primary outcome (stroke, systemic embolism, myocardial infarction or vascular death) and for stroke prevention, with similar rates of major bleeding. However, this advantage was largely confined to patients who were already receiving VKA therapy at study entry [26]. In line with the importance of INR control, further analysis of the ACTIVE-W results showed that the superiority of warfarin for stroke prevention compared with antiplatelet therapy is lost below a threshold TTR of approximately 58% [26]. The impact of the TTR on clinical outcomes, such as ischaemic stroke and mortality, was also analysed in an observational setting [32]: a 10% decrease in TTR resulted in a 10% increase in the risk of ischaemic strokes and a 29% increase in the risk of mortality. Taken together, these findings suggest that the efficacy of warfarin needs to be assessed in the context of the TTR.

De Caterina and colleagues noted that, despite the superiority of VKAs over clopidogrel plus aspirin for the primary outcome in ACTIVE-W, the trial did not demonstrate a significant difference with regard to mortality. They therefore investigated the net benefit of treatment. Their analysis of the risk of subsequent mortality after the occurrence of nonfatal vascular and bleeding events in ACTIVE-W demonstrated that disabling strokes (Rankin score ≥3) were associated with increased mortality (hazard ratio 14.3) but non-disabling strokes were not. Severe bleeding also increased mortality (hazard ratio 5.7), in contrast to nonsevere major bleeding [41]. On the basis of this analysis of net benefit, clopidogrel plus aspirin was associated with a significantly higher number of severe events overall (disabling stroke, myocardial infarction, severe bleeding and vascular death) than VKAs (relative risk 1.28).

In terms of preventing severe strokes, some of the benefit of VKAs was lost compared with clopidogrel and aspirin, mainly because of an increase in haemorrhagic strokes in the warfarin group. Indeed, the benefit of VKAs compared with clopidogrel and aspirin decreased with increasing stroke severity (= 0.036); the relative risks for nondisabling (modified Rankin score 0–2) and disabling/fatal strokes (modified Rankin score 3–6) were 2.49 and 1.47, respectively [41].

Under-use of warfarin

Available data show that only 15–44% of eligible patients with AF are prescribed oral anticoagulant therapy with warfarin [42]. One study of Swedish practice revealed that 40% of eligible patients with a moderate to high risk of stroke received neither oral anticoagulant therapy nor aspirin [43]. Factors associated with decreased warfarin use included: age <55 and ≥85 years, prior intracranial and gastrointestinal haemorrhage, predisposition to falls and alcohol or other drug abuse or dependence [44].

Because ~25% of strokes in those aged 80–89 years can be attributed to AF [4], it is especially important that the elderly receive adequate anticoagulation. However, warfarin is under-used in the elderly [45-47]. In a study of 405 elderly patients with AF, 51% were prescribed warfarin. The remaining patients were deemed unsuitable for warfarin therapy, even though 83% had at least two major risk factors for stroke. Haemorrhage, falls, patient refusal or a history of nonadherence accounted for nearly 80% of the reasons cited by doctors for not prescribing warfarin. Other reasons included active alcohol abuse, terminal illness and cognitive impairment [46].

Similarly, an analysis of medical records in the UK General Practice Research Database found that elderly patients (≥85 years old) with chronic AF were less likely to start warfarin and more likely to receive aspirin than patients with AF aged 40–64 years. A higher CHADS2 score did not lead to increased initiation of warfarin. Furthermore, on average, about 30% of all patients stopped taking warfarin within 1 year, and 40%, within 2 years [48].

The new anticoagulants

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

The under- and suboptimal use of warfarin are common. Some patients have true contraindications to warfarin, such as pregnancy, haemorrhagic tendencies or blood dyscrasias. In patients with other conditions, such as severe-to-moderate hepatic/renal insufficiency or severe diabetes, it is essential that physicians carefully assess the associated risks and benefits before prescribing warfarin. In addition, certain diseases including cancer and hyperthyroidism may affect the activity of warfarin [49]. Many other patients are deemed to be ‘ineligible’ for reasons discussed above. Traditionally, the only alternative for these patients has been aspirin; however, aspirin cannot provide the same level of protection against stroke as warfarin. Therefore, there is a requirement for new anticoagulants that are as effective and safe as warfarin, but more convenient to use [50].

Efficacy and safety of new anticoagulants

Table 3 summarizes the key pharmacological properties of the new oral anticoagulants [51, 52]. Several trials have assessed the efficacy and safety of these anticoagulants compared with warfarin for stroke prevention in patients with AF. Whereas the dose of warfarin was adjusted in these trials to a target INR of 2.0–3.0, the new oral anticoagulants were given in fixed doses. Key differences between the trials of dabigatran etexilate, rivaroxaban and apixaban and their results are summarized in Table 4 [53-56]. In an additional trial [57], apixaban and aspirin have been compared.

Table 3. Pharmacological characteristics of new oral anticoagulants [51, 52]
AnticoagulantTargetHalf-life t max ExcretionDosing frequency for stroke prevention
  1. tmax, time to maximum concentration in plasma.

DabigatranThrombin12–14 h0.5–2 hRenal 80%Twice daily
RivaroxabanFactor Xa9–13 h2–4 hRenal 66%Biliary 33%Once daily
ApixabanFactor Xa8–15 h1–4 hBiliary 75%Renal 25%Twice daily
Table 4. An overview and comparison of the RE-LY®, ROCKET-AF and ARISTOTLE trials [[53-56]]
 RE-LY®ROCKET-AFARISTOTLE
Overview
Patients, n18 11314 26418 201
DesignOpen-label, blinded end-point adjudication (PROBE)Double-blind, double-dummy (sham INR)Double-blind, double-dummy (sham INR)
TreatmentsDabigatran etexilate 110 mg bid vs. 150 mg bid (blinded) vs. open-label warfarin (INR 2.0–3.0)Rivaroxaban 20 mg once daily (or 15 mg with moderate renal impairment) vs. warfarin (INR 2.0–3.0)Apixaban 5 mg bid (or 2.5 mg bid with ≥2 of: age ≥80 years, weight ≤60 kg, serum creatinine ≥133 μmol L−1) vs. warfarin (INR 2.0–3.0)
Inclusion criteriaAF and ≥1 other risk factor for strokeAF and a history of stroke or ≥2 other risk factors for strokeAF and ≥1 other risk factor for stroke
AnalysisIntention-to-treat (for noninferiority then superiority)On-treatment (per protocol compliant population) for noninferiority, followed by superiority in safety-on-treatment population and then intention-to-treat (for sensitivity testing of superiority)Intention-to-treat (for noninferiority then superiority)
ResultsDabigatran 110 mgDabigatran 150 mgWarfarinRivaroxabanWarfarinApixabanWarfarin
  1. AF, atrial fibrillation; INR, international normalized ratio; bid, twice daily; RR, relative risk; ICH, intracranial haemorrhage.

  2. aIntention-to-treat analysis. bP values for superiority. cSafety-on-treatment analysis.

  3. Both dabigatran doses were noninferior to warfarin for stroke or systemic embolism. Rivaroxaban was noninferior to warfarin in the primary on-treatment analysis of ROCKET-AF: rivaroxaban 1.71% per year versus warfarin 2.16% per year; hazard ratio 0.79 (95% CI 0.66–0.96); < 0.001 for noninferiority.

Time in therapeutic range  

64% (mean)

67% (median)

 

55% (mean)

58% (median)

 

62% (mean)

66% (median)

Mean CHADS2 score2.12.22.13.483.462.12.1
Stroke or systemic embolism (% per year)a1.541.111.712.12.41.271.60
RR versus warfarinb

0.90

(= 0.30)

0.65

(< 0.001)

 

0.88

(= 0.12)

 

0.79

(= 0.01)

 
Major bleeding (% per year)2.873.323.573.6c3.4c2.133.09
RR versus warfarin

0.80

(= 0.003)

0.93

(= 0.32)

 

1.04c

(= 0.58)

 

0.69

(< 0.001)

 
ICH (% per year)0.230.320.760.50.70.330.80
RR versus warfarin

0.30

(< 0.001)

0.41

(< 0.001)

 

0.67

(= 0.02)

 

0.42

(< 0.001)

 

The RE-LY® (Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate) study included patients with AF and at least one of the following additional stroke risk factors: previous stroke or transient ischaemic attack; left ventricular ejection fraction <40%; heart failure symptoms of at least New York Heart Association class II within 6 months before screening; age ≥75 years; or age 65–74 years plus diabetes mellitus, hypertension or coronary artery disease. Dabigatran etexilate 150 mg twice daily (bid) was superior to warfarin in preventing stroke and systemic embolism, without increased major bleeding. Patients randomly assigned to dabigatran etexilate 110 mg bid experienced fewer major bleeding episodes than those in the warfarin group, whilst this dose was noninferior for stroke reduction. Furthermore, rates of ICH were significantly lower with both doses of dabigatran etexilate in comparison with warfarin [53, 54].

In the ROCKET-AF (Rivaroxaban-Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for the prevention of stroke and Embolism Trial in Atrial Fibrillation) study, patients had a history of stroke or at least two additional risk factors. In the primary analysis of patients taking study drug per protocol and whilst receiving treatment, rivaroxaban was noninferior to warfarin for the reduction of stroke and systemic embolism. It was also noninferior in the traditional intention-to-treat analysis. Rivaroxaban only achieved superiority in the population receiving at least one dose of study drug (regardless of adherence to protocol) when analysed for the on-treatment period. For the composite of major and nonmajor bleeding, rates were similar for rivaroxaban and warfarin. This was also true for major bleeding alone. Significantly fewer cases of fatal bleeding and ICH were reported in patients receiving rivaroxaban [56].

In the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) trial, twice daily apixaban was compared with warfarin in patients with AF and at least one additional stroke risk factor. Apixaban was superior for the prevention of stroke and systemic embolism and was associated with a lower rate of major bleeding. ICH was also significantly reduced with apixaban. Furthermore, apixaban was associated with an 11% statistically significant reduction in mortality [55].

In the AVERROES (Apixaban VERsus acetylsalicylic acid to pRevent strOkES) study, the efficacy of apixaban versus aspirin was evaluated in patients with AF who had at least one risk factor for stroke and were considered unsuitable for VKA therapy. Subjects were randomly assigned to receive either apixaban 5 mg bid (or 2.5 mg bid in selected patients) or aspirin (81–324 mg bid). As expected, the annual rate of stroke or systemic embolism was lower in the apixaban group: aspirin, 4.0% per year; apixaban, 1.7% per year. The incidence of ICH was 0.4% per year, regardless of therapy, and the rate of major haemorrhage was similar in the two treatment arms (aspirin, 1.2% per year; apixaban, 1.5% per year) [57]. The study was terminated prematurely because apixaban provided superior protection against stroke without an increase in major bleeding (compared with aspirin). This means, however, that the comparison between apixaban and aspirin with regard to ICH and major bleeding rates should be interpreted with caution due to the relatively short exposure to study drugs.

Although dabigatran etexilate was not tested head-to-head against aspirin, its superiority may be inferred from comparisons with warfarin, which has been shown to reduce the risk of stroke by 38%, compared with aspirin, but with 128% greater risk of ICH [9, 58]. In recent trials, in patients at similar baseline risk of stroke, the rate of ICH with aspirin was 0.2% per year in ACTIVE [58], 0.2% and 0.3% per year with dabigatran etexilate 110 and 150 mg bid, respectively, in RE-LY® [53] and 0.3% per year with apixaban in ARISTOTLE [55]. In the warfarin arms of these three trials, the rates of ICH were similar: 0.8%, 0.8% and 0.7% per year, respectively. With rivaroxaban, in patients at higher stroke risk, the rate of ICH was 0.5% per year [56]. The consequence of these findings is that the argument for using aspirin instead of a VKA in patients classified as having CHADS2 or CHA2DS2-VASc scores of 1 is negated when the choice is between aspirin and one of the new oral anticoagulants.

New anticoagulants in clinical practice

In light of these recent trials, the 2010 and 2012 European Society of Cardiology guidelines [1, 2] recommend that new anticoagulant drugs may be considered as alternatives to VKA therapy (depending on local regulatory approval).This would apply to patients with CHA2DS2-VASc score ≥1. Other updates have also been published recently. The American Heart Association/American Stroke Association guidelines of 2011 for the primary prevention of stroke note that direct thrombin inhibitors, such as dabigatran etexilate, may be a potential alternative to warfarin [7]. With regard to new non-VKA anticoagulants, the Canadian Cardiovascular Society also recommends that most patients should receive dabigatran in preference to warfarin when an oral anticoagulant is indicated for stroke prevention. Possible exceptions to this include patients with a tendency towards dyspepsia, gastrointestinal bleeding or both, and those at substantial risk of coronary events [59]. A 2012 focused update extended the preference for new anticoagulants to apply to rivaroxaban or apixaban (when approved) [60]. The updated guidelines from the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society recommend dabigatran as a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolism who do not have a prosthetic heart valve or haemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL min−1) or advanced liver disease (impaired baseline clotting function) [61]. Finally, 2012 guidelines from the American College of Chest Physicians suggest that dabigatran etexilate should be used rather than a VKA for patients with a recommendation for oral anticoagulation [those with intermediate or high risk of stroke (CHADS2 score = 1 or ≥2, respectively)] [62].

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

Atrial fibrillation increases the risk of stroke. Therefore, it is important that patients with AF at risk of stroke receive adequate anticoagulation. Historically, warfarin or antiplatelet therapy have been the options available for stroke prevention in AF. Studies have demonstrated that warfarin is significantly more effective than aspirin as an anticoagulant. Updated European Society of Cardiology guidelines include the use of CHA2DS2-VASc, a refined tool for assessing the risk of stroke, and in doing so have minimized the group of patients for whom antithrombotic recommendations were ambiguous (either aspirin or warfarin).

However, due to the inconvenience of warfarin therapy, approximately half of at-risk AF patients either receive no anticoagulant therapy or receive aspirin. In those who do use warfarin, discontinuation rates are high, and the narrow therapeutic window is problematic. Recent figures show that, on average, patients achieve appropriate anticoagulation only 60% of the time on-treatment. This means that, during the remaining time, patients are at risk of stroke or bleeding.

The emergence of new anticoagulants is promising in terms of treatment for patients with AF. The clinical profiles of these agents make them easier to use, with fewer drug and food interactions, and noninferiority or superiority to warfarin for efficacy and/or safety, which suggests that they might be adopted in preference to VKAs in the future. Whilst some patients (such as the elderly) will still be at an intrinsically higher risk of bleeding, it is hoped that rates of ICH and fatal bleeding will remain lower than with VKAs. It is essential, however, to use the new anticoagulants according to the label recommendations, as their benefits can best be achieved under these conditions [47]. Whilst their rate of introduction into clinical practice may be controlled because many patients currently on VKA therapy can achieve stable INR values, new patients or those having difficulty with warfarin will be logical candidates to use new oral anticoagulants.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References

The author would like to thank Lauren Godwin PhD and Keith Day PhD, of PAREXEL, for editorial assistance in the preparation of the manuscript, with funding from Boehringer Ingelheim.

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  4. Search strategy and selection criteria
  5. Overview of the current status of stroke prevention in AF
  6. Warfarin and the importance of INR control
  7. The new anticoagulants
  8. Conclusions
  9. Conflict of interest statement
  10. Acknowledgements
  11. References
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