• From Medscape Education
  • Gregory Y. H. Lip, MD

IntroductionAfter nearly 6 decades of oral anticoagulation therapy (OAC) with vitamin K antagonists (VKA), novel anticoagulants are poised to replace them. Fueled by positive results of recent randomized clinical trials, these agents promise to usher in a new era in anticoagulation therapy.

At the 2011 Congress of the European Society of Cardiology (ESC) in Paris, AF was an important topic. Considerable excitement was generated by the late-breaking clinical trial ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), which studied the novel anticoagulant apixaban (an oral factor Xa inhibitor) in patients at risk for stroke from nonvalvular AF. This Expert Column will summarize the scope of AF-related stroke, present the latest ESC guidelines for AF stroke risk assessment, and comment on and discuss what we have learned from the recent ARISTOTLE trial.

Atrial Fibrillation-Related Stroke

Atrial fibrillation is the most common sustained cardiac arrhythmia, with a prevalence of 1%-2% in the general population.[1] Six million Europeans have AF, and the prevalence is expected to double in the next 50 years.[2] The latest data from Iceland show how AF may grow to epidemic prop

ortions over the next few years (Figure 1).[3]

Figure 1. Projected burden of diagnosed atrial fibrillation in individuals 20 to 99 years of age in Iceland — 2008-2050. Reprinted with permission from Stefansdottir H., et al. Europace. 2011;13:1110-1117.[3]

The risk for stroke is increased 5-fold by AF, and AF-related stroke is associated with higher mortality and greater disability rates, longer hospital stays, and lower rates of discharge to the patient’s own home. Death rates are doubled by AF independent of other known predictors of mortality, and only anticoagulation therapy has been shown to reduce AF-related deaths.[2,4,5] Paroxysmal AF carries the same stroke risk as permanent or persistent AF.[6]

Although patients with AF have an increased risk for stroke, the absolute rate depends on age and the presence of comorbidities. Quantifying the stroke risk in AF patients can aid clinicians in the selection of antithrombotic therapy. The most widely used stroke risk assessment scheme is the CHADS2 score, which came into clinical use a decade ago. This stroke risk index uses a simple scoring system that assigns points for the presence of various patient characteristics (Table 1).[7]

Table 1. CHADS2 Stroke Risk Index

Risk Factor Score
Congestive heart failure 1 point
Hypertension 1 point
Age ≥ 75 1 point
Diabetes mellitus 1 point
Stroke or TIA 2 points

TIA = transient ischemic attack

Over the years, the various pros and cons of the CHADS2 score have been debated, and a recent systematic review and meta-analysis even concluded that the pooled C statistic and calibration analysis suggests minimal clinical utility of CHADS2 in predicting ischemic stroke across all risk strata and that further validation of CHADS2 should perhaps be undertaken.[8,9] Thus, various adjustments to the CHADS2 stroke risk assessment scheme have been proposed, schemes that include additional common stroke risk factors seen in everyday clinical practice.[10]

Indeed, the 2006 ACC/AHA/ESC guidelines recommended consideration of “less validated or weaker risk factors” (as the state of knowledge in 2006), such as age 65-74, female gender, coronary artery disease, and thyrotoxicosis, when making decisions on antithrombotic therapy.[11]

Given the availability of the new oral anticoagulants, the focus has shifted away from identifying the high-risk individuals to be subjected to an “inconvenient” drug, warfarin. Now, greater efforts are being directed toward identifying truly “low–risk” patients with AF who do not need any antithrombotic therapy, while those with ≥1 stroke risk factors can be considered for effective stroke prevention with oral anticoagulation (whether well-controlled warfarin or 1 of the new oral anticoagulants). This is recognizing that aspirin has minimal efficacy for stroke prevention in AF and may not be any safer than warfarin in terms of major bleeding or intracranial hemorrhage, especially in the elderly.[12,13,14] Even in moderate-risk patients, warfarin is far superior to aspirin in stroke prevention, with similar rates of bleeding.

To be more inclusive (rather than exclusive) of common stroke risk factors, the 2010 ESC Guidelines for the management of atrial fibrillation recommended use of the CHA2DS2-VASc score. This score was derived to complement the CHADS2 score in decision making and formally validates the use of additional stroke risk factors, such as age 65-74, female gender, and vascular disease (Table 2). Indeed, numerous validation studies have now shown that the CHA2DS2-VASc score is consistently better than CHADS2 in defining “low-risk” patients and is as good as — and possibly better than — CHADS2 in defining “high-risk” subjects.[2]

Table 2. 2010 ESC Antithrombotic AF Guidelines: CHA2DS2VASc scoring system

Risk Factor Score
Congestive heart failure/left ventricular dysfunction 1
Hypertension 1
Age ≥ 75 2
Diabetes mellitus 1
Stroke/TIA/systemic embolism 2
Vascular disease 1
Age 65 – 74 1
Sex category (ie, female sex) 1
Maximum score 9

From Camm AJ, et al. Eur Heart J. 2010;31:2369-2429.[2]

The approach to thromboprophylaxis in patients with AF encapsulated in the ESC guidelines includes the CHA2DS2-VASc score as part of the decision-making process (Table 3).

Table 3. 2010 ESC Antithrombotic AF Guidelines: Risk Categories, CHA2DS2-VASc Score, and Recommended Antithrombotic Therapy

Risk Category CHA2DS2-VASc Score Recommended Antithrombotic Therapy
1 major risk factor or ≥2 clinically relevant nonmajor risk factors ≥ 2 OAC*
1 clinically relevant nonmajor risk factor 1 Either OAC* or aspirin 75-325 mg daily Preferred: OAC rather than aspirin
No risk factor 0 Either aspirin 75-325 mg daily or no antithrombotic therapy Preferred: no antithrombotic therapy rather than aspirin

*OACs such as a VKA, adjusted to an intensity range of INR 2.0-3.0 (target 2.5). New OAC drugs, which may be viable alternatives to a VKA, may ultimately be considered.
From Camm AJ, et al. Eur Heart J. 2010;31:2369-2429.[2]

Antithrombotic therapy for Stroke Prevention in AF

Antithrombotic therapy for the prevention of atrial fibrillation-related stroke has been studied extensively over the past 2 decades. Between 1989 and 1992 there were 5 large randomized clinical trials of primary prevention studying VKA therapy (principally warfarin). A meta-analysis concluded that OAC therapy resulted in a 64% relative reduction in stroke, corresponding to an absolute annual risk reduction of 2.7%; also, warfarin resulted in a significant 26% reduction in all-cause mortality vs placebo/control.[15] Many of the strokes observed in OAC patients occurred when the patients were either not taking the drugs or had a subtherapeutic INR (international normalized ratio).[2]

Antiplatelet therapy vs placebo/control shows a significant 22% stroke risk reduction (with a nonsignificant impact on mortality). This is of a similar magnitude to giving antiplatelet therapy for vascular disease. And AF is commonly associated with vascular disease!

If confined to aspirin-only trials, there is a nonsignificant 19% reduction in stroke vs placebo/control, which is driven by 1 single positive trial, SPAF-I, which has important internal heterogeneity for the aspirin effect vs placebo.[16]

Even warfarin is superior to aspirin plus clopidogrel for stroke prevention, and such combination antiplatelet therapy carries significant risk for major bleeding, comparable to that seen with anticoagulation.[17,18]

The historical trials have been criticized for only randomizing <10% of patients screened. However, more complementary data from “real-world” cohorts is available. In a huge nationwide cohort study, Olesen et al recently reported that aspirin is neither effective nor safe and that there is no evidence of any positive net clinical benefit balancing ischemic stroke vs intracranial hemorrhage in aspirin-treated patients.[19]

Limitations of VKA Therapy

Despite the impressive efficacy of VKA therapy in reducing stroke rates in nonvalvular AF, these agents have limitations that significantly impact their usefulness in clinical practice. It has been estimated that only half of patients eligible for OAC actually receive therapy because of the difficulty in maintaining patients on these drugs.[20]

Principal among these limitations is the fact that VKAs have an unpredictable dose response that is affected by both intrinsic (inderindividual variability, ie, genetics) and extrinsic factors such as diet and drug interactions. Thus, regular laboratory monitoring using a surrogate marker for intensity of anticoagulation (the prothrombin time expressed as a “corrected” ratio, the INR) is required to maintain patients within a narrow therapeutic range to achieve an adequate amount of attenuation of coagulation while avoiding undue interference with normal hemostasis.[2]

VKAs are very nonspecific in that they affect several coagulation proteins (including some proteins such as C and S that are actually “anticoagulant” in nature). The long-sought solution to this has been to discover and develop compounds that achieve an anticoagulant effect in a predictable dose-dependent fashion, and this has been achieved by targeting specific coagulation proteins such as thrombin (factor IIa) and factor Xa. In so doing, effective oral anticoagulation can be achieved without the need for regular laboratory monitoring. [21] [Editor’s note: The absence of regular monitoring associated with these more “targeted” agents has raised some concerns; however, the predictable dose response of these drugs has been validated in large randomized clinical trials demonstrating equivalent or superior efficacy and safety over warfarin. It should also be noted that there are no specific antidotes for these novel anticoagulants. While there is also no specific antidote for vitamin K antagonists, the administration of vitamin K1 is recommended to “reverse” the anticoagulant effects, and if urgent reversal is required, administration of prothrombin complex concentrate, fresh frozen plasma, or activated factor VII may be considered.]

Novel Anticoagulants

A number of coagulation factor-specific inhibitors have been discovered and are either in development or in clinical use. Three of them have completed large randomized clinical trials in the prevention of AF-related stroke: the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban (Table 4).[22-26] [Editor’s note: As of October 2011, dabigatran is the only novel anticoagulant approved for marketing in Europe and North America.]

Table 4. Novel Anticoagulants in Phase 3 Trials

Trial N Drug Dose Comparator Trial Design
RE-LY 18,113 Dabigatran 110 mg and 150 mg twice daily Warfarin Open
AVERROES 5599 Apixaban 5 mg twice daily Aspirin Double blind
ROCKET AF 14,264 Rivaroxaban 15 and 20 mg once daily Warfarin Double blind
ARISTOTLE 18,201 Apixaban 5 mg twice daily* Warfarin Double blind
ENGAGE-AF ~20,500 Edoxaban 30 and 60 mg once daily Warfarin Double blind

*2.5 mg twice daily was administered to 428 patients (4.7%) aged ≥ 80 years or with body weight ≤ 60 kg or with serum creatinine ≥ 1.5 mg/dL.


When presented at the ESC 2011 Congress, the final results of the ARISTOTLE trial were enthusiastically received. This study of over 18,000 patients with nonvalvular AF compared the novel anticoagulant apixaban with warfarin.

Apixaban is an orally bioavailable, highly selective, direct acting/reversible inhibitor of factor Xa. It is rapidly absorbed and has a 12-hour half life. It is both metabolized and renally excreted (~25%).[21]

In a previously published randomized clinical trial, AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment), apixaban (5 mg twice daily) reduced the rate of stroke or systemic embolism by 55% without increasing the risk for major bleeding when compared to aspirin (81-324 mg daily).[24]

Trial Design

ARISTOTLE was designed to reflect current clinical practice in that the patient population was selected to represent a broad range of AF patients at risk for ischemic stroke, essentially those with one or more stroke risk factors (Figure 2).‡[25,27] [Editor’s note: The baseline characteristics of the trial patients revealed that approximately one-third had a CHADS2 score of 1, one-third had a score of 2, and the remaining third had a CHADS2 score of ≥3.]

Figure 2. ARISTOTLE trial design. From Lopes RD, et al. Am Heart J. 2010;159:331-339.[27]

The primary objective of ARISTOTLE was to determine whether apixaban was noninferior to warfarin in reducing the rate of stroke or systemic embolism. The primary safety outcome was major bleeding (ISTH criteria). The secondary objectives were to determine whether apixaban was superior to warfarin with respect to the primary outcome and to the rates of major bleeding and death from any cause (Table 5).

Hierarchical sequential testing was performed first on the primary outcome for noninferiority, then on the primary outcome for superiority, then on major bleeding, and finally on death from any cause.

Table 5. Efficacy Results From ARISTOTLE

Outcome Apixaban
Hazard Ratio
(95% CI)
P value
Event Rate
Primary outcome: stroke or systemic embolism 1.27 1.60 0.79 (0.66-0.95) .01
      Stroke 1.19 1.51 0.79 (0.65-0.95) .01
      Ischemic or uncertain type of stroke 0.97 1.05 0.92 (0.74-1.13) .42
      Hemorrhagic stroke 0.24 0.47 0.51 (0.35-0.75) <.001
      Systemic embolism 0.09 0.10 0.87 (0.44-1.75) .70
Key secondary efficacy outcome: death from any cause 3.52 3.94 0.89 (0.80-0.998) .047

From Granger CB, et al. N Engl J Med. 2011;365:981-992.[25]

In ARISTOTLE, the reduction in the primary endpoint of stroke was driven by the impressive reduction in hemorrhagic stroke vs warfarin, with no significant difference in the ischemic stroke rate between apixaban and warfarin. This is in contrast to dabigatran 150 mg twice daily, which significantly reduced both ischemic and hemorrhagic stroke vs warfarin. Both RE-LY and ARISTOTLE studied a broader AF population, with ≥1 stroke risk factors, in contrast to ROCKET AF, which studied a higher-risk patient population. [Editor’s note: The baseline characteristics of the ROCKET AF trial patients revealed that about 87% had a CHADS2 score of ≥3.]

Serious bleeds (ie, major and clinically relevant nonmajor bleeds) were significantly lower with apixaban vs warfarin, but this was not seen in ROCKET AF (where serious bleeds was the primary safety endpoint). Total bleeds (major plus nonmajor) were significantly lower with both doses of dabigatran in RE-LY and with apixaban in ARISTOTLE but not with rivaroxaban in ROCKET AF when compared to warfarin (Table 6).

Table 6. Safety Results From ARISTOTLE

Outcome Apixaban
Hazard Ratio
(95% CI)
P value
Event Rate
Bleeding safety outcome: ISTH major bleeding 2.13 3.09 0.69 (0.60-0.80) <.001
Intracranial 0.33 0.80 0.42 (0.30-0.58) <.001
Other location 1.79 2.27 0.79 (0.68-0.93) .004
Gastrointestinal 0.76 0.86 0.89 (0.70-1.15) .37
Major or clinically relevant nonmajor bleeding 4.07 6.01 0.68 (0.61-0.75) <.001
GUSTO severe bleeding 0.52 1.13 0.46 (0.35-0.60) <.001
GUSTO moderate or severe bleeding 1.29 2.18 0.60 (0.50-0.71) <.001
TIMI major bleeding 0.96 1.69 0.57 (0.46-0.70) <.001
TIMI major or minor bleeding 1.55 2.46 0.63 (0.54-0.75) <.001
Any bleeding 18.1 25.8 0.71 (0.68-0.75) <.001

From Granger CB, et al. N Engl J Med. 2011;365:981-992.[25]


In ARISTOTLE, reduction of hemorrhagic stroke was the predominant effect, with apixaban preventing hemorrhagic stroke in 4 patients per 1000. Additionally, apixaban prevented an ischemic or unknown type of stroke in 2 patients per 1000. There was consistency in subgroups with respect to previous warfarin exposure, age, sex, level of renal impairment, and risk factors for stroke. The rate of discontinuation of apixaban was lower than was observed with warfarin (25.3% and 27.5%, respectively). The rates of intracranial hemorrhage and fatal bleeding were lower with apixaban versus warfarin. Lower intracranial hemorrhage observed with all 3 new OACs suggest “specific risk associated with warfarin,” postulating a mechanism involving tissue factor VIIa complexes in the brain. [28]


The most exciting late-breaking clinical trial for AF at ESC was the ARISTOTLE trial. We see efficacy in reducing strokes (by 21%), major bleeding (by 31%), and all-cause mortality (by 11%) vs warfarin. These new drugs will offer convenience and safety compared to warfarin. This is a clear justification for the major paradigm shift in thromboprophylaxis in AF: we can identify the truly low-risk patients with AF (CHA2DS2-VASc score=0), so that those with 1 or more stroke risk factors can be considered for oral anticoagulation.


  1. Stewart S, Hart CL, Hole DJ, McMurray JJ. Population prevalence, incidence and predictors of atrial fibrillation in the Renfrew/Paisley study. Heart. 2001;86:516-521.
  2. Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.
  3. Stefansdottir H, et al. Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections. Europace. 2011;13:1110-1117.
  4. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the longterm risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med. 2002;113:359-364.
  5. Hylek EM, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349:1019-1026.
  6. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J. 2010;31:967-975.
  7. Gage BF, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870.
  8. Karthikeyen G, Eikelboom JW. Validation of the CHADS2 clinical prediction rule to predict ischaemic stroke: a systematic review and meta-analysis. Thromb Haemost. 2011;106:528-538.
  9. Keogh C, et al. The CHADS2 score for stroke risk stratification in atrial fibrillation — friend or foe? Thromb Haemost. 2010;104:45-48.
  10. Lip YH, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137:263-272.
  11. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation — executive summary. Circulation. 2006;114:700-752.
  12. Mant J, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370:493-503.
  13. van Walraven C, et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the Atrial Fibrillation Investigators. Stroke. 2009;40:1410-1416.
  14. Rash A, et al. A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age and Ageing. 2007;36:151-156.
  15. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
  16. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation: final report. Circulation. 1991;84:527-539.
  17. ACTIVE Writing Group of the ACTIVE investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial. Lancet. 2006;367:1903-1912.
  18. ACTIVE investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066-2078.
  19. Olesen JB, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a “real world” nationwide cohort study. Thromb Haemost. 2011;106(4). [epub ahead of print]
  20. Go AS, et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med. 1999;131:927-934.
  21. Raghavan N, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37:74-81.
  22. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
  23. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
  24. Connolly SJ, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817.
  25. Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
  26. Global Study to Assess the Safety and Effectiveness of DU-176b vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (Engage AF TIMI 48). http://www.clinicaltrials.gov/ Accessed October 17, 2011.
  27. Lopes RD, et al. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159:331-339.
  28. Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 2009;108:1447-1452.