Stroke Prevention in AF: CHA2DS2-VA and DOAC Evidence

1. Slide 1 · Stroke Prevention in Atrial Fibrillation

   Stroke Prevention in Atrial Fibrillation

   CHA2DS2-VA risk scoring and DOAC versus warfarin evidence for clinical practice

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   Speaker notes

   Thank you for your time today. Atrial fibrillation remains a major driver of ischemic stroke, and anticoagulation decisions are made daily in your clinics. In the next few minutes I will cover four points. First, why stroke prevention in AF is still suboptimal. Second, how the sex-neutral CHA2DS2-VA score, adopted by the 2024 ESC guidelines, changes risk stratification. Third, what the pivotal randomized trials and their meta-analyses show for direct oral anticoagulants compared with warfarin, including bleeding and limitations. Finally, practical dosing and populations where evidence is limited. All data come from published trials, meta-analyses and current guidelines, and I will present benefits together with safety data.

2. Slide 2 · Stroke prevention in AF remains suboptimal

   Stroke prevention in AF remains suboptimal

   1st

   AF is the leading cause of ischemic stroke, largely preventable once diagnosed

   OR 0.79

   Women with CHA2DS2-VA ≥1 less likely than men to receive OAC

   HR 1.17

   Higher ischemic stroke/SE with off-label underdosed vs on-label DOACs

   HR 1.27

   Higher intracranial hemorrhage with off-label underdosed vs on-label DOACs

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   [1, 2, 3, 4]

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   Speaker notes

   Let us start with the unmet need. AF is described as the first cause of ischemic stroke, and much of this burden is preventable when patients are identified and adequately anticoagulated. Yet gaps persist. In a European cohort of more than ten thousand patients, women were less likely to receive anticoagulation than men despite eligible risk scores. Inappropriate dosing is the second gap: in a meta-analysis of Asian observational studies, off-label underdosing was associated with more ischemic events and, unexpectedly, more intracranial hemorrhage than label-adherent dosing. The 2026 ACC scientific statement highlights the same underuse and misdosing. So the question is not only whether to anticoagulate, but whom, and at what dose.

3. Slide 3 · CHA2DS2-VA: sex-neutral score in 2024 ESC guidelines

   CHA2DS2-VA: sex-neutral score in 2024 ESC guidelines

   Letter	Risk factor	Points
   C	Chronic heart failure	1
   H	Hypertension	1
   A2 / A	Age ≥75 years / age 65–74 years	2 / 1
   D	Diabetes mellitus	1
   S2	Prior stroke, TIA or arterial thromboembolism	2
   V	Vascular disease (prior MI, PAD, aortic plaque)	1

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   [1, 5, 6]

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   Speaker notes

   The 2024 ESC guidelines replaced CHA2DS2-VASc with CHA2DS2-VA, removing the sex category. The components are otherwise unchanged, with a maximum of eight points. In practice: a score of 2 or more is a Class I indication to start oral anticoagulation, and a score of 1 means anticoagulation should be considered, Class IIa, weighing patient preference and bleeding risk. Remember that the 2023 ACC/AHA/ACCP/HRS guideline still uses CHA2DS2-VASc, with anticoagulation recommended at an annual stroke risk of 2% or more, so check which framework your institution follows. A practical tip: rescore at every review, because age thresholds and new comorbidities quickly change eligibility.

4. Slide 4 · Removing sex category: supporting data and caveats

   Removing sex category: supporting data and caveats

   Supporting evidence

   UK cohort, 78,852 patients: no sex difference in ischemic stroke/thromboembolism (HR 1.00)

   CHA2DS2-VA AUC 0.651 vs 0.639 for composite outcome

   Only 3.2% of women reclassified to very low risk (score <2)

   Caveats

   European cohort: similar discrimination (AUC 0.603 vs 0.605)

   Net reclassification index −0.088 vs CHA2DS2-VASc

   Both scores only modest predictors of individual risk

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   [2, 7, 8, 9]

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   Speaker notes

   Why remove sex? In a UK primary care cohort of almost 79,000 non-anticoagulated patients, women and men had the same adjusted rate of ischemic stroke and thromboembolism, and CHA2DS2-VA discriminated slightly better. In a cohort of incident AF, very few women were reclassified as very low risk. However, fair balance matters: a European prospective cohort found similar discrimination for both scores and slightly worse reclassification with CHA2DS2-VA, and earlier reviews urged caution. The take-home is that both scores have modest discrimination, so they guide rather than replace clinical judgment. CHA2DS2-VA simplifies decisions and avoids sex-based thresholds, without leading to undertreatment of women.

5. Slide 5 · Mechanisms: targeted inhibition versus vitamin K antagonism

   Mechanisms: targeted inhibition versus vitamin K antagonism

   Warfarin (VKA)

   Inhibits VKORC1, lowering factors II, VII, IX, X and proteins C/S

   Narrow window: INR target 2.0–3.0, regular monitoring

   Numerous food and drug interactions, slow onset and offset

   DOACs

   Dabigatran: direct thrombin inhibitor, predominantly renal clearance

   Apixaban, edoxaban, rivaroxaban: direct factor Xa inhibitors

   Predictable pharmacokinetics, fixed dosing, no routine INR monitoring

   Specific reversal: idarucizumab; andexanet alfa for selected anti-Xa agents

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   [4]

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   Speaker notes

   Briefly on mechanism. Warfarin acts indirectly by blocking vitamin K epoxide reductase, reducing several coagulation factors and also proteins C and S. That explains its variable response, the need for INR monitoring and the many interactions. DOACs act directly on a single target: thrombin for dabigatran, factor Xa for apixaban, edoxaban and rivaroxaban. This gives predictable pharmacokinetics and fixed dosing. The 2026 ACC statement summarizes them as having fewer interactions and improved safety versus VKAs. But note that renal function matters for all DOACs, especially dabigatran, and that P-gp and strong CYP3A4 interactions still need checking. With mechanism covered, let us look at outcomes.

6. Slide 6 · Pivotal trials: fewer strokes and intracranial bleeds

   Pivotal trials: fewer strokes and intracranial bleeds

   71,683

   Patients pooled from RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48

   HR 0.81

   Stroke/SE, standard-dose DOAC vs warfarin (3.01% vs 3.69%)

   HR 0.55

   Intracranial hemorrhage, DOAC vs warfarin, consistent across TTR strata

   HR 1.00

   Major bleeding vs warfarin when center TTR above 66%

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   [10, 11]

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   Speaker notes

   The strongest evidence comes from COMBINE AF, an individual patient-level analysis of all four pivotal trials, over 71,000 patients. Standard-dose DOACs were associated with a 19% relative reduction in stroke or systemic embolism versus warfarin. A meta-analysis stratified by time in therapeutic range showed lower stroke or embolism risk across low, intermediate and high INR control, and roughly halved intracranial hemorrhage. Now the fair balance: major bleeding was lower only where INR control was poor or intermediate; in centers with time in range above 66%, major bleeding was similar to warfarin. So the consistent safety signal is intracranial hemorrhage, not overall bleeding.

7. Slide 7 · Agent-level efficacy and bleeding versus warfarin

   Agent-level efficacy and bleeding versus warfarin

   Agent and dose	Stroke/SE vs warfarin, OR (95% CI)	Major bleeding vs warfarin
   Apixaban 5 mg BID	0.79 (0.66–0.94)	Reduced: 0.71 (0.61–0.81)
   Dabigatran 150 mg BID	0.65 (0.52–0.81)	No significant reduction
   Dabigatran 110 mg BID	Not reported here	Reduced: 0.80 (0.69–0.93)
   Edoxaban 60 mg OD	0.86 (0.74–1.01)	Reduced: 0.78 (0.69–0.90)
   Rivaroxaban 20 mg OD	0.88 (0.74–1.03)	No significant reduction

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   [12]

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   Speaker notes

   This BMJ network meta-analysis of 23 randomized trials and almost 95,000 patients shows agent-level estimates against warfarin. All-cause mortality was lower with all DOACs than with warfarin. For stroke or systemic embolism, confidence intervals for edoxaban 60 and rivaroxaban 20 crossed one. For major bleeding, reductions were seen with apixaban 5, dabigatran 110 and edoxaban, but not with dabigatran 150 or rivaroxaban 20. An important caution: these are indirect comparisons across trials with different populations, designs and warfarin control. No head-to-head randomized trial exists, so this table supports individualization, for example by bleeding history, rather than ranking agents.

8. Slide 8 · Fair balance: benefits, limits and evidence gaps

   Fair balance: benefits, limits and evidence gaps

   Established in AF trials

   Lower stroke/SE vs warfarin regardless of INR control

   Lower intracranial hemorrhage vs warfarin

   Lower all-cause mortality with all DOACs in network meta-analysis

   Limitations and cautions

   Bleeding risk persists; not for mechanical valves or moderate-severe MS

   Dialysis: observational data only, no significant stroke/SE reduction

   Child-Pugh C cirrhosis: inadequate evidence; A/B standard-dose DOAC

   Device-detected AF: no net benefit of edoxaban in NOAH-AFNET 6 analysis

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   [10, 11, 12, 13, 14, 15]

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   Speaker notes

   Let me be balanced. The benefits on stroke, intracranial hemorrhage and mortality are consistent. But DOACs are anticoagulants and bleeding remains the main risk. They are not indicated in mechanical heart valves or moderate to severe mitral stenosis. In long-term dialysis, a meta-analysis of observational studies found no significant stroke reduction with apixaban or warfarin, though warfarin carried more major bleeding. ISTH guidance supports standard-dose DOACs in Child-Pugh A and B cirrhosis, but evidence is inadequate in Child-Pugh C. And in device-detected AF, a win-ratio analysis of NOAH-AFNET 6 found no net advantage of edoxaban over no anticoagulation, with death and major bleeding as the commonest events.

9. Slide 9 · Dose by label criteria, not by intuition

   Dose by label criteria, not by intuition

   Agent	Standard AF dose	Reduced dose and criteria (EU SmPC)
   Apixaban	5 mg BID	2.5 mg BID if ≥2: age ≥80 y, weight ≤60 kg, creatinine ≥1.5 mg/dL
   Rivaroxaban	20 mg OD with food	15 mg OD if CrCl 15–49 mL/min
   Edoxaban	60 mg OD	30 mg OD if CrCl 15–50, weight ≤60 kg or selected P-gp inhibitors
   Dabigatran	150 mg BID	110 mg BID if age ≥80 y or verapamil; consider at 75–80 y or high bleeding risk

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   [3, 4, 5]

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   Speaker notes

   Practically, efficacy depends on correct dosing. These are the dose-reduction criteria from the European product labels; please check your local prescribing information, as thresholds differ slightly between regions. Calculate creatinine clearance with Cockcroft-Gault, using actual body weight, and recheck renal function at least yearly, more often in elderly or CKD patients. A common pitfall is reducing apixaban for a single criterion, such as age alone. Remember the observational signal we saw earlier: off-label underdosing was associated with more ischemic events and more intracranial bleeding than label-adherent dosing. Also review interacting drugs and assess modifiable bleeding risk factors at every visit.

10. Slide 10 · References

    References

    1. 1.Sellal JM, Hammache N, Echivard M. [Atrial fibrillation in 2025: Diagnosis and treatment]. Rev Med Interne. 2025. doi:10.1016/j.revmed.2025.02.010
    2. 2.Mei DA, Romiti GF, Vitolo M, et al. Atrial fibrillation and female sex: use of oral anticoagulants in a large European cohort and residual risk of thromboembolism and stroke. Eur Heart J Qual Care Clin Outcomes. 2025. doi:10.1093/ehjqcco/qcaf075
    3. 3.Mongkhon P, Singkham N, Ponok K, et al. Comparative Effectiveness and Safety of Off-Label Underdosed Direct Oral Anticoagulants in Asian Patients with Atrial Fibrillation: A Systematic Review and Meta-analysis. Drug Saf. 2025. doi:10.1007/s40264-024-01476-8
    4. 4.Kumbhani DJ, Armbruster AL, Cheng RK, et al. Direct Oral Anticoagulants in Primary and Secondary Prevention of Thrombotic Events: 2026 ACC Scientific Statement: A Report of the American College of Cardiology. J Am Coll Cardiol. 2026. doi:10.1016/j.jacc.2026.05.033
    5. 5.Van Gelder IC, Rienstra M, Bunting KV, et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2024. doi:10.1093/eurheartj/ehae176
    6. 6.Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024. doi:10.1161/CIR.0000000000001193
    7. 7.Champsi A, Mobley AR, Subramanian A, et al. Gender and contemporary risk of adverse events in atrial fibrillation. Eur Heart J. 2024. doi:10.1093/eurheartj/ehae539
    8. 8.Clua-Espuny JL, Panisello-Tafalla A, Lucas-Noll J, et al. Stroke Risk Stratification in Incident Atrial Fibrillation: A Sex-Specific Evaluation of CHA2DS2-VA and CHA2DS2-VASc. J Cardiovasc Dev Dis. 2025. doi:10.3390/jcdd12070259
    9. 9.Nielsen PB, Overvad TF. Female Sex as a Risk Modifier for Stroke Risk in Atrial Fibrillation: Using CHA2DS2-VASc versus CHA2DS2-VA for Stroke Risk Stratification in Atrial Fibrillation: A Note of Caution. Thromb Haemost. 2020. doi:10.1055/s-0040-1710014
    10. 10.Carnicelli AP, Hong H, Connolly SJ, et al. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex. Circulation. 2022. doi:10.1161/CIRCULATIONAHA.121.056355
    11. 11.Lee JJ, Ha ACT, Dorian P, et al. Meta-Analysis of Safety and Efficacy of Direct Oral Anticoagulants Versus Warfarin According to Time in Therapeutic Range in Atrial Fibrillation. Am J Cardiol. 2021. doi:10.1016/j.amjcard.2020.10.064
    12. 12.López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017. doi:10.1136/bmj.j5058
    13. 13.Kuno T, Takagi H, Ando T, et al. Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis. J Am Coll Cardiol. 2020. doi:10.1016/j.jacc.2019.10.059
    14. 14.Carlin S, Cuker A, Gatt A, et al. Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH. J Thromb Haemost. 2024. doi:10.1016/j.jtha.2024.05.023
    15. 15.Becher N, Köllner G, Bertaglia E, et al. Effects of anticoagulation in patients with device-detected atrial fibrillation and multiple stroke risk factors: a win ratio analysis of the NOAH-AFNET 6 trial. Eur Heart J Qual Care Clin Outcomes. 2025. doi:10.1093/ehjqcco/qcaf087
    16. 16.Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018. doi:10.1016/j.chest.2018.07.040

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11. Slide 11 · Key messages and questions

    Key messages and questions

    Score with CHA2DS2-VA, prefer label-dosed DOACs over warfarin, and reassess bleeding and renal function

    [5, 6, 10, 16]

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    Speaker notes

    To conclude, three messages. First, use CHA2DS2-VA: a score of 2 or more indicates anticoagulation, and 1 warrants consideration, regardless of sex. Second, in eligible patients without mechanical valves or moderate to severe mitral stenosis, guidelines prefer DOACs over warfarin, based on lower stroke, intracranial hemorrhage and mortality in randomized trials, while bleeding risk persists. Third, dose by label criteria and reassess renal function, interactions and bleeding risk regularly, with caution in dialysis, advanced cirrhosis and device-detected AF. Thank you for your attention. I am happy to take your questions or discuss specific patients from your practice.

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