Widespread Anticoagulation Has Lowered Stroke but Not Intracranial Bleeding in the Very Elderly: Insights from a Danish Nationwide AF Cohort (1999–2022)

Highlight

– Nationwide Danish data (1999–2022) including 243,938 new-onset AF patients show marked decreases in stroke risk across age groups coincident with broad uptake of oral anticoagulants (OACs).

– Five-year absolute improvement in stroke-free survival was greatest in ages 75–84 (+12.8%) and 65–74 (+10.1%), but only +3.5% in patients ≥85.

– Intracerebral haemorrhage (ICH) risk rose among elderly and very elderly patients despite increased OAC uptake, whereas older adults did not experience increased bleeding once OACs were broadly implemented.

Background: disease burden and clinical context

Atrial fibrillation (AF) is common in later life and confers a substantially increased risk of ischemic stroke. Oral anticoagulation reduces stroke risk by roughly two-thirds when taken appropriately. Over the past two decades, treatment paradigms have shifted from vitamin K antagonists (warfarin) toward direct oral anticoagulants (DOACs), which randomized trials and meta-analyses show to be at least non-inferior to warfarin for stroke prevention and generally associated with lower intracranial haemorrhage (ICH) risk. Nevertheless, older age remains the principal driver of both thromboembolic and bleeding risks. Clinical decisions in patients ≥85 years are particularly challenging because comorbidities, frailty, renal dysfunction, polypharmacy, falls, and cerebral small vessel disease (including cerebral amyloid angiopathy) modify both benefit and harm. High-quality, contemporary, population-level data are therefore needed to describe how anticoagulant uptake has translated to population outcomes across age strata.

Study design and methods

Binding et al. performed a Danish nationwide cohort study including patients with new-onset AF from 1999 through 2022. The cohort was stratified into three age groups at diagnosis: older adults (65–74 years), elderly (75–84 years), and very elderly (≥85 years). The primary aims were to document temporal trends in initiation of oral anticoagulants (OACs; encompassing warfarin and DOACs) and to examine trends in major clinical outcomes: stroke-free survival, major bleeding (including ICH), and all-cause mortality. Nationwide registries provided data on diagnoses, prescriptions, hospitalizations, and vital status, enabling evaluation of 5-year outcome probabilities across calendar periods and age groups. The analysis examined absolute changes in 5-year probabilities over the study interval and reported OAC uptake by age and year.

Key findings

Population and anticoagulant uptake

The study included 243,938 patients with incident AF: 89,184 (36.6%) aged 65–74, 99,002 (40.6%) aged 75–84, and 55,752 (22.8%) aged ≥85. By 2022, uptake of OACs increased substantially across age groups; notably, 71% of very elderly patients with AF were receiving OACs in 2022. The period covers the pre-DOAC era (predominantly warfarin) and the DOAC era after their introduction and guideline endorsement.

Stroke outcomes

Across the two-decade span, the 5-year probability of stroke-free survival improved in all age groups, reflecting reduced ischemic stroke incidence among patients diagnosed with AF. Absolute improvements in 5-year stroke-free survival were reported as follows: +10.1% for older adults (65–74 years), +12.8% for elderly patients (75–84 years), and +3.5% for very elderly patients (≥85 years). These gains are temporally aligned with rising OAC use and the transition to DOACs.

Bleeding and intracerebral haemorrhage

The patterns for major bleeding diverged by age. In the older adult group (65–74), the study found no increase in bleeding risk over time despite near-complete implementation of OAC therapy in the DOAC era. Conversely, the 5-year absolute risk of intracerebral haemorrhage increased among elderly (75–84) and very elderly (≥85) AF patients. The report therefore demonstrates a trade-off in the oldest patients: smaller absolute stroke prevention gains combined with a rise in ICH.

Mortality and broader outcomes

The study also evaluated all-cause mortality and major bleeding events, finding improvements in overall outcomes across much of the cohort but persistent vulnerability in the ≥85 group. The very elderly group derived smaller absolute reductions in stroke and continued to experience elevated bleeding-related risks.

Interpretation and clinical implications

These findings document a favorable population-level benefit of modern anticoagulation strategies: as OACs became widely used, stroke incidence fell across age groups. The greatest absolute reductions in 5-year stroke risk were observed in the 65–84 age range, consistent with large absolute baseline event rates and high relative efficacy of OACs.

However, the attenuated stroke benefit and the concurrent increase in ICH among patients ≥85 years raise several important considerations for clinical practice and health policy:

• Risk–benefit balance differs in the very elderly. Age interacts with competing risks—higher baseline bleeding risk (notably ICH) and comorbidities such as hypertension, prior stroke, dementia, and frailty—that may blunt net benefit from anticoagulation at the population level.
• Selection, dosing, and adherence matter. Real-world patterns of DOAC dosing (including appropriate renal-adjusted dosing versus underdosing), polypharmacy, and adherence influence both effectiveness and safety. Underdosing reduces stroke protection, whereas supratherapeutic exposure and drug interactions can increase bleeding.
• Residual causes for rising ICH may include increased recognition and coding of ICH, higher lifespan and comorbidity burden, prevalence of cerebral small vessel disease and cerebral amyloid angiopathy in the very elderly, and use of concomitant antiplatelet agents. Some of these causes may be modifiable (e.g., blood pressure control, deprescribing antiplatelets when not indicated).
• Guideline-based practice still favors anticoagulation in the majority of older adults with AF because absolute risk reductions in ischemic stroke are substantial; however, in very elderly patients the decision must be individualized with geriatric assessment, shared decision-making, and careful modifiable bleeding risk mitigation.

Mechanistic and practical insights

DOACs offer several practical advantages over warfarin (fixed dosing, fewer interactions, no routine INR monitoring), and pivotal randomized trials (RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48) plus meta-analyses have shown lower ICH rates with DOACs compared with warfarin. Despite that, the absolute incidence of ICH remains higher in older age due to age-related vascular fragility and comorbidities. Therefore, population-level reductions in ischemic stroke can coexist with rising ICH rates in the very elderly if competing risks and patient mix change over time.

Mitigation strategies clinicians should consider include stringent blood-pressure control (the strongest modifiable predictor of ICH), careful review of concomitant medications (particularly antiplatelets and non-steroidal anti-inflammatory drugs), assessment of renal function for appropriate DOAC dosing, and use of comprehensive geriatric assessments to evaluate fall risk, cognition, and frailty. For selected very elderly patients at particularly high ICH risk (for example suspected cerebral amyloid angiopathy), the net clinical benefit of anticoagulation may be marginal and warrants individualized discussion.

Study strengths and limitations

Strengths: The study leverages high-quality, nationwide registries with near-complete follow-up and large sample size, enabling robust trend analyses over more than two decades. Division into clinically meaningful age strata highlights heterogeneity of treatment effects across older age ranges.

Limitations: As with all observational registry studies, residual confounding is possible. Administrative data lack granular clinical detail on frailty, functional status, cognitive impairment, imaging findings (e.g., microbleeds, cortical superficial siderosis), appropriateness of OAC dosing, adherence, and over-the-counter medication use. Coding practices and event ascertainment may have evolved over the long study period. Finally, the study reports absolute trends but cannot definitively attribute changes to DOAC use versus other temporal changes (e.g., improved cardiovascular care, hypertension management, or stroke imaging and prevention strategies).

Implications for practice, policy, and research

Clinical practice: For most patients with AF aged 65–84, the data reinforce strong support for guideline-directed OAC therapy because population-level stroke reductions have been substantial with no offsetting increase in major bleeding in the younger-old group. For patients ≥85, clinicians should individualize decisions: assess thrombotic versus bleeding risk, optimize blood pressure and medication regimens, check renal function and apply evidence-based DOAC dosing, and involve patients and families in shared decision-making.

Policy and systems: Efforts to extend appropriate DOAC access to older adults should continue, but with parallel investment in geriatric-focused anticoagulation programs that incorporate frailty screening, medication reconciliation, and monitoring for bleeding risk factors.

Research: Randomized data for the very elderly (≥85) remain limited. Future trials or pragmatic randomized evaluations that specifically enroll very elderly, frail individuals—plus studies of interventions to reduce ICH risk (e.g., strict BP targets, deprescribing of antiplatelets)—are needed. Observational studies with imaging substudies (microbleeds, CAA markers) and linkage to primary care records for medication adherence would further clarify mechanisms.

Conclusion

Binding et al.’s Danish nationwide study documents a clear public health success: expanded OAC use has translated into meaningful reductions in ischemic stroke among patients with AF, particularly those aged 65–84. However, the modest stroke gains and rising intracerebral haemorrhage in patients aged ≥85 underscore that anticoagulation in the very elderly requires nuanced, individualized care focused on risk modification, appropriate dosing, and shared decision-making. Clinicians and health systems should continue to promote evidence-based anticoagulation while investing in strategies to identify and mitigate bleeding risk in the oldest patients.

Funding and clinicaltrials.gov

Funding and trial registration details are reported in the original publication: Binding C et al., Eur Heart J 2025 (see reference below). This analysis used administrative registries rather than a registered interventional trial.

References

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