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No Net Benefit from Adding Antiplatelet Therapy to Anticoagulation After Stroke in Patients with Atrial Fibrillation and Atherosclerosis: Results from the ATIS‑NVAF Randomized Trial

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No Net Benefit from Adding Antiplatelet Therapy to Anticoagulation After Stroke in Patients with Atrial Fibrillation and Atherosclerosis: Results from the ATIS‑NVAF Randomized Trial

Highlight

• In the ATIS‑NVAF randomized trial (NCT03062319), adding an antiplatelet agent to anticoagulation after ischemic stroke or TIA in patients with nonvalvular atrial fibrillation (AF) and atherosclerotic cardiovascular disease produced no reduction in the composite of ischemic events and major bleeding at 2 years.

• The combination strategy did not significantly lower ischemic cardiovascular events (11.1% vs 14.2%; HR 0.76, 95% CI 0.39–1.48), but substantially increased major and clinically relevant nonmajor bleeding (19.5% vs 8.6%; HR 2.42, 95% CI 1.23–4.76).

Background: clinical context and unmet need

<pPatients with ischemic stroke or transient ischemic attack (TIA) who have comorbid nonvalvular atrial fibrillation face dual and competing vascular risks. AF is a potent risk factor for cardioembolic stroke and is managed principally with oral anticoagulation to reduce systemic embolism and recurrent stroke. Concurrent atherosclerotic cardiovascular disease (including extracranial/intracranial stenosis, ischemic heart disease, or peripheral artery disease) imparts additional risk from platelet-mediated arterial thrombosis.

In practice, clinicians sometimes add an antiplatelet agent to anticoagulation for perceived incremental prevention of atherothrombotic events. However, combining anticoagulants and antiplatelets raises bleeding risk, particularly intracranial and gastrointestinal hemorrhage, and there is limited randomized evidence to guide this tradeoff for patients whose index event is stroke/TIA rather than percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS).

Study design

The ATIS‑NVAF trial is a multicenter, open‑label, randomized clinical trial conducted at 41 sites across Japan between November 2016 and March 2025. Eligible participants were adults with ischemic stroke or TIA within 8 to 360 days of onset, documented nonvalvular AF, and at least one manifestation of atherosclerotic cardiovascular disease (carotid or intracranial artery stenosis, prior noncardioembolic stroke, ischemic heart disease, or peripheral artery disease).

Participants were randomized to either combination therapy (an anticoagulant plus a single antiplatelet agent) or anticoagulant monotherapy. The primary outcome was a composite of ischemic cardiovascular events and major bleeding over 2 years. Secondary outcomes included ischemic cardiovascular events alone; safety outcomes included major bleeding and clinically relevant nonmajor bleeding.

The trial planned enrollment larger than the eventual sample but was stopped early for futility after an interim analysis; 316 patients were randomized (combination n = 159; monotherapy n = 157). The mean age was 77.2 years (SD 7.4) and 28.5% were female. Data were analyzed between April and October 2024; final follow‑up and reporting extend into 2025.

Key findings

The cumulative incidence of the primary composite outcome at 2 years was 17.8% in the combination therapy group and 19.6% in the anticoagulant monotherapy group (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.53–1.55; P = .64), indicating no statistically significant net clinical benefit from adding an antiplatelet.

When components were examined separately, ischemic cardiovascular events occurred in 11.1% of combination-treated patients versus 14.2% with monotherapy (HR 0.76; 95% CI 0.39–1.48; P = .41). These point estimates numerically favored combination therapy but were imprecise and did not reach statistical significance.

Bleeding was the dominant driver of harm. Major and clinically relevant nonmajor bleeding occurred in 19.5% of patients assigned to combination therapy compared with 8.6% on monotherapy (HR 2.42; 95% CI 1.23–4.76; P = .008). Thus, adding an antiplatelet approximately doubled bleeding risk in this population.

Put another way, the combination approach produced a small, non‑significant reduction in ischemic events while causing a substantial, statistically significant increase in bleeding — yielding no net benefit on the primary composite endpoint.

Safety details and subgroup considerations

The excess bleeding in the combination arm included both major bleeds and clinically relevant nonmajor bleeds, which are particularly consequential in an older population (mean age >77) where even nonmajor hemorrhage can prompt hospitalization, transfusion, or discontinuation of effective therapy. The trial report did not demonstrate a clear subgroup in which ischemic benefit clearly outweighed bleeding risk, although power for meaningful subgroup analyses was limited.

Expert commentary and comparison with prior evidence

ATIS‑NVAF fills an important evidence gap by directly testing routine addition of an antiplatelet to anticoagulation in patients whose index event was stroke/TIA and who also have atherosclerotic disease. Its principal finding — no net clinical benefit and markedly increased bleeding — aligns with the broader AF literature showing heightened hemorrhagic risk when antiplatelets are added to anticoagulation without compelling indication.

Evidence from PCI and ACS populations has repeatedly demonstrated that minimizing the duration of dual or triple therapy reduces bleeding without substantially increasing ischemic events when managed carefully. Trials such as WOEST (Lancet 2013), PIONEER AF‑PCI (NEJM 2016), RE‑DUAL PCI (NEJM 2017), and AUGUSTUS (NEJM 2019) showed that shorter or simplified regimens (e.g., anticoagulant plus single P2Y12 inhibitor) reduce bleeding and support tailored dual therapy after PCI rather than prolonged triple therapy. However, those studies address a different patient population (post‑PCI/ACS) and cannot be directly extrapolated to stable cerebrovascular disease after stroke/TIA.

The COMPASS trial (NEJM 2017) evaluating low‑dose rivaroxaban plus aspirin in stable atherosclerotic disease (without AF) showed fewer major cardiovascular events but more major bleeding compared with aspirin alone, illustrating the same tradeoff between ischemic benefit and bleeding. The ATIS‑NVAF results suggest that in patients with AF — where standard anticoagulation already addresses cardioembolism — routine addition of antiplatelet therapy to target atherosclerotic events does not clearly improve net outcomes and meaningfully increases harm.

Strengths and limitations

Strengths of ATIS‑NVAF include randomized design, multicenter conduct, pragmatic inclusion of patients with a common and clinically important comorbidity cluster (stroke/TIA + AF + atherosclerosis), and clinically meaningful endpoints combining ischemia and bleeding to reflect net clinical benefit.

Limitations are notable and temper interpretation. The trial was open‑label, which may influence management and reporting of some outcomes, though major bleeding and ischemic events are generally objective. Early termination for futility reduced statistical power and increased uncertainty around point estimates for ischemic outcomes. The sample size (n=316) was modest, and the population was older and geographically confined to Japan, which may limit generalizability to younger or ethnically different cohorts. Details on the specific antiplatelet agents used and anticoagulant types/dosing were not emphasized in the summary report; heterogeneity in agents may moderate effects. Finally, follow‑up was limited to 2 years — longer-term effects (both ischemic and bleeding) remain uncertain.

Clinical implications and practical recommendations

For clinicians managing patients with ischemic stroke/TIA, nonvalvular AF, and concurrent atherosclerotic disease, ATIS‑NVAF provides randomized evidence that routine addition of an antiplatelet agent to anticoagulation offers no net clinical benefit and substantially increases bleeding risk. In most such patients, anticoagulant monotherapy appears preferable unless there is a separate, compelling indication for antiplatelet therapy — most commonly recent ACS or recent PCI/stent placement, where short‑term combined therapy may be indicated following contemporary protocols and careful bleeding risk mitigation.

Decision making should remain individualized, balancing ischemic risk (CHA2DS2‑VASc, burden of atherosclerotic disease, recent coronary interventions) against bleeding risk (HAS‑BLED, age, prior hemorrhage, concomitant medications). When an antiplatelet is required, clinicians should employ the shortest effective duration, choose agents with more favorable bleeding profiles when possible, optimize blood pressure control and gastroprotection, and reassess need at regular intervals.

Research gaps and future directions

Key unanswered questions include whether specific subgroups (for example, patients with high‑risk intracranial atherosclerotic stenosis, multiple prior atherothrombotic events, or extensive coronary artery disease) derive clear ischemic benefit that offsets bleeding; whether particular antiplatelet agents or dosing strategies might modulate the risk–benefit ratio; and how differences between vitamin K antagonists and direct oral anticoagulants (DOACs) affect combined therapy outcomes. Larger, adequately powered randomized trials and pooled patient‑level meta‑analyses could clarify these issues, as could pragmatic trials stratified by plaque burden and by DOAC versus VKA use.

Conclusion

The ATIS‑NVAF randomized trial found that in patients with ischemic stroke or TIA, nonvalvular AF, and atherosclerotic cardiovascular disease, adding a single antiplatelet agent to anticoagulant therapy did not improve the composite of ischemic events and major bleeding over 2 years and markedly increased bleeding. These findings support anticoagulant monotherapy as the default strategy in this population absent other strong indications for antiplatelet therapy, and emphasize individualized risk assessment and short‑term, targeted use of combined regimens when necessary.

Funding and trial registration

Trial registration: ClinicalTrials.gov Identifier: NCT03062319. Funding sources were reported in the original publication (Okazaki et al., JAMA Neurology 2025); readers should consult the full text for sponsor details and disclosures.

References

1. Okazaki S, Tanaka K, Yazawa Y, et al.; ATIS-NVAF Trial Investigators. Optimal Antithrombotics for Ischemic Stroke and Concurrent Atrial Fibrillation and Atherosclerosis: A Randomized Clinical Trial. JAMA Neurol. 2025 Dec 1;82(12):1227-1234. doi:10.1001/jamaneurol.2025.3662.

2. Eikelboom JW, Connolly SJ, Bosch J, et al.; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Nov 23;377(14):1319-1330. doi:10.1056/NEJMoa1709118.

3. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open‑label, randomized, controlled trial (WOEST). Lancet. 2013 Mar 16;381(9872):1107-1115. doi:10.1016/S0140-6736(12)62022-7.

4. Gibson CM, Mehran R, Bode C, et al.; PIONEER AF‑PCI Investigators. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Feb 18;374(6):512-523. doi:10.1056/NEJMoa1509249.

5. Cannon CP, Bhatt DL, Oldgren J, et al.; RE‑DUAL PCI Steering Committee and Investigators. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017 Dec 28;377(23):1513-1524. doi:10.1056/NEJMoa1708454.

6. Lopes RD, Heizer G, Aronson R, et al.; AUGUSTUS Investigators. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Patients with Atrial Fibrillation. N Engl J Med. 2019 Apr 4;380(14):1509-1524. doi:10.1056/NEJMoa1817083.

7. Hindricks G, Potpara T, Dagres N, et al.; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2021 Feb 1;42(5):373-498. doi:10.1093/eurheartj/ehaa612.

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Posted inCardiology Neurology news

No Net Benefit from Adding Antiplatelet Therapy to Anticoagulation After Ischemic Stroke With Atrial Fibrillation and Atherosclerosis — Higher Bleeding Risk

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No Net Benefit from Adding Antiplatelet Therapy to Anticoagulation After Ischemic Stroke With Atrial Fibrillation and Atherosclerosis — Higher Bleeding Risk

Highlight

– In patients with ischemic stroke or transient ischemic attack (TIA) who have nonvalvular atrial fibrillation (AF) and concomitant atherosclerotic cardiovascular disease, adding an antiplatelet to anticoagulant therapy provided no net clinical benefit over anticoagulant monotherapy at 2 years.
– The combination strategy produced a numerically smaller (but statistically nonsignificant) reduction in ischemic events (11.1% vs 14.2%) but caused a marked increase in major or clinically relevant nonmajor bleeding (19.5% vs 8.6%; HR 2.42, 95% CI 1.23–4.76, P = .008).
– Absolute effects translate to roughly one additional major/clinically relevant bleed for every 9 patients treated with combination therapy (NNH ≈ 9) versus an uncertain prevention of ischemic events (NNT ≈ 32, not statistically significant).

Background

Patients with ischemic stroke or TIA and concurrent nonvalvular atrial fibrillation are at high risk of recurrent ischemic stroke from cardiac embolism. At the same time, a substantial proportion have coexisting atherosclerotic cardiovascular disease — carotid or intracranial stenosis, prior noncardioembolic stroke, ischemic heart disease, or peripheral artery disease — that may be expected to respond to antiplatelet therapy. Clinicians commonly face the dilemma whether combining antiplatelet therapy with oral anticoagulation yields incremental ischemic protection that outweighs bleeding harm.

Guideline documents generally recommend oral anticoagulation for stroke prevention in AF and reserve addition of antiplatelet therapy to situations with specific indications (for example, recent acute coronary syndrome or percutaneous coronary intervention). However, high absolute ischemic risk from coexisting atherosclerotic disease has prompted uncertainty and heterogeneity in practice. The ATIS-NVAF randomized trial was designed to address the net clinical benefit of combination antiplatelet plus anticoagulant therapy versus anticoagulant monotherapy in this high-risk population.

Study design

ATIS-NVAF was a multicenter, open-label randomized clinical trial conducted at 41 sites in Japan (November 2016 to March 2025). The trial enrolled adults with ischemic stroke or TIA 8 to 360 days before randomization, documented nonvalvular AF, and at least one manifestation of atherosclerotic cardiovascular disease (carotid or intracranial artery stenosis, noncardioembolic stroke, ischemic heart disease, or peripheral artery disease). Participants were randomized to either combination therapy (oral anticoagulant plus antiplatelet agent) or anticoagulant monotherapy. The anticoagulant regimen (vitamin K antagonist or direct oral anticoagulant) and the specific antiplatelet agent were chosen by treating clinicians per standard practice; details of regimens are reported in the primary manuscript.

The primary outcome was a composite of ischemic cardiovascular events and major bleeding within 2 years. Secondary and safety outcomes included ischemic cardiovascular events separately, and major and clinically relevant nonmajor bleeding events. The trial was open-label and planned to enroll a larger sample, but an interim analysis led to early termination for futility on July 18, 2023. Data were analyzed through October 2024.

Key findings

316 patients were randomized (159 to combination therapy; 157 to monotherapy). The cohort was elderly (mean age 77.2 years) with 28.5% female participants. Key outcomes at 2 years were:

  • Primary composite outcome (ischemic events plus major bleeding): 17.8% in the combination group vs 19.6% in the monotherapy group (hazard ratio [HR] 0.91; 95% CI 0.53–1.55; P = .64). No statistically significant difference.
  • Ischemic cardiovascular events alone: 11.1% vs 14.2% (HR 0.76; 95% CI 0.39–1.48; P = .41). Numerically fewer ischemic events with combination therapy but not statistically significant.
  • Major and clinically relevant nonmajor bleeding: 19.5% vs 8.6% (HR 2.42; 95% CI 1.23–4.76; P = .008). Combination therapy more than doubled the risk of clinically important bleeding.

Absolute event differences illustrate the clinical trade-offs: the absolute increase in clinically important bleeding with combination therapy was 10.9% (19.5% minus 8.6%), yielding a number needed to harm (NNH) of approximately 9. The absolute reduction in ischemic events was 3.1% (14.2% minus 11.1%), corresponding to a number needed to treat (NNT) of about 32 to prevent one ischemic event — a benefit that did not reach statistical significance and must be interpreted cautiously given early termination and limited power.

Interpretation and clinical implications

The ATIS-NVAF trial provides randomized evidence that routine addition of an antiplatelet agent to anticoagulation in patients with ischemic stroke/TIA, AF, and atherosclerotic disease does not confer a net clinical advantage and substantially increases clinically important bleeding. The findings are consistent with prior randomized data and guideline recommendations that oral anticoagulation is the mainstay for preventing cardioembolic stroke in AF and that antiplatelet therapy should not be added routinely unless there is a separate, compelling atherosclerotic indication (for example, recent coronary stenting or acute coronary syndrome where short-term dual therapy is indicated).

Two practical points follow. First, clinicians should carefully review the indication for any antiplatelet therapy in a patient already on anticoagulation and avoid long-term combination therapy without clear benefit. Second, when combination therapy is required (for example, after percutaneous coronary intervention), the duration should be minimized and bleeding risk mitigation strategies (radial access, proton pump inhibitor for GI protection, use of DOAC rather than warfarin when appropriate) should be employed.

Strengths and limitations

Strengths of ATIS-NVAF include randomized allocation, a clinically relevant composite primary outcome that incorporated both ischemic and bleeding events to assess net clinical benefit, and enrollment of an older, comorbid population commonly encountered in practice.

Important limitations temper the findings. The trial was open-label, which could affect ascertainment and management of some outcomes, although objective endpoints like stroke and major bleeding are less susceptible to observer bias. The study was terminated early for futility, resulting in a smaller-than-planned sample size and reduced statistical power to detect modest differences in ischemic events. The specific composition and dosing of antiplatelet agents and the mix of anticoagulants (warfarin vs DOACs) were determined by treating clinicians and may vary from other settings; detailed subgroup outcome data are necessary to explore heterogeneity (for instance, patients with prior coronary stents vs carotid stenosis only). Finally, the trial population was Japanese and elderly (mean age 77); generalizability to younger populations or different ethnic groups should be considered cautiously.

How this fits with prior evidence

The trial’s risk–benefit trade-off echoes findings from other cardiovascular trials where combination antithrombotic strategies reduced ischemic events at the cost of higher bleeding (for example, COMPASS demonstrated that low-dose rivaroxaban plus aspirin reduced major adverse cardiovascular events in stable atherosclerotic disease but increased major bleeding). However, the AF population differs because anticoagulation alone provides robust prevention of cardioembolic stroke, so the incremental benefit of adding antiplatelet therapy is smaller and more likely to be offset by bleeding harm. AF management guidelines generally recommend anticoagulation as first-line stroke prevention and reserve antiplatelet agents for specific concomitant indications; ATIS-NVAF provides randomized trial evidence supporting this approach in patients with prior ischemic stroke/TIA and atherosclerosis.

Expert commentary and practice recommendations

For practicing clinicians, the trial supports the following pragmatic approach:
– Prioritize anticoagulant monotherapy for stroke prevention in AF unless a clear separate indication for antiplatelet therapy exists (e.g., recent coronary stenting or acute coronary syndrome).
– If short-term combination therapy is required, minimize duration, choose lower-risk strategies (use of DOACs when appropriate, employ gastroprotection), and reassess the ongoing need for antiplatelet therapy at follow-up.
– Use individualized bleeding-risk assessment (eg, HAS-BLED) and shared decision-making when discussing combination therapy risks and benefits with patients and caregivers.

From a research standpoint, adequately powered randomized trials or pooled patient-level meta-analyses are needed to address whether particular subgroups (for example, patients with high-burden intracranial atherosclerosis or recent coronary stent placement) might derive net benefit from carefully selected combination strategies and to determine optimal durations and drug choices.

Conclusion

In patients with ischemic stroke or TIA, nonvalvular AF, and concomitant atherosclerotic cardiovascular disease, adding an antiplatelet agent to anticoagulation did not reduce the composite of ischemic events and major bleeding and resulted in a substantially higher risk of clinically important bleeding. These data support anticoagulant monotherapy as the default strategy in this population and caution against routine long-term combination antithrombotic therapy except when specific atherosclerotic indications exist.

Funding and clinicaltrials.gov

Trial registration: ClinicalTrials.gov Identifier: NCT03062319.
Funding sources and detailed disclosures are reported by the authors in the primary publication (Okazaki et al., JAMA Neurol. 2025).

References

1. Okazaki S, Tanaka K, Yazawa Y, et al; ATIS-NVAF Trial Investigators. Optimal Antithrombotics for Ischemic Stroke and Concurrent Atrial Fibrillation and Atherosclerosis: A Randomized Clinical Trial. JAMA Neurol. 2025 Oct 6:e253662. doi: 10.1001/jamaneurol.2025.3662. PMID: 41051787; PMCID: PMC12501853.

2. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (BAFTA): randomized controlled trial. Lancet. 2007;370(9586):493–503.

3. Eikelboom JW, Connolly SJ, Bosch J, et al.; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319–1330.

4. Kirchhof P, Benussi S, Kotecha D, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2020;42(5):373–498. (Guideline summary and management recommendations relevant to antithrombotic strategies in AF.)

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