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Edoxaban patients with CAD/PAD show higher stroke, ACS, and cardiovascular death ratesPatients with heart disease face higher risks on edoxaban

Journal of thrombosis and thrombolysis Published August 9, 2026 Study authors: de Vries Tim A C, de Groot Joris R, Pisters Ron, Hemels Martin E W, Komen Joris J, Smolnik Rüdiger, … PubMed ↗ NCT02944019 ↗ DOI ↗ Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

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Key Takeaway

Note that edoxaban patients with CAD/PAD have higher rates of stroke, ACS, and cardiovascular death than those without.

This prospective cohort study (ETNA-AF-Europe) evaluated 13,164 patients with atrial fibrillation (AF) receiving edoxaban in a routine practice setting. The primary objective was to assess major clinical event rates and compare outcomes between patients with atherosclerotic disease (CAD/PAD) and those without such conditions, while also comparing real-world data to the ENGAGE-AF TIMI-48 trial results.

Patients were categorized based on the presence of coronary artery disease or peripheral artery disease. The study focused on edoxaban as the primary intervention in a routine care environment. This setting allows for the observation of outcomes in a broader, non-trial population compared to strictly controlled clinical trials.

Primary outcome results indicated that patients with CAD/PAD experienced significantly higher rates of stroke and systemic embolism (0.87% per year) compared to those without CAD/PAD (0.59% per year; HR 1.5; 95% CI 1.14-1.88). Acute coronary syndrome was notably more frequent in the CAD/PAD group, with a rate of 1.24% per year versus 0.37% per year for those without CAD/PAD (HR 3.3; 95% CI 2.60-4.27). Additionally, cardiovascular death was higher in patients with CAD/PAD (1.59% per year) than in those without (0.85% per year; HR 1.9; 95% CI 1.54-2.26).

Secondary outcomes also showed significant differences based on atherosclerotic status. Major bleeding occurred at a rate of 1.06% per year in the CAD/PAD group versus 0.81% per year in the non-CAD/PAD group (HR 1.3; 95% CI 1.04-1.63). All-cause death was higher in patients with CAD/PAD (6.02% per year) compared to those without (3.53% per year; HR 1.7; 95% CI 1.55-1.89).

When comparing the ETNA-AF-Europe cohort to the ENGAGE-AF TIMI-48 trial, several differences emerged. The rate of stroke/systemic embolism was lower in the ETNA-AF-Europe cohort (0.87% per year) than in the ENGAGE-AF TIMI-48 trial (1.5% per year). Major bleeding was also lower in the ETNA-AF-Europe cohort (1.04% per year) compared to the trial (3.0% per year). Cardiovascular death was lower in the real-world cohort (1.59% per year) than in the trial (3.7%). However, non-cardiovascular mortality was higher in the ETNA-AF-Europe cohort (4.43% per year) compared to the trial (1.6% per year).

Safety and tolerability data indicated that deaths and bleeding were the most common events among patients treated with edoxaban. No specific rates for serious adverse events or discontinuation rates were reported. The study highlights a significant divergence in risk profiles between trial participants and real-world patients; specifically, ENGAGE-AF TIMI-48 participants with CAD/PAD had substantially higher cardiovascular risks but lower non-cardiovascular risks than those treated in daily practice.

Methodological limitations include the fact that this is an observational study, meaning results indicate association rather than direct causality. The study was a prospective cohort and not a randomized controlled trial for the primary analysis of routine practice. Several parameters, including specific follow-up durations and certain confidence intervals or p-values for comparative outcomes, were not reported.

Clinically, these results suggest that patients with atherosclerotic disease (CAD/PAD) treated with edoxaban in routine care face higher risks of stroke, ACS, and cardiovascular death than those without such conditions. The disparity between trial data and real-world data suggests that the patient profile in large trials may not perfectly mirror the general population. Practitioners should recognize these differing risk profiles when managing patients with comorbid atherosclerotic disease. Questions remain regarding the specific factors driving the higher non-cardiovascular mortality in the real-world cohort compared to trial participants and how these differences impact long-term management strategies for AF patients with complex comorbidities.

How this fits prior evidence

How this fits prior evidence: This study addresses a gap by providing real-world data on edoxaban use in routine practice, contrasting it with results from the ENGAGE-AF TIMI-48 trial. While previous findings noted that NOAC monotherapy reduces net adverse clinical events in older patients with atrial fibrillation and stents, this study highlights how atherosclerotic disease specifically influences stroke and cardiovascular death rates in a broader population.

Living with atrial fibrillation (AF) can be stressful. It is an irregular heartbeat that can lead to serious problems like strokes or blood clots. To manage this risk, many people take a medication called edoxaban. While this medicine helps prevent clots, new data suggests that for some patients, the risks might be higher depending on their existing health history.

Researchers looked at a large group of over 13,000 people who were taking edoxaban in their daily lives. They specifically wanted to see how those with a history of atherosclerotic disease (clogged arteries) fared compared to those without that specific condition. This is important because many people with atrial fibrillation also have underlying heart issues, and doctors need to know how different conditions change the way a medication works in the real world.

The study found that patients who had existing heart disease and took edoxaban faced higher rates of several serious events compared to those without that history. Specifically, these patients saw higher yearly rates of stroke or systemic embolism, as well as more cases of acute coronary syndrome (a sudden blockage of a heart artery). The data also showed higher rates of major bleeding and cardiovascular death for those with pre-existing heart disease. For example, the rate of acute coronary syndrome was significantly higher in the group with heart disease compared to the group without it.

While these findings are important, there are things to keep in mind before changing how you feel about your treatment. This was an observational study, which means researchers observed what happened in real life rather than controlling every variable in a strict clinical trial. Because of this, we can see a link between heart disease and higher risks, but we cannot say for certain that the medication itself caused those specific differences. For patients right now, these results do not mean you should stop your medication or panic. Instead, they highlight how important it is to have an open conversation with your doctor. Your medical team can look at your specific history of heart disease and atrial fibrillation to ensure your treatment plan is the safest and most effective option for your unique body. This study helps doctors better understand the different risks involved so they can provide more personalized care.

What this means for you:

Patients with both atrial fibrillation and heart disease may face higher stroke and bleeding risks on edoxaban.

Study Details

Study typeRct

Sample sizen = 13,164

EvidenceLevel 2

PublishedAug 2026

TrialNCT02944019

View Original Abstract ↓

To estimate major clinical event rates for patients with atrial fibrillation (AF) and atherosclerotic disease treated with edoxaban in routine practice, and to evaluate how well such patients were represented in ENGAGE AF-TIMI 48, the seminal randomized trial comparing edoxaban against warfarin for AF. ETNA-AF-Europe is a prospective cohort of AF patients receiving edoxaban in routine care. We compared patients with coronary or peripheral artery disease (CAD/PAD) to: (1) those without CAD/PAD in ETNA-AF-Europe, and (2) CAD/PAD patients in ENGAGE AF-TIMI 48. Of 13,164 patients in ETNA-AF-Europe, 23.3% had CAD/PAD. Compared with those without, patients with CAD/PAD had higher rates of stroke/systemic embolism (0.87%/year vs. 0.59%/year; HR 1.5, 95%-CI 1.14-1.88), acute coronary syndrome (1.24%/year vs. 0.37%/year; HR 3.3, 95%-CI 2.60-4.27), major bleeding (1.06%/year vs. 0.81%/year; HR 1.3, 95%-CI 1.04-1.63), cardiovascular death (1.59%/year vs. 0.85%/year; HR 1.9, 95%-CI 1.54-2.26), and all-cause death (6.02%/year vs. 3.53%/year; HR 1.7, 95%-CI 1.55-1.89). Compared with CAD/PAD patients in ENGAGE-AF TIMI-48, those in ETNA-AF-Europe had fewer cardiovascular comorbidities, less prevalent aspirin use (20.2% vs. 50.3%), and lower rates of stroke/systemic embolism (0.87%/year vs. 1.5%/year), major bleeding (1.04%/year vs. 3.0%/year), and cardiovascular death (1.59%/year vs. 3.7%), but higher non-cardiovascular mortality (4.43%/year vs. 1.6%/year). In routine practice, deaths and bleeding were the most common events in edoxaban-treated patients with AF. This pattern was consistent between those with and without atherosclerosis. ENGAGE-AF TIMI-48 participants with CAD/PAD had substantially higher cardiovascular but lower non-cardiovascular risks than those treated in daily practice.Trial registration number: NCT02944019 (ClinicalTrials.gov Identifier).