Clinical trial NCT06954610: Cardiac Assessment for Recurrent Stroke Risk Evaluation in Atrial Fibrillation
Official title: CARE-AF: Cardiac Assessment for Recurrent Stroke Risk Evaluation in Atrial Fibrillation
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Ischemic Stroke
Atrial Fibrillation
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Vascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Brain Infarction
Brain Ischemia
Infarction Cerebral
Stroke
Cardioembolic Stroke
Ischemia
Keywords: Ischemic stroke
Direct oral anticoagulation
Anticoagulation
Breakthrough stroke
Risk stratification
Atrial fibrillation
Anticoagulant therapy
Direct oral anticoagulant
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2025-05-01
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: All patients with ischemic stroke and atrial fibrillation that are admitted to the stroke center of the Inselspital, University Hospital Bern, Switzerland.

Atrial fibrillation may be known prior to the index stroke or newly diagnosed and patients may be anticoagulated or not.

Brief summary: Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting up to 10% of the elderly. Ischemic stroke is the main complication of AF and cardioembolism is one of the leading causes of ischemic stroke, accounting for approximately one third of cases. Oral anticoagulant therapy (OAC) is a cornerstone in stroke prevention in patients with AF. According to randomized controlled trials of direct oral anticoagulants, a residual risk of ischemic stroke of 1-2% per year for so-called "breakthrough stroke" remains, despite adequate intake of OAC. The majority (\>70%) of these breakthrough strokes are cardioembolic in nature and only a minority are related to medication issues (e.g. non-compliance) or other, non-AF related etiologies. Stroke recurrence risk after such a breakthrough stroke markedly increases to 8-9% per year indicating a particularly high-risk situation. Why OAC fails in certain patients, but not in others remains as poorly understood, as does the reason why the subsequent risk of stroke is so high.

Current risk stratification tools, such as the widely used CHA2DS2-VA(Sc)-score, fail to predict stroke risk in such a high-risk cohort, as they were intended to guide the initiation of OAC in low to moderate risk patients. In light of new therapeutic strategies currently being investigated, such as percutaneous left atrial appendage occlusion in patients with breakthrough strokes (ELAPSE - NCT05976685) or in AF-patients deemed high-risk (LAAOS IV - NCT05963698), improved risk stratification and characterization of high-risk AF patients is highly warranted.

Several clinical factors, such as those reflected in the CHA2DS2-VA(Sc)-score, and especially a high AF-burden are associated with increased risk of cardioembolic stroke. Several cardiac serum biomarkers are thought to be surrogates not only of cardiac function, but also of cardioembolic risk. Reflecting ventricular and atrial wall tension, myocardial injury, oxidative stress and thrombogenicity, elevated NT-proBNP, MR-proANP, high-sensitive Troponin T and D-Dimers have all been associated with cardioembolic stroke in different AF and non-AF populations. As the main location of thrombus formation, the left atrium (LA) and more specifically its appendage (LAA) are of particular interest in the pathogenesis of cardioembolism. Pronounced LA-enlargement, compared to a normal-sized LA, correlates with an increased risk of cardioembolism in AF-patients. As over 80% of thrombi form within the LAA, several LAA-characteristics, such as slower LAA-flow velocity and larger LAA-orifice area have also been demonstrated to be associated with higher stroke risk. Although there is data on each one of these factors, they have only been investigated in low to moderate risk populations, such as AF-patients without prior stroke, OAC-naïve patients, or even within the general population as a whole. Their role in high-risk AF-patients and in breakthrough stroke is unknown.

Hypothesis

The investigators hypothesize that specific clinical factors, serum cardiac biomarkers and markers of LA- and LAA-morphology and function are associated with breakthrough stroke / OAC-failure and may improve risk stratification.

Methods

CARE-AF is a single-center, prospective cohort study conducted at the Stroke Center of the Inselspital, University Hospital Bern, Switzerland. Patients with an index ischemic stroke and AF (breakthrough and non-breakthrough cases) will be enrolled. The investigators will collect clinical data, serum cardiac biomarkers and echocardiographic indices of the LA and LAA. All patients will receive standardized annual follow-ups until the end of the study, defined as 12 months after the inclusion of the last participant. The primary endpoint is ischemic stroke or systemic embolism during follow-up. First, in a cross-sectional design, the study will assess the association between serum cardiac biomarkers and echocardiographic indices among patients with breakthrough vs. non-breakthrough stroke as index event, applying multivariate regression models. Second, the investigators will perform a longitudinal analysis assessing the association between the variables mentioned above and breakthrough stroke as index event with the primary endpoint, using multivariate Cox regression models. The study aims to enroll a minimum of 500 patients, which provides sufficient power to detect a clinically meaningful adjusted hazard ratio for recurrent stroke of 1.5 with 80% power at an alpha level of 5%.

Conclusion

The results of this project will enhance understanding of the role of specific clinical factors, cardiac serum biomarkers and echocardiographic indices in the residual risk of stroke in patients with AF on anticoagulation therapy. They may improve current risk stratification and have the potential to help guide therapeutic decisions in high-risk situations considering evolving therapeutic possibilities.


Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Written informed consent (by patient, next of kin or legally authorised representative)
* Permanent, persistent, or paroxysmal AF previously known or diagnosed during the index hospitalisation
* Acute (≤7 days), symptomatic ischemic stroke

Exclusion Criteria:

* Life expectancy \<1 year according to the opinion of the investigator
* Patient is unlikely to attend follow-up visits

Primary outcomes:
measure: Composite of recurrent ischemic stroke or systemic embolism
timeFrame: Assessed in first follow-up visit at 12 months (+/- 30 days) after enrolment. Subsequent assessments/visits will be every 12 months and at the end of study (if last visit has taken place >90days prior). Minimal Follow up per patient is 12 months.
Secondary outcomes:
measure: All-cause death
timeFrame: Assessed in first follow-up visit at 12 months (+/- 30 days) after enrolment. Subsequent assessments/visits will be every 12 months and at the end of study (if last visit has taken place >90days prior). Minimal Follow up per patient is 12 months.
measure: MACE (major adverse cardial events), defined as a composite outcome of myocardial infarction (MI), ischemic and haemorrhagic stroke, transient ischemic attack (TIA), systemic embolism and cardiovascular death
timeFrame: Assessed in first follow-up visit at 12 months (+/- 30 days) after enrolment. Subsequent assessments/visits will be every 12 months and at the end of study (if last visit has taken place >90days prior). Minimal Follow up per patient is 12 months.
measure: Episodes of symptomatic AF
timeFrame: Assessed in first follow-up visit at 12 months (+/- 30 days) after enrolment. Subsequent assessments/visits will be every 12 months and at the end of study (if last visit has taken place >90days prior). Minimal Follow up per patient is 12 months.
measure: Functional outcome: modified Rankin Scale
timeFrame: Assessed in first follow-up visit at 12 months (+/- 30 days) after enrolment. Subsequent assessments/visits will be every 12 months and at the end of study (if last visit has taken place >90days prior). Minimal Follow up per patient is 12 months.
measure: Functional outcome: Quality of life
timeFrame: Assessed in first follow-up visit at 12 months (+/- 30 days) after enrolment. Subsequent assessments/visits will be every 12 months and at the end of study (if last visit has taken place >90days prior). Minimal Follow up per patient is 12 months.
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Inselspital Bern
Study officials:
affiliation: Department of Neurology, Inselspital, University Hospital Bern, Switzerland
name: David Seiffge, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References: