Stroke Risk Assessment and Markers of Blood Clotting in Patients With Newly Diagnosed Non-valvular Atrial Fibrillation (NVAF), Who Have Not Received Oral Anticoagulation Therapy (OAC-therapy) Prior to Inclusion

NCT06949319 | Recruiting

• 1 other identifier: S-20240018
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide. Globally, there are 37.5 million people with AF. AF increases the risk of death, heart failure, and stroke, which severely affect patients and also lead to high healthcare costs. Around 25% of all strokes are caused by AF, and patients with stroke due to AF tend to have a higher risk of death and more disability compared to stroke patients without AF. Stroke prevention is, therefore, an important part of AF treatment, in which blood thinning medication has an important role. However, blood thinners increase the risk of bleeding. Therefore, it is important to divide patients with AF into different risk groups, known as risk assessment, to figure out who will benefit the most from blood thinners. To be able to divide patients into different risk groups, various stroke risk assessment tools have been developed, such as the CHA2DS2-VASc score and the ABC-stroke score. The most commonly used tool is the CHA2DS2-VASc score, including only clinical risk factors, such as high blood pressure, diabetes, etc. The ABC-stroke score, which includes blood markers of heart function, has been proven to outperform the CHA2DS2-VASc score in terms of predicting stroke in AF patients. However, the CHA2DS2-VASc score remains the primary stroke risk assessment tool for AF patients in current guidelines. After looking at the different risk factors, patients are divided into three groups: low, intermediate, and high risk. High-risk patients must take blood-thinning medication for life, while low-risk patients do not need it. In the medium-risk group, it remains uncertain whether blood thinners should be given or not. Despite the broad use of the CHA2DS2-VASc score, the score itself has limitations. The score does not include important factors, such as the duration of AF, the size and function of the upper heart chambers, as well as the stiffness of the heart, and markers of blood clotting, which are proven markers of a state that inceases the risk of blood clots. Furthermore, the CHA2DS2-VASc score does not consider whether heart failure, high blood pressure, and diabetes are well-controlled or not, which could lead to overuse of blood thinners. Therefore, the current risk assessment tools for patients with AF are incomplete, and improvements are needed. Overall hypothesis: Overall hypothesis is that the different components of the CHA2DS2-VASc score and ABC-stroke score affect blood clotting markers differently, depending on whether conditions like heart failure, high blood pressure, and diabetes (modifiable risk factors) are well-controlled or not. Investigators also expect to see differences in blood clotting markers across different stroke risk groups (low, intermediate, and high risk, based on the CHA2DS2-VASc score and ABC-stroke score) in AF patients who have not yet started blood thinning medication. Furthermore, investigators believe that the duration of AF, the size/function of the upper heart chambers, as well as the stiffness of the heart, can reflect an increased risk of blood clots in AF patients. Overall goal of the study: The overall goal of the study is to help improve the current tools used to assess the risk of stroke in patients with newly diagnosed AF. This will be done by adding more factors to the current risk assessment tools that reflect an increased risk of stroke, such as the burden of AF, the size/function of the heart's upper chambers, as well as the stiffness of the heart, and using biomarkers that show the blood's ability to clot as a substitute measure for stroke risk. Methods: The study is a cross-sectional, single-center observational study and will take place at Esbjerg Hospital - University Hospital of Southern Denmark, involving collaboration between the Unit for Thrombosis Research, Department of Clinical Diagnostics and the Department of Cardiology. The study population will consist of 150 participants with newly diagnosed AF. The participants must not be taking a specific type of blood thinner, called anticoagulant therapy (OAC-therapy), before being included in the study. The participants will be recruited with the help of the general practitioners (GPs). The general practitioners will be thoroughly informed about the study and the importance of waiting to start OAC-therapy until the participants have been seen at the cardiology outpatient clinic. The participants will be scheduled for a blood test, an ultrasound of the heart (echocardiography), and a 7-day heart rhythm monitoring within 4 days after their first meeting with the GP.

Conditions

Atrial Fibrillation (AF); Atrial Fibrillation (Prevention of Stroke); Atrial Fibrillation New Onset; Non Valvular Atrial Fibrillation; Stroke (in Patients With Atrial Fibrillation); Stroke; Thrombosis

Keywords

Stroke risk assessment in patients with atrial fibrillation; OAC-naïve patients with newly diagnosed atrial fibrillation; Hemostatic biomarkers; CHA2DS2-VASc score; ABC-stroke score; AF-burden; Left Atrial Function Index (LAFI); Echocardiography; HFA-PEFF score; H2FPEF score; Heart failure with preserved ejection fraction (HFpEF); Stroke; Oral anticoagulant therapy; Non-valvular atrial fibrillation

Outcome Measures

Primary Outcomes (9)

• Thrombin generation assessed by lag time

  Thrombin generation plays a pivotal role in blood clotting and thus serve as primary outcome measure. Thrombin generation will be assessed through measurement of lag time (min), using the calibrated automated thrombography (CAT) method.

  Thrombin generation, assessed by lag time, will be measured at baseline (enrollment).

• Thrombin generation assessed by peak thrombin concentration

  Thrombin generation plays a pivotal role in blood clotting and thus serve as primary outcome measure. Thrombin generation will be assessed through measurement of peak thrombin concentration (nmol/L), using the calibrated automated thrombography (CAT) method.

  Thrombin generation, assessed by peak thrombin concentration, will be measured at baseline (enrollment).

• Thrombin generation assessed by time to peak

  Thrombin generation plays a pivotal role in blood clotting and thus serve as primary outcome measure. Thrombin generation will be assessed through measurement of time to peak (min), using the calibrated automated thrombography (CAT) method.

  Thrombin generation, assessed by time to peak, will be measured at baseline (enrollment).

• Thrombin generation assessed by endogenous thrombin potential

  Thrombin generation plays a pivotal role in blood clotting and thus serve as primary outcome measure. Thrombin generation will be assessed through measurement of endogenous thrombin potential (nmol/L x min), using the calibrated automated thrombography (CAT) method.

  Thrombin generation, assessed by endogenous thrombin potential, will be measured at baseline (enrollment).

• Kallikrein generation assessed by lag time

  Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis, therefore it will serve as a primary outcome measure. Kallikrein generation will be assessed through measurement of lag time (min), using the calibrated automated thrombography (CAT) method.

  Kallikrein generation, assessed by lag time, will be measured at baseline (enrollment).

• Kallikrein generation assessed by peak kallikrein concentration

  Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis, therefore it will serve as a primary outcome measure. Kallikrein generation will be assessed through measurement of peak kallikrein concentration (nmol/L), using the calibrated automated thrombography (CAT) method.

  Kallikrein generation, assessed by peak kallikrein concentration, will be measured at baseline (enrollment).

• Kallikrein generation assessed by time to peak

  Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis, therefore it will serve as a primary outcome measure. Kallikrein generation will be assessed through measurement of time to peak (min), using the calibrated automated thrombography (CAT) method.

  Kallikrein generation, assessed by time to peak, will be measured at baseline (enrollment).

• Kallikrein generation assessed by endogenous kallikrein potential

  Kallikrein generation plays an important role in the contact activation system of the secondary hemostasis, therefore it will serve as a primary outcome measure. Kallikrein generation will be assessed through measurement of endogenous kallikrein potential (nmol/L\*min), using the calibrated automated thrombography (CAT) method.

  Kallikrein generation, assessed by endogenous kallikrein potential, will be measured at baseline (enrollment).

• Concentrations of prothrombin fragment 1 + 2

  Activation of the inactive prothrombin to the active thrombin will be estimated from concentrations of prothrombin fragment 1 + 2 (pmol/L), using a commercial enzyme-linked immunosorbent assay (ELISA). Prothrombin fragment 1 + 2 are the byproducts of the abovementioned activation process.

  Prothrombin fragment 1 + 2 will be assessed at baseline (enrollment).

Secondary Outcomes (31)

• Levels of von Willebrand factor (vWF) antigen

  von Willebrand factor antigen will be assessed at baseline (enrollment).

• Concentration of cleaved high-molecular weight kininogen (cHK)

  cHK will be assessed at baseline (enrollment).

• Concentration of coagulation factor XII (FXII)

  FXII will be assessed at baseline (enrollment).

• Concentration of prekallikrein

  Prekallikrein will be assessed at baseline (enrollment).

• Concentration of high-molecular weight kininogen (HK)

  HK will be assessed at basline (enrollment).

Study Arms (1)

Oral anticoagulant-naïve (OAC-naïve) patients with non-valvular atrial fibrillation (NVAF).

The study population will consist of patients with newly diagnosed non-valvular atrial fibrillation (NVAF). Patients will have to be naïve to oral and parenteral anticoagulants prior to inclusion. Patients with newly diagnosed NVAF who are willing to participate in this study and sign the patient consent form will be scheduled for fast track outpatient clinic visit within four days for blood sampling, transthoracic echocardiography (TTE), and heart rhythm monitoring. OAC treatment will be initiated immediately after blood sampling, based on current guidelines for the management of NVAF. Demographic data will be collected, as well. Likewise, symptoms attributable to NVAF will be quantified according to the modified EHRA-score (European Heart Rhythm Association). Investigators will also determine whether hypertension and diabetes are effectively managed by home blood pressure (BP) measurements and HbA1c levels.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of patients with newly diagnosed non valvular atrial fibrillation (NVAF). Patients will have to be naïve to oral and parenteral anticoagulants prior to inclusion. Study participants will be enrolled from the catchment area of the University Hospital of Southern Denmark, Esbjerg. Collaboration with the general practitioners will be essential for patient inclusion. Investigators will provide comprehensive information to general practitioners about this study and the importance of withholding OAC treatment before subacute referral to the Department of Cardiology. Patients with newly diagnosed NVAF who are willing to participate in this study and sign the patient consent form will be scheduled for fast track outpatient clinic visit within four days of their consultation with the general practitioner for blood sampling, transthoracic echocardiography (TTE), and heart rhythm monitoring.

You may qualify if:

• Age ≥ 18 years.
• Signed informed consent.

You may not qualify if:

• Valvular AF (mechanical heart valves or moderate-severe mitral stenosis).
• Secondary AF due to an acute reversible precipitant (e.g., infection, surgery, thyrotoxicosis, etc.).
• Pregnant or breastfeeding women.
• Treatment with oral contraceptives.
• End-stage renal disease (creatinine clearance \<15 mL/min as calculated by the Cockcroft-Gault equation).
• Connective tissue diseases.
• Active cancer (cancer diagnosis not followed by curative procedures six months from the date of diagnosis).
• Major surgery (\< three months).
• Thrombophilia.
• Significant liver disease.
• Significant hematological disease.

Sponsors & Collaborators

• Nedim Tojaga: lead
• Esbjerg Hospital - University Hospital of Southern Denmark: collaborator
• Karola Jørgensens Foundation and Foundation for Cardiology in Southwest Denmark.: collaborator
• Grosserer L.F. Foghts Foundation: collaborator
• Direktør Kurt Bønnelycke og Hustru fru Grethe Bønnelyckes Fond: collaborator
• The Faculty of Health Sciences SDU: collaborator
• Research Electronic Data Capture (REDCap): collaborator
• Region of Southern Denmark: collaborator

Study Sites (1)

Esbjerg Hospital - University Hospital of Southern Denmark, involving collaboration between the Unit for Thrombosis Research, Department of Clinical Diagnostics and the Department of Cardiology.

Esbjerg, Region Syddanmark, 6700, Denmark

RECRUITING

Related Publications (8)

• Ariyaratnam JP, Mishima RS, Kadhim K, Emami M, Fitzgerald JL, Thiyagarajah A, Dziano JK, Howie JO, Middeldorp ME, Sanders P, Elliott AD. Utility and Validity of the HFA-PEFF and H2FPEF Scores in Patients With Symptomatic Atrial Fibrillation. JACC Heart Fail. 2024 Jun;12(6):1015-1025. doi: 10.1016/j.jchf.2024.01.015. Epub 2024 Mar 20.

  PMID: 38520461 BACKGROUND

• Thomas L, Hoy M, Byth K, Schiller NB. The left atrial function index: a rhythm independent marker of atrial function. Eur J Echocardiogr. 2008 May;9(3):356-62. doi: 10.1016/j.euje.2007.06.002. Epub 2007 Aug 7.

  PMID: 17689293 BACKGROUND

• Glowicki B, Matusik PT, Plens K, Undas A. Prothrombotic State in Atrial Fibrillation Patients With One Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex). Can J Cardiol. 2019 May;35(5):634-643. doi: 10.1016/j.cjca.2019.01.014. Epub 2019 Jan 30.

  PMID: 30955928 BACKGROUND

• Ding WY, Gupta D, Lip GYH. Atrial fibrillation and the prothrombotic state: revisiting Virchow's triad in 2020. Heart. 2020 Oct;106(19):1463-1468. doi: 10.1136/heartjnl-2020-316977. Epub 2020 Jul 16.

  PMID: 32675218 BACKGROUND

• Tilly MJ, Geurts S, Pezzullo AM, Bramer WM, de Groot NMS, Kavousi M, de Maat MPM. The association of coagulation and atrial fibrillation: a systematic review and meta-analysis. Europace. 2023 Feb 8;25(1):28-39. doi: 10.1093/europace/euac130.

  PMID: 35942591 BACKGROUND

• Benz AP, Hijazi Z, Lindback J, Connolly SJ, Eikelboom JW, Oldgren J, Siegbahn A, Wallentin L. Biomarker-Based Risk Prediction With the ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation. Circulation. 2021 May 11;143(19):1863-1873. doi: 10.1161/CIRCULATIONAHA.120.053100. Epub 2021 Apr 14.

  PMID: 33849281 BACKGROUND

• Hijazi Z, Lindback J, Alexander JH, Hanna M, Held C, Hylek EM, Lopes RD, Oldgren J, Siegbahn A, Stewart RA, White HD, Granger CB, Wallentin L; ARISTOTLE and STABILITY Investigators. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J. 2016 May 21;37(20):1582-90. doi: 10.1093/eurheartj/ehw054. Epub 2016 Feb 25.

  PMID: 26920728 BACKGROUND

• Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010 Feb;137(2):263-72. doi: 10.1378/chest.09-1584. Epub 2009 Sep 17.

  PMID: 19762550 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Fasting blood samples will be drawn from an antecubital vein with minimal stasis, using a 21 gauge needle. The first 2 mL of blood will be discarded, and the following 6 x 2.7 mL blood will be collected into 0.109 M sodium citrate tubes for APTT, INR, and hemostasis variables. Then, 2 x 3 mL of blood will be collected in Li-Heparin tubes for lipids, liver enzymes, renal function, CRP, NT-proBNP, and hs-TNT. Finally, 3 mL of blood will be collected in EDTA-tubes for HbA1c and full blood count. To generate platelet poor plasma (PPP), the tubes will be centrifuged at 2000 g for 20 min. at room temperature. PPP will be stored at -80°C until analysis.

MeSH Terms

Conditions

Atrial Fibrillation; Stroke; Thrombosis

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Embolism and Thrombosis

Central Study Contacts

Nedim Tojaga, Medical degree & PhD-student.

CONTACT

+4552752212; nedim.tojaga@rsyd.dk

Axel Brandes, Medical degree and Professor.

CONTACT

+4522903487; Axel.Brandes2@rsyd.dk

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal investigator.

Study Record Dates

• First Submitted: February 5, 2025
• First Posted: April 29, 2025
• Study Start: August 16, 2024
• Primary Completion: September 1, 2025
• Study Completion: September 1, 2025
• Last Updated: April 29, 2025

Record last verified: 2025-04

Locations

DK (1)