Apixaban in Adults With Congenital Heart Disease and Atrial Arrhythmias: the PROTECT-AR Study (PROTECT_AR)

A Prospective, Observational, Multicenter Study on the Safety and Efficacy of Apixaban for the Prevention of Thromboembolism in Adults With Congenital Heart Disease and Atrial Arrhythmias: the PROTECT-AR Study

The purpose of this study is to evaluate the safety and efficacy of apixaban for the prevention of thromboembolism in adult patients with congenital heart disease (CHD) and non-valvular atrial arrhythmias (AA)

Study Overview

• Status: Completed
• Conditions: Thromboembolism; Congenital Heart Disease; Atrial Arrhythmia; Anticoagulants Causing Adverse Effects in Therapeutic Use

Detailed Description

Adult patients with congenital heart disease (ACHD) represent a rapidly growing population due to the progress of surgical techniques and optimal medical management. Non-valvular atrial arrhythmias (AA) carries a significant burden for long-term morbidity and potentially mortality in ACHD patients. AA occur three times more frequently in ACHD compared to the general population. When complicating ACHD, AA convey a twofold increase in the risk for stroke, contributing to an up to 100-fold higher prevalence of stroke in the ACHD population compared to age-matched healthy controls. At present, the European Society of Cardiology (ESC) Guidelines suggest oral anticoagulation (OAC) in all adult patients with AA and intracardiac repair, cyanosis, Fontan palliation, or systemic right ventricle. In the remaining ACHD patients with AA, OAC is suggested if CHA2DS2-Vasc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score is ≥1 (Class of recommendation IIa, level of evidence C).

Non-vitamin K oral anticoagulants (NOACs) are increasingly preferred over vitamin-K antagonists (VKAs) in most clinical scenarios due to improved safety (with regard to intracranial and other major bleeding) and efficacy (prevention of embolic stroke or systemic embolism) along with the convenience they offer for patients and physicians (fixed dose, no food and drug interactions, no INR monitoring). On the other hand, scarce data is available on the use of NOAC in ACHD.

In order to address this gap in evidence, we propose a prospective multicenter single arm, observational cohort trial, which will provide data on the efficacy and safety of apixaban used for the prevention of thromboembolism in ACHD patients with AA.

• Study Type: Observational
• Enrollment (Actual): 218

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece, 12462
    • Attikon University Hospital
  • Athens, Greece, 17674
    • Onassis Cardiac Surgery Centre
  • Athens, Greece, 15123
    • Mitera Children's Hospital
  • Thessaloníki, Greece, 54636
    • Ahepa University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients with Congenital Heart Disease and Non-Valvular Atrial Arrhythmias who are routinely treated with apixaban (i.e., new or ongoing users) for stroke prevention at any health-care level in Greece

Description

Inclusion Criteria:

1. Male or female patients aged ≥18 years.
2. Presence of congenital heart disease (intracardiac repair, cyanosis, Fontan palliation, or systemic right ventricle or other congenital heart disease).
3. Non-Valvular Atrial Arrhythmia (including at least one electrocardiographically documented episode).
4. Signed written informed consent by the patient for participation in the study and agreement to comply with the medication and the follow-up schedule.

Exclusion Criteria:

1. moderate-to-severe mitral stenosis or mechanical valves
2. patient unwilling or unable to complete follow-up procedures

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Adults with CHD & non-valvular atrial arrhythmias; Adults with congenital heart disease and non-valvular atrial arrhythmias (atrial fibrillation, atrial flutter or intra-atrial re-entrant tachycardia)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroke, systemic or pulmonary arterial thromboembolism and intracardiac thrombosis.	The composite endpoint of all-cause stroke, systemic and pulmonary embolism and intracardiac thrombosis	up to 58 months
Major bleeding	Defined as clinically overt bleeding that is associated with: A fall in hemoglobin of 2 g/dL or more; A transfusion of ≥2 units of packed red blood cells or whole blood; Bleeding in a critical site: intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal; Death (fatal bleeding)	up to 58 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transient ischemic attack	Defined as new neurologic symptoms or deficit lasting less than 24 hours with no new infarction on neuroimaging (if available).	up to 58 months
Myocardial infarction	Defined as the detection of a significant rise/fall of Troponin in association with symptoms of ischemia, ECG changes, proof of ischemia on imaging or intracoronary thrombus at angiography. [Fourth definition of myocardial infarction; European Society of Cardiology (ESC) 2018]	up to 58 months
Death from cardiovascular causes	Cardiovascular deaths were classified as deaths due to: ischemic stroke, hemorrhagic stroke, systemic or pulmonary embolism, other cardiovascular (i.e., myocardial infarction, sudden death, heart failure) and unobserved deaths.	up to 58 months
Τhe composite of major and clinically relevant nonmajor bleeding	Clinically relevant nonmajor bleeding bleeding=bleeding that is clinically overt, that satisfies none of the additional criteria required for the event to be adjudicated as a major bleeding event, that led to either hospital admission for bleeding, physician-guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy.	up to 58 months
Τhe composite of stroke, systemic or pulmonary arterial thromboembolism and intracardiac thrombosis, transient ischemic attack, myocardial infarction, or cardiovascular death		up to 58 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
General quality of life	Assessed with questionnaire SF-36	Baseline
Apixaban persistence	The proportion of patients who were on apixaban at enrolment and continued receiving apixaban at the end of the study period.	up to 58 months
Apixaban adherence	Assessed by reviewing electronic pharmacy prescription data	up to 58 months

Collaborators and Investigators

• Sponsor: AHEPA University Hospital
• Collaborators: Onassis Cardiac Surgery Centre; Attikon Hospital; MITERA Children's Hospital
• Investigators: Study Chair: Georgios Giannakoulas, MD, PhD, Ahepa University Hospital

Publications and helpful links

General Publications

• Kartas A, Doundoulakis I, Ntiloudi D, Koutsakis A, Kosmidis D, Rampidis G, Apostolopoulou S, Frogoudaki A, Tzifa A, Avramidis D, Ntzoyvara O, Liori S, Mousiama T, Mouratoglou SA, Karvounis H, Giannakoulas G. Rationale and design of a prospective, observational, multicentre study on the safety and efficacy of apixaban for the prevention of thromboembolism in adults with congenital heart disease and atrial arrhythmias: the PROTECT-AR study. BMJ Open. 2020 Sep 22;10(9):e038012. doi: 10.1136/bmjopen-2020-038012.

Helpful Links

• CHALLENGE Registry

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): April 30, 2023
• Study Completion (Actual): May 30, 2023

Study Registration Dates

• First Submitted: February 23, 2019
• First Submitted That Met QC Criteria: February 23, 2019
• First Posted (Actual): February 26, 2019

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; NOAC; Congenital Heart Disease; Thromboembolism; Apixaban; Atrial arrhythmias
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Embolism and Thrombosis; Cardiovascular Abnormalities; Heart Diseases; Arrhythmias, Cardiac; Thromboembolism; Heart Defects, Congenital
• Other Study ID Numbers: PROTECT_AR_trial_01102018_v1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No