Rationale: Adult patients with congenital heart disease (CHD) with atrial tachyarrhythmias need to be anticoagulated. It is not known whether non-vitamin K antagonist oral anticoagulants (NOAC) in this patient group are efficient and safe.
Aim: The purpose of the NOTE registry is to evaluate the efficacy and safety of NOACs for thromboembolic prevention in atrial tachyarrhythmia's in adult patients with CHD.
Methods: In this multicenter prospective registry adult CHD patients with atrial tachyarrhythmia's on NOACs will be followed for a period of two years.
Patient population: Registry population consists of CHD patients with tachyarrhythmia's, defined as atrial fibrillation (AF) or atrial tachycardia's (AT), including atrial flutter, on NOACs. Patients with new-onset atrial tachyarrhythmia's who are eligible for NOACs, will be started directly on a NOAC. Patients on vitamin K antagonists (VKA) can be switched actively to NOACs during outpatient clinic visits, in case of agreement of both patient and physician. The switch can be initiated for various reasons, including bleeding complications on VKA, unstable INR measurements, and user friendliness. Eligibility for NOAC use is defined conform clinical practice, i.e. a patient with nonvalvular atrial tachyarrhythmia's, but without a mechanical heart valve, significantly elevated risk of bleeding, impaired renal function, or pregnancy.
Registration process: Patients will be included in the registry at start of NOAC treatment. Exclusion criteria are an expected survival of less than two years and an additional indication for anticoagulation besides atrial tachyarrhythmia's. At baseline general patient characteristics will be registered. Standard echocardiography and laboratory assessments for follow-up in adult CHD patients will be recorded during the registration period. Quality of life and therapy adherence will be assessed with questionnaires. Registry follow-up will be warranted by telephone contact or during outpatient clinic visits. At each follow-up point the occurrence of pre-defined events will be recorded. A detailed description of each variable used by the registry is provided in the protocol. Anonymized data will be collected at each investigational site and entered in a central database at the main investigational site (Academic Medical Center, Amsterdam, The Netherlands).
Quality assurance: At all investigational sites the investigators are trained to the registry protocol, case report forms and registry procedures prior to enrolling subjects. The assigned monitoring investigator at the main site, will assure regular site monitoring and auditing at all investigational sites. Source data will be verified by comparing the data to medical records and case report forms in the form of a random sample. To avoid or minimize bias, an independent clinical events committee at the main investigational site, consisting of independent physicians, assesses all primary endpoint clinical events. Intermediate evaluation will take place one year after enrollment of the last patient and consists of a verification of recorded data, assessment of accuracy of patient follow-up and primary endpoint analysis.
Drop-outs: Patients who quite NOACs or are lost to follow-up are considered drop-outs. Those who (temporarily) quite NOACs will be followed until the total follow-up of 2 years will be completed. The events that occur in the period off-NOAC will not be included in the analyses. A clear description of the reason of NOAC arrest or interruption and possible alternative anticoagulant therapy is assessed.
Endpoints: Primary efficacy endpoints are defined as thromboembolism, i.e. the composite of ischemic stroke, systemic and pulmonary embolism and intracardiac thrombosis, and as the composite of stroke and systemic embolism. Primary safety endpoint is defined as major bleeding according to the ISTH criteria. Secondary endpoints include each thromboembolic or bleeding event analyzed separately, all-cause mortality, therapy adherence, quality of life, risk assessment of stroke and evaluation of natural history of atrial tachyarrhythmia in adult CHD patients.
Sample size: By using estimates of event rates in the described patient population (thromboembolism event rate of 1.4% per year, mainly on VKA; unpublished data) and a relative risk reduction of 0.81 for stroke or systemic embolism on NOACs compared to VKA \[Ruff et al, Lancet 2013\], a sample size of 300 patients followed for two years is necessary to demonstrate the safety of NOACs for thromboembolic prevention with a safety margin of 2.7% thromboembolic events per year.
Statistical analysis: Endpoint assessment will be performed with a per protocol analysis, and demonstrated as Kaplan Meyer (KM) estimates of event free survival and event rates per year. The results will be compared with KM estimates and event rates from a historical similar cohort on VKA in a non-inferiority assay. Drop-outs (see below) will be censored at time of drop-out in time-to-event analyses, and included for event-rate analyses up to time of drop-out. No adjustment or imputation of missing data will be performed and all available data will be presented.
