The LOOP study aims to clarify whether stroke and peripheral emboli can be prevented by monitoring the heart rhythm with a small device (called a loop recorder). The recorder which is placed under the skin on the front of the chest wall allows monitoring of the heart rhythm 24-hours a day 7 days a week.
The study has 6,000 participants with risk factors for stroke (age >70 years, and at least one of the diseases: diabetes, hypertension, heart failure or previous stroke) but without a history of atrial fibrillation, of which 1,500 will have a loop recorder implanted and 4,500 will be included in a control group. Participants are randomised to receive a loop recorder or not (control).
If a participant has atrial fibrillation of more than 6 min duration the study participant will start oral anticoagulation therapy according to local guidelines.
Stroke is a major health problem, which affects approximately 16,000 people annually in Denmark, causing severe and burdensome consequences for its victims, who suffer a significant loss in quality of life (QOL), and their families. Stroke is often caused by atrial fibrillation (AF), which is the most common type of cardiac arrhythmia. Effective management of AF with anticoagulation therapy is available and may have considerable benefits for patients as well as society. Difficult to detect, however, asymptomatic AF is usually only diagnosed by chance. Recently developed technology (implantable loop recorder; ILR) allows continuous long-term electrocardiography (ECG) monitoring and may constitute a substantial improvement in AF diagnosis.
The primary objective of this study is to determine, whether patients with increased risk of stroke have a high occurrence of AF without symptoms when studied by continuous ECG monitoring using an ILR and whether the risk of stroke and peripheral emboli can be reduced by initiating anticoagulation therapy according to pre-specified local study guidelines;
a) Whether analysis of ECG intervals obtained from a single ECG lead (from the ILR ) and from conventional ECG can predict future development of AF; and b) Whether the use of an expensive monitor technology - such as an ILR - for the diagnosis of AF will be cost effective in a health economics analysis due to a reduction in the number of strokes.
Randomized, un-blinded, controlled parallel two group trial.
Primary endpoint: Strokes and peripheral embolic episodes. Secondary: AF burden, major bleeding complications, death or acute (non-elective) hospitalisation due to cardiac reasons or complications, health economy, QOL, presence of brain infarcts and white matter hyper-intensity on MRI, safety aspects of device implants, inflammation markers and AF, genetic prediction of stroke, cardiac fibrosis on MRI, electrocardiographic markers to predict AF and stroke.
In total 6,000 subjects will participate: 1,500 randomised to receive an implantable loop recorder (ILR group) and 4,500 randomised to receive standard care (control group).
Summary of Subject Eligibility Criteria:
Subjects will be 70 years of age or older and will have at least one of the following diseases: hypertension, diabetes, heart failure or previous stroke (and biologically a candidate for OAC).
Patients randomised to the ILR group will receive the monitoring device and if AF is detected anticoagulation therapy will be given according to study guidelines.
Patients will be treated according to standard care.
The study comprises a screening period of up to 12-18 months followed by at treatment phase of a minimum of 36 months. The total study duration will therefore be approximately 5 years.
Screening and Randomisation:
Treatment: After randomisation patients allocated to the ILR group should receive the implantation as fast as possible, and preferably within 4 weeks.
The population is expected to have a stroke risk of 0.7%/year if AF is not present and 2%/year if AF is present. Approximately 20% are expected to have AF during monitoring for a period of more than two years, which is a conservative estimate since 10% in the ASSERT study cohort (pacemaker patients over the age of 65 with hypertension but without a history of AF) had AF in the course of 3 months ECG monitoring. As a result, there will be approximately four non-AF patients (controls) per experimental subject (AF). We expect to have an accrual interval of two years and additional follow-up after the accrual interval of 2 years. The population will consist of patients at risk of developing stroke due to AF and patients at risk of developing stroke unrelated to AF. The AF-related strokes are expected to be reduced by oral anticoagulation therapy (hazard ratio 0.2), while strokes unrelated to AF will not be influenced by this. Thus, the overall hazard ratio is expected to be 0.65 (35% reduction of stroke in the ILR group). With a power of 80% and a type I error of 5% we need 584 patients in the ILR group. We have increased the sample size to 1.500 patients in the ILR group to increase the possibility to reach secondary endpoints. If the event rate is lower than expected follow-up can be increased. With a follow-up of 3 years, the total number of strokes is expected to be 230 adjudicated strokes and the study is expected to continue until this number of events has been reached.
Primary Endpoint Analysis:
The principal analysis for the primary endpoint (time to one of the events in the combined endpoint) will employ the intent-to-threat principle and use a survival analysis. For each randomised group, Kaplan-Meier curves will be estimated, graphically displayed and compared using a logrank test. A co-variate adjusted analysis of the combined primary endpoint using a Cox proportional regression model will be performed as a supportive analysis. The hazard ratios and the corresponding 95% confidence intervals will be estimated. Subjects completing the study and not reaching the composite endpoint will be censored.
Secondary Endpoint Analysis:
All time-to-event secondary endpoints will be analysed similarly to the primary endpoint.
Hazard rates have been estimated from previous studies, including the ASSERT study. Assuming 12-18 months recruitment period and 36 months follow-up period and a randomisation ratio of one active vs. 9 controls (where active subjects will receive an ILR and subsequent anticoagulation therapy if subclinical AF is detected) a total of 584 subjects randomised to ILR group will provide a power of 80% and a type I error of 5% we need 584 patients in the ILR group. By increasing the number of study participants in the ILR group we expect to reach statistical power to evaluate secondary endpoints. If the event rate is lower than expected follow-up can be increased. With a follow-up of 3 years, approximately 20 stroke patients in the ILR group are needed. The total number of strokes is expected to be 230 and the study is expected to continue until this number of events are reached.
An event adjudication committee will classify endpoint events throughout the study.
Research grants have been obtained from the Danish National Foundation for Strategic Research (DKK 15.6 mio), the Research Foundation for the Capital Region of Denmark (DKK 2.0 mio) and the Danish Heart Foundation (DKK 150.000). Medtronic (manufacturer of the ILRs will donate an unrestricted research grant to the study covering costs related to 900 ILRs (which has a value of DKK 5.4 mio (reduced price) or DKK 22.5 mio (ordinary list price)) and a grant to cover salary for research nurses at the hospitals (DKK 1.9 mio).
Additional research grants will be applied for from private and public research foundations as well as from industry.
- LOOP recorder (Medtronic LINQ device) Device
Intervention Desc: A LOOP recorder will be implanted in a 1:3 randomization ARM 1: Kind: Experimental Label: ILR group Description: A LOOP recorder will be implanted. The device sampled arrhythmia information is transmitted to a core facility and evaluated. Data are sent automatically. When AF with a duration of 6 min or more is detected the participant will be advised to start oral anticoagulation therapy according to local preference.
- Allocation: Randomized
- Masking: Open Label
- Purpose: Treatment
- Endpoint: Safety/Efficacy Study
- Intervention: Parallel Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Time to stroke or peripheral embolic episode||3 years of follow-up (FU)||No|
|Secondary||Major bleeding complications||3 years of FU||No|
|Secondary||death||3 years of FU||No|
|Secondary||cerebral haemorrhage and Transitory Ischaemic Attacks (TIA)||3 years of FU||No|
|Secondary||Time to AF, AF burden, and other arrhythmia (bradyarrhythmia and ventricular arrhythmia),||3 years of FU||No|
|Secondary||Quality of Life (QOL)||3 years of FU||No|
|Secondary||Presence of brain infarcts and white matter hyperintensity on Magnetic Resonance Imaging (MRI; semiquantitative evaluation),||3 years of FU||No|
|Secondary||Health economic costs||3 years of FU||No|
|Secondary||ECG markers ability of predicting AF||3 years of FU||No|
|Secondary||Acute hospitalisation||3 years of FU||No|
|Secondary||Composite endpoint of time to stroke or peripheral embolic episode or death||3 years of FU||No|