Clinical trial NCT02036450: Atrial Fibrillation Detected by Continuous ECG Monitoring
Official title: Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Atrial Fibrillation
Stroke
Hypertension
Diabetes
Keywords: atrial fibrillation
cardiac arrhythmia
stroke
implantable loop recorder
bleeding
anticoagulation
hypertension
diabetes
heart failure
mortality
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Bispebjerg Hospital
name: Zealand University Hospital
name: Odense University Hospital
name: University of Southern Denmark
name: Aalborg University
First posted: 2014-01-15
Enrollment: 6000
Sex: ALL
Minimum age (years): 70
Maximum age (years): 90
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The LOOP study aims to determine whether screening for atrial fibrillation (AF) with implantable loop recorder and initiation of oral anticoagulation (OAC) if AF is detected will reduce the risk of stroke and systemic arterial embolism in patients with risk factors for stroke.

Detailed description: Background:

Ischemic stroke is an increasing health problem world-wide (Heidenreich PA, et al. Circulation 2011; PMID 21262990). At least 20% of ischemic strokes are attributable to atrial fibrillation (AF) (Marini C, et al. Stroke J Cereb Circ 2005; PMID 15879330). Another 30% are so-called cryptogenic, possibly related to undiagnosed AF (Brachmann J, et al. Circ Arrhythm Electrophysiol 2015; PMID 26763225). In approximately 30% of a general population of pacemaker or cardioverter defibrillator patients, previously unknown AF will be detected during the first 2-3 years after implantation (Healey JS, et al. N Engl J Med 2012; PMID 22236222; ASSERT). Although the majority of these AF episodes are short-lasting and asymptomatic, the ASSERT study found that such AF is associated with risk of stroke. Since this was published, screening for AF has received intensified attention by researchers and the industry, although available evidence does not yet support systematic mass screening.

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Aims:

The LOOP study will determine whether long-term continuous screening and initiation of OAC for AF episodes lasting ≥6 minutes will reduce the risk of stroke in patients with stroke risk factors.

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Methods:

Patients from the general population will receive a letter of invitation from one of four study centers located in 3 of Denmark's 5 administrative regions.

Eligible study participants must be ≥70 years old and have ≥1 of the following stroke risk factors; hypertension, diabetes, heart failure or previous stroke, while any history of AF or existing cardiac implantable electronic device are exclusion criteria.

A total of 6000 participants will be randomized 3:1 to control (n=4500) or to receive an implantable loop recorder with continuous remote monitoring (n=1500) and initiation of OAC if AF is detected.

The primary endpoint is time to first stroke or systemic arterial embolism. The trial is event-driven and planned to continue until 279 adjudicated primary events have occurred.

Sub-studies include AF characterization, health economic analyses, quality-of-life assessments, cognitive function assessments, and studies of risk markers from 12-lead ECG, genetics, cardiac and brain imaging, biochemistry, and more.

Eligibility criteria: Inclusion Criteria:

* Age 70-90 years, and
* Previously diagnosed with ≥1 of:

  * Diabetes mellitus (type 1 or type 2, with or without medical therapy)
  * Hypertension (with or without medical therapy)
  * Heart failure
  * Previous diagnosed stroke (previous transient ischemic attack is not considered an inclusion criterion)

Exclusion Criteria:

* History of atrial fibrillation or flutter irrespective of type
* Cardiac pacemaker or defibrillator (with or without re-synchronization therapy)
* Contraindication to oral anticoagulation therapy
* Anticoagulation therapy; vitamin K antagonists, direct oral anticoagulants, or (low-molecular) heparins. Therapy with platelet inhibitors such as acetyl-salicylic acid, clopidogrel, persantine is not considered an exclusion criterion
* Renal failure treated with permanent dialysis
* Uncorrected congenital heart disease, or severe valvular stenosis, obstructive cardiomyopathy, active myocarditis, or constrictive pericarditis.
* On a waiting list for major surgery (cardiac, thoracic or abdominal)
* Cardiac or thoracic surgery has been performed within 3 months from inclusion
* Any major organ transplant (e.g. lung, liver, heart, or kidney)
* Cytotoxic or cytostatic chemotherapy and/or radiation therapy for treatment of a malignancy within 6 months before randomization or clinical evidence of current malignancy with the following exceptions: Basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable, localized disease with a life expectancy of \> 2.5 years in the opinion of the investigator)
* Life-expectancy shorter than 6 months
* Known to be human immunodeficiency virus (HIV) positive with an expected survival of less than 5 years due to HIV infection
* Recent (within 3 months) history of alcohol or drug abuse based on self-reporting
* Any condition (e.g. psychiatric illness, dementia) or situation, that in the investigators opinion could put the subject at significant risk, confound the study results, or interfere significantly with the subject participation in the study
* Unwillingness to participate or patient does not understand Danish language

Primary outcomes:
measure: Time to adjudicated stroke or systemic arterial embolism
timeFrame: At the completion of the event-driven trial, expected 4 years
Secondary outcomes:
measure: Time to adjudicated ischemic stroke/transient ischemic attack/systemic arterial embolism
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to adjudicated stroke, or systemic arterial embolism, or cardiovascular death
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to adjudicated cardiovascular death
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to death by any cause
timeFrame: At the completion of the event-driven trial, expected 4 years
Other outcomes:
measure: Time to diagnosis of AF
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to initiation of OAC
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to adjudicated intracranial hemorrhage not classified as stroke
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to adjudicated hemorrhagic stroke
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Time to major bleeding as defined by the International Society on Thrombosis and Haemostasis criteria
timeFrame: At the completion of the event-driven trial, expected 4 years
measure: Presence of complications related to loop recorder implantation; infection, hematoma, or other complication related to device implantation requiring intervention
timeFrame: During implantable loop recorder monitoring, expected 3 years
measure: Change from baseline in quality of life
timeFrame: 3 years (from baseline to the at the fourth study visit)
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Jesper H Svendsen, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012 Jan 12;366(2):120-9. doi: 10.1056/NEJMoa1105575.
citation: Brachmann J, Morillo CA, Sanna T, Di Lazzaro V, Diener HC, Bernstein RA, Rymer M, Ziegler PD, Liu S, Passman RS. Uncovering Atrial Fibrillation Beyond Short-Term Monitoring in Cryptogenic Stroke Patients: Three-Year Results From the Cryptogenic Stroke and Underlying Atrial Fibrillation Trial. Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003333. doi: 10.1161/CIRCEP.115.003333.
citation: Marini C, De Santis F, Sacco S, Russo T, Olivieri L, Totaro R, Carolei A. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005 Jun;36(6):1115-9. doi: 10.1161/01.STR.0000166053.83476.4a. Epub 2005 May 5.
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citation: Diederichsen SZ, Frederiksen KS, Xing LY, Haugan KJ, Hojberg S, Brandes A, Graff C, Olesen MS, Krieger D, Kober L, Svendsen JH. Severity and Etiology of Incident Stroke in Patients Screened for Atrial Fibrillation vs Usual Care and the Impact of Prior Stroke: A Post Hoc Analysis of the LOOP Randomized Clinical Trial. JAMA Neurol. 2022 Oct 1;79(10):997-1004. doi: 10.1001/jamaneurol.2022.3031.
citation: Xing LY, Diederichsen SZ, Hojberg S, Krieger DW, Graff C, Olesen MS, Brandes A, Kober L, Haugan KJ, Svendsen JH. Systolic Blood Pressure and Effects of Screening for Atrial Fibrillation With Long-Term Continuous Monitoring (a LOOP Substudy). Hypertension. 2022 Sep;79(9):2081-2090. doi: 10.1161/HYPERTENSIONAHA.122.19333. Epub 2022 Jul 8.
citation: Bonnesen MP, Frodi DM, Haugan KJ, Kronborg C, Graff C, Hojberg S, Kober L, Krieger D, Brandes A, Svendsen JH, Diederichsen SZ. Day-to-day measurement of physical activity and risk of atrial fibrillation. Eur Heart J. 2021 Oct 7;42(38):3979-3988. doi: 10.1093/eurheartj/ehab597.
citation: Svendsen JH, Diederichsen SZ, Hojberg S, Krieger DW, Graff C, Kronborg C, Olesen MS, Nielsen JB, Holst AG, Brandes A, Haugan KJ, Kober L. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet. 2021 Oct 23;398(10310):1507-1516. doi: 10.1016/S0140-6736(21)01698-6. Epub 2021 Aug 29.
citation: Bertelsen L, Diederichsen SZ, Haugan KJ, Brandes A, Graff C, Krieger D, Kronborg C, Kober L, Peters DC, Olesen MS, Hojberg S, Vejlstrup N, Svendsen JH. Left Atrial Late Gadolinium Enhancement is Associated With Incident Atrial Fibrillation as Detected by Continuous Monitoring With Implantable Loop Recorders. JACC Cardiovasc Imaging. 2020 Aug;13(8):1690-1700. doi: 10.1016/j.jcmg.2020.03.024. Epub 2020 Jun 17.
citation: Diederichsen SZ, Haugan KJ, Kronborg C, Graff C, Hojberg S, Kober L, Krieger D, Holst AG, Nielsen JB, Brandes A, Svendsen JH. Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder. Circulation. 2020 May 12;141(19):1510-1522. doi: 10.1161/CIRCULATIONAHA.119.044407. Epub 2020 Mar 2.
citation: Diederichsen SZ, Haugan KJ, Brandes A, Lanng MB, Graff C, Krieger D, Kronborg C, Holst AG, Kober L, Hojberg S, Svendsen JH. Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders. J Am Coll Cardiol. 2019 Dec 3;74(22):2771-2781. doi: 10.1016/j.jacc.2019.09.050.
citation: Olsen FJ, Svendsen JH, Kober L, Hojberg S, Haugan K, Jensen JS, Biering-Sorensen T. Impact of transducer frequency setting on speckle tracking measures. Int J Cardiovasc Imaging. 2018 Mar;34(3):457-463. doi: 10.1007/s10554-017-1254-4. Epub 2017 Nov 3.
citation: Bertelsen L, Svendsen JH, Kober L, Haugan K, Hojberg S, Thomsen C, Vejlstrup N. Flow measurement at the aortic root - impact of location of through-plane phase contrast velocity mapping. J Cardiovasc Magn Reson. 2016 Sep 7;18(1):55. doi: 10.1186/s12968-016-0277-7.