Final Research Plan

Atrial Fibrillation: Screening

July 16, 2020

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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This figure is the proposed analytic framework depicting the six key questions about screening for atrial fibrillation and the research approach that will guide the evidence review outlined in this research plan. In general, the figure illustrates the overarching question (key question 1): whether screening asymptomatic adults age 50 years or older with selected tests for atrial fibrillation leads to improved health outcomes. Health outcomes include all-cause mortality, stroke, stroke-related morbidity and mortality, and quality of life. The framework starts on the left with the patient population of interest: asymptomatic adults age 50 years or older. Moving from left to right, the figure depicts the ability of screening with selected tests to diagnose atrial fibrillation compared to usual care (key question 2), the diagnostic accuracy of selected screening tests (key question 3), and the potential harms of screening with selected tests (key question 4). For older adults with screen-detected atrial fibrillation, whether treatment with anticoagulation improves health outcomes (key question 5) or results in harms (key question 6) completes the framework on the right.

  1. Does screening for atrial fibrillation (AF) with selected tests improve health outcomes (i.e., reduce all-cause mortality, reduce morbidity or mortality from stroke, or improve quality of life) in asymptomatic older adults?
    1. Does improvement in health outcomes vary for subgroups defined by stroke risk (e.g., based on CHA2DS2-VASc score), age, sex, or race/ethnicity?
  2. Does systematic screening for AF with selected tests identify older adults with previously undiagnosed AF more effectively than usual care?
  3. What is the accuracy of selected screening tests for diagnosing AF in asymptomatic adults?
  4. What are the harms of screening for AF with selected tests in older adults?
    1. Do the harms of screening vary for subgroups defined by stroke risk (e.g., based on CHA2DS2-VASc score), age, sex, or race/ethnicity?
  5. What are the benefits of anticoagulation therapy on health outcomes in asymptomatic, screen-detected older adults with AF?
    1. Do the benefits of anticoagulation vary for subgroups defined by stroke or bleeding risk (e.g., based on CHA2DS2-VASc or HAS-BLED score), age, sex, race/ethnicity, or AF burden (i.e., number of episodes, duration of episodes, and proportion of time spent in AF)?
  6. What are the harms of anticoagulation therapy in asymptomatic, screen-detected older adults with AF?
    1. Do the harms of anticoagulation therapy vary for subgroups defined by stroke risk or bleeding risk (e.g., based on CHA2DS2-VASc or HAS-BLED score), age, sex, race/ethnicity, or AF burden?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What is the prevalence of previously unrecognized or undiagnosed AF in unselected or explicitly asymptomatic adults? Does the prevalence vary by age, primary care vs. community setting, method of diagnosis (e.g., single electrocardiogram vs. ambulatory electrocardiography monitoring), sex, or race/ethnicity?
  2. What is the stroke risk for the following populations?
    • Asymptomatic older adults with previously unrecognized or undiagnosed AF
    • Older adults with paroxysmal vs. persistent AF
    • Older adults with paroxysmal AF who have a lower vs. higher AF burden

The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions.

  Include Exclude
Condition definition AF (paroxysmal or persistent) Other cardiac arrhythmias, non-arrhythmia–related cardiovascular disease (e.g., coronary heart disease, hypertension). Studies reporting atrial flutter will not be excluded as long as the focus is on AF.
Populations KQs 1, 2, 4: Unselected or explicitly asymptomatic older adults (age ≥50 years) without known AF; older adults selected for increased risk of nonvalvular AF (e.g., those with obesity, smoking, alcohol use, hypertension); studies of mixed populations of asymptomatic and symptomatic persons are eligible if results are reported separately for asymptomatic persons or less than 10% of the sample is symptomatic.

KQ 3: Unselected or explicitly asymptomatic older adults without known AF; mixed populations of asymptomatic and symptomatic persons with and without AF or that include younger adults are eligible if results are reported separately for asymptomatic persons, those without known AF, or the older population, or less than 50% of the population is symptomatic, has known AF, or is younger than age 50 years.

KQs 5, 6: Older adults with AF. To approximate screen-detected persons with AF, we will aim to stratify analyses based on whether participants are asymptomatic/screen-detected vs. symptomatic (if possible); however, knowing that most studies enroll mixed populations or do not clearly enroll screen-detected or asymptomatic populations, we will not exclude studies based on whether participants were screen detected. To approximate “screening” vs. “disease management” populations, we will limit our analyses to studies of individuals not selected because of known heart disease, heart failure, and/or previous stroke or transient ischemic attack.

 KQs 1–4: Symptomatic adults; adults with known AF; children, adolescents, and adults younger than age 50 years; adults at high(est) risk for AF (including but not limited to those with mitral valve disease or repair/replacement); and adults with history of stroke or transient ischemic attack

KQs 5, 6: Adults needing antiplatelet or anticoagulation medications for conditions other than AF; adults with AF and known heart disease, heart failure, and/or previous stroke or transient ischemic attack. Studies that exclusively enroll these populations will be excluded.
Screening test or intervention KQs 1, 2, 4: Systematic screening using ECG or other technologic approach. Eligible approaches include:
  • One-time 12-lead or less than 12-lead ECG
  • Intermittent or continuous ambulatory ECG such as Holter monitoring, event loop recorders, or patch monitors
  • One-time intermittent or continuous ambulatory photoplethysmography that includes an AF detection algorithm
  • One-time, intermittent, or continuous oscillometric blood pressure measurement devices that include an AF detection algorithm
  • Commercially available technologies directed to consumers (e.g., smartwatches, smartphone apps, heart rate or rhythm monitors)

KQ 3: Eligible index tests include:

  • One-time 12-lead or less than 12-lead ECG interpreted by primary care provider, with or without ECG machine algorithm interpretation
  • Intermittent ambulatory ECG such as event loop recorders or patch monitors
  • One-time or intermittent ambulatory photoplethysmography that includes an AF detection algorithm
  • One-time or ambulatory oscillometric blood pressure measurement devices with an AF detection algorithm
  • Two-stage screening tests involving a single initial test followed by a second test
KQs 5, 6: Medical treatment with anticoagulants (e.g., apixaban, dabigatran, edoxaban, rivaroxaban, warfarin). Results will be stratified by type of medication.		 KQs 1, 2, 4: Physical examination (including one-time in-office pulse palpation or heart auscultation); one-time in-office manual or automated pulse, blood pressure measurement, or pulse oximetry; two-stage approach in which a physical examination component or vital sign measurement is the initial test and only persons with irregular pulse or vital sign receive ECG

KQ 3: Same as excluded tests for KQs 1, 2, and 4 plus ECG (any number of leads) interpreted by a cardiologist*; continuous ambulatory ECG monitoring*; and cardiac monitoring with an implantable device

KQs 5, 6: Nonpharmacologic treatment to prevent stroke (e.g., implantable devices), treatment or management of AF for reasons other than prevention of stroke (e.g., rate or rhythm control, cardioversion, ablation), antiplatelet therapy, and combinations of antiplatelet and anticoagulation treatment (e.g., aspirin plus warfarin)
Comparisons KQs 1, 2, 4: No screening, nonsystematic screening, or usual care (which may include pulse palpation, single manual or automated blood pressure measurement, or cardiac auscultation during a physical examination)

KQ 3: For persistent AF, single 12-lead ECG interpreted by one or more cardiologists; for paroxysmal AF, continuous ambulatory ECG monitoring interpreted by one or more cardiologists and implantable cardiac monitor interpreted by one or more cardiologists. Interpretation of ECG can be with or without a device-embedded AF detection algorithm.

KQs 5, 6: Placebo, no treatment

 KQs 1, 2, 4: No comparison, nonconcordant historical control

KQ 3: No reference standard, reference standard other than 12-lead ECG, continuous ambulatory ECG monitoring, or implantable cardiac monitor all interpreted by one or more cardiologists with or without a device-embedded AF detection algorithm

KQs 5, 6: Active treatment (i.e., other anticoagulation medications or nonpharmacologic treatment)
Outcomes KQ 1: All-cause mortality, stroke, stroke-related morbidity or mortality, and quality of life

KQ 2: Comparative diagnostic yield (i.e., number of persons diagnosed with AF in one group vs. another [unscreened/nonsystematically screened] group)

KQ 3: Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, true positives, true negatives, false positives, false negatives

KQ 4: Anxiety, labeling, harms of subsequent procedures or interventions initiated as a result of screening (e.g., subsequent ablation with complications), frequency of findings other than AF

KQ 5: All-cause mortality, cardioembolic stroke, cardioembolic stroke–related morbidity or mortality, and quality of life

KQ 6: Any harms requiring unexpected or unwanted medical attention (e.g., hemorrhagic stroke, major bleeding, allergic reaction)

 KQs 4, 6: Nonserious events (e.g., bleeding not requiring or resulting in medical attention)
Study designs KQs 1, 2, 4–6: RCTs and controlled clinical trials

KQ 3: Diagnostic test accuracy studies or systematic reviews of diagnostic test accuracy studies

KQs 4: Large prospective cohort studies are also eligible

KQ 5: Systematic reviews of relevant trials are also eligible

KQ 6: Systematic reviews of relevant trials and large prospective cohort studies are also eligible

 All other designs, narrative reviews, case reports, case series, editorials, letters, cross-sectional studies, case-control studies, small prospective cohort studies, and retrospective cohort studies
Setting KQs 1–4: Studies performed in primary care or primary care–referable settings, community settings

KQs 5, 6: Studies performed in primary care or specialty settings

 KQs 1–4: Studies performed in specialty settings (including the emergency department), studies of patients undergoing preoperative evaluation, and inpatient settings

KQs 5, 6: Studies conducted primarily in inpatient settings
Country Studies conducted in countries categorized as “Very High” on the 2018 Human Development Index (as defined by the United Nations Development Programme) Studies conducted in countries that are not categorized as “Very High” on the 2018 Human Development Index
Language English Non-English
Study quality Good or fair Poor (according to design-specific USPSTF criteria)

* 12-lead ECG and continuous ambulatory ECG interpreted by a cardiologist and implantable cardiac monitoring are excluded from KQ 3 (diagnostic accuracy) because these tests are considered the reference standard. Single-lead ECG interpreted by a cardiologist is not eligible because this review focuses on accuracy of conducting/interpreting tests in a primary care setting.

Abbreviations: AF=atrial fibrillation; ECG=electrocardiography; KQ=key question; RCT=randomized, controlled trial; USPSTF=U.S. Preventive Services Task Force.

The draft Research Plan was posted on the USPSTF website for public comment from March 26, 2020, to April 22, 2020. Several comments asked for additional clarification about the included population and requested additional subgroups. In response, the USPSTF added language to clarify the populations of interest and subgroups, specifically the age of eligible populations (which was decreased to age 50 years). Several comments requested clarifications and offered suggestions related to the interventions or comparators specified. In response the USPSTF provided additional detail to specify eligible index and reference tests and removed “with electrocardiography” from the title, analytic framework, and key questions to reflect the use of technologies other than electrocardiography for screening. One comment asked for clarification regarding the inclusion of placebo comparators and exclusion of active comparators for the key questions related to benefits and harms of anticoagulation for stroke prevention. The USPSTF considers comparative effectiveness to be outside of its scope. The applicability of evidence from existing placebo-controlled trials to screen-detected populations is uncertain; thus, this remains an important part of the analytic framework for this review.