
Statistical Challenges Related to Population Screening for AFChristine M. Albert, MD, MPHDirector, Center for Arrhythmia Prevention, Brigham and Women’s HospitalProfessor of Medicine, Harvard Medical School
Screening: AF Prevalence • Effectiveness of Screening • Sensitivity and Specificity of the Test • Prevalence of AF in the Population. . Relationship between Disease Prevalence and Positive and Negative Predictive Value • False Positives • Expense of monitoring • Exposure to risks of AOC without benefit Sensitivity 95% and Specificity 85%
SAFE Trial: Cluster Randomized Trial of Office -Based ECG Screening for Atrial Fibrillation Overall Yield: 0.6 % new AF Focused on “Men over 85” 4.2% AF Fitzmaurice et al. BMJ 2007l
Mass Screening for Atrial Fibrillation in 75 Year OldsThe STROKESTOP Study • Screened twice daily with a handheld device for 2 weeks • AF Defined as: Irregular rhythm lasting 30 secs, or 2 episodes of at least 10 seconds 1% of Unknown AF Diagnosed on Baseline ECG 12% • Add > 1 stroke risk factor to 75+: 7.4% have undetected AF. Svennberg E et al. Circulation 2015;131:2176-84 Engdahl J et al. Circulation 2013: 127:930-93
Characteristics of Patients with SCAF Detected Female sex, lower weight, and absence of vascular disease were significantly associated with no detection of AF. CHA2DS2-VASc was not associated with AF detection Svennberg E et al. Circulation 2015;131:2176-84
Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation Twice weekly iECGs over 12 months • The REHEARSE-AF Study • 1001 Patients • Age>65 • CHADS-VASc >2.0 19 versus 5 diagnosed with AF Log-rank P=0.004 (Mantel-Cox). 1.2% Cost per AF diagnosis of $10,780 Kaplan-Meier plot showing the estimated detection probabilities for atrial fibrillation (AF) in each study arm over the 52 weeks of the trial. Shaded areas represent 95% confidence regions. Halcox JPJ et al. Circulation 2017; 136:1784-1794
The mHealth Screening to Prevent Strokes (mSToPS)Trial Impact of Immediate Monitoring with a 2 week ECG-Patch Intention to Treat Results: Incidence of new AF cases: • AF Incidence 3.9% (53/1366) in the immediate monitoring group vs 0.9% (12/1293) in the delayed monitoring group • Absolute difference, 3.0% [95% CI,1.8%-4.1%]). Population: 2659 individuals Randomized: • Age 75 years or older • Male > 55 years or Female > 65 years with 1 or more comorbidities Intervention: • Randomized to Immediate (within 2 weeks) versus delayed monitoring (within 4 months) • 3476 Matched Control Group with no monitoring • 34.5% did not wear the patch Endpoint: • >30 seconds of AF or new AF diagnosis in Claims Data Steinhubl SR et al. JAMA 2018; 320:146-155
US Taskforce: Analytic Framework: Screening for Atrial Fibrillation With Electrocardiography Jonas DE et al. JAMA 2018; 320:485-498
Screening for Atrial Fibrillation with Electrocardiography Systematic Review for the US Preventive Services Task Force Inadequate Evidence to Support ECG Screening for AF Jonas DE et al. JAMA 2018; 320:485-498
ECG Screening for AF • Sample Calculation of NNS for AF With ECG to Prevent 1 Stroke • New AF found on initial ECG in 0.5% of screened population • NNS to diagnose 1 new case of AF, 1/0.005 = 200 people • Estimated absolute risk reduction from anticoagulation, 2% • Number needed to treat to prevent 1 stroke, 1/0.02 = 50 people • NNS to prevent 1 stroke, 200 x 50 = 10,000 people Mandrola J et al. JAMA Internal Medicine 2018; 178:1296-1298 Kinsinger LS et al. JAMA Internal Medicine 2017; 177:399-406
Stroke Stop: TwoWeek Monitor Screening for AF NNS to Prevent 1 Stroke in Patients over Age 75 Sample Calculation: • New AF found in 3.0% of screened population • NNS to diagnose 1 new case of AF, 1/0.03 = 33 people • Estimated absolute risk reduction from anticoagulation, 2% • Number needed to treat to prevent 1 stroke, 1/0.02 = 50 people • NNS to prevent 1 stroke, 33 x 50 = 1650 people • Svennberg E et al. Circulation 2015;131:2176-84
Stroke Stop:Two Week Monitor Screening for AF NNSto Prevent 1 Stroke in Patients over Age 75 with 1 Stroke Risk factor Sample Calculation: • New AF found in 7.4% of screened population • NNS to diagnose 1 new case of AF, 1/0.074 = 13 people • Estimated absolute risk reduction from anticoagulation, 2% • Number needed to treat to prevent 1 stroke, 1/0.02 = 50 people • NNS to prevent 1 stroke, 13 x 50 = 650 people Svennberg E et al. Circulation 2015;131:2176-84
Sensitivity and Specificity of Different Methods of Screening for Atrial Fibrillation Freedman B et al. Circulation 2017; 135:1851-1867 Paper #6: Table 4
Passive Detection of Atrial Fibrillation using Neural Network Analysis of a Commercially Available Smartwatch 51 patients in Health eHeart Study ECG Diagnosis 1617 patients in Health eHeart Study Self Report of Persistent AF C-Statistic 0.97 C-Statistic 0.72 Sensitivity 98.0% Specificity 90.2% Sensitivity 67.7% Specificity 67.6% Tue MP et al. JAMA Cardiol 2018; 3:409-416
Screening for Atrial Fibrillation: False Positives: Importance of Prevalence Sample Calculation of Misdiagnosis at ECG Specificity of 95% • Screening Specificity, 95% • Screened population, 1,000,000 people • AF prevalence, 3% • Number with AF, 0.03 x 1,000,000 = 30,000 people • Number without AF, 1,000,000 – 30,000 = 970,000 people • True negative, 0.95 x 970,000 = 884,450 people reassured they have no AF • False positive, 0.05 x 970,000 = 48,500 people falsely diagnosed with AF Mandrola J et al. JAMA Internal Medicine 2018; 178:1296-1298 Paper #2: Box 2
Screening for Atrial Fibrillation: False Positives: Importance of Prevalence Sample Calculation of Misdiagnosis at ECG Specificity of 98% • Screening Specificity, 98% • Screened population, 1,000,000 people • AF prevalence, 10% • Number with AF, 0.10 x 1,000,000 = 100,000 people • Number without AF, 1,000,000 – 100,000 = 900,000 people • True negative, 0.98 x 900,000 = 882,000 people reassured they have no AF • False positive, 0.02 x 900,000 = 18,000 people falsely diagnosed with AF Modified from Mandrola J et al. JAMA Internal Medicine 2018; 178:1296-1298 Paper #2: Box 2
Subclinical Atrial Fibrillation detected on Continuous Monitoring (PPM or ILR) REVEAL-AF ASSERT-I ASSERT-II Van Gelder IC et al. Eur Heart J 2017; 38:1339-1344 Healey JS et al. Circulation 2017; 136:1276-1283 Reiffel JA et al. JAMA Cardiol 2017; 2:1120-1127
What are the implications of detecting short durations of AF?
ASSERT: Ischemic Stroke/Systemic Embolism According to Time-Dependent Durations of AF Van Gelder IC et al. European Heart Journal 2017; 38:1339-1344
Uncertainty of AbsoluteStroke Rate in Population (events per 100 person-years) Resultant Variability in NNS Quinn GR et al. Circulation 2017; 135:208-219
Reported Stroke Rates Stratified by CHA2DS2-VASc Scores of 0, 1, and 2 According to Different Cohorts *<1% annual stroke rate, low or no expected net clinical benefit from anticoagulation. †1% to 2% annual stroke rate, indeterminate expected net clinical benefit from anticoagulation. ‡>2% annual stroke rate, high expected net clinical benefit from anticoagulation. ACTIVE indicates Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events; AF, atrial fibrillation; ATRIA, AnTicoagulation and Risk Factors In Atrial Fibrillation; AVERROES, Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; J-Rhythm, Japanese Rhythm Management Trial for Atrial Fibrillation; and NHIRD, National Health Insurance Research Database. Quinn GR et al. Circulation 2017; 135:208-219
Statistical Challenges for Population Screening for AF Summary • Positive Predictive Value (PPV) of AF Screening in the population is dependent on the prevalence of undetected AF in the population. • Screening higher risk individuals will improve the PPV and the number needed to screen (NNS) to prevent one stroke. • The NNS to prevent one stroke also depends on the absolute incidence of stroke in the population and the benefit of anticoagulants in that population. • Even in high risk populations using high specificity measures, thepositive predictive value will still be limited resulting in potentially large numbers of false positives. • Continuous monitoring suggests the prevalence of brief episodes of AF may be as high as 30-40% in high risk populations, but the stroke risk and response to anticoagulation is unknown. • Randomized trials are required before adopting systematic AF screening.