title: Evaluation of the Quality of Prognosis Studies in Systematic Reviews Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial Detection of atrial high-rate events by continuous Home Monitoring: clinical significance in the heart failure–cardiac resynchronization therapy population Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. The Relationship Between Daily Atrial Tachyarrhythmia Burden From Implantable Device Diagnostics and Stroke Risk: The TRENDS Study Atrial High Rate Episodes Detected by Pacemaker Diagnostics Predict Death and Stroke: Report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST) Potential value of automated daily screening of cardiac resynchronization therapy defibrillator diagnostics for prediction of major cardiovascular events: results from Home-CARE (Home Monitoring in Cardiac Resynchronization Therapy) study Probing oral anticoagulation in patients with atrial high rate episodes: Rationale and design of the Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH–AFNET 6) trial Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices. Performance of a New Leadless Implantable Cardiac Monitor in Detecting and Quantifying Atrial Fibrillation Results of the XPECT Trial Rationale and design of the Apixaban for the Reduction of Thrombo‐Embolism in Patients With Device‐Detected Sub‐Clinical Atrial Fibrillation (ARTESiA) trial Multicenter randomized study of anticoagulation guided by remote rhythm monitoring in patients with implantable cardioverter-defibrillator and CRT-D devices: Rationale, design, and clinical characteristics of the initially enrolled cohort The IMPACT study. Incidence of Previously Undiagnosed Atrial Fibrillation Using Insertable Cardiac Monitors in a High-Risk Population: The REVEAL AF Study
abstract: Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation ( AF ) . We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation . Methods and results Patients r and omized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ( ROCKET-AF ) trial ( n = 14 264 ) were grouped by baseline AF category : paroxysmal or persistent . Multivariable adjustment was performed to compare thrombo-embolic events , bleeding , and death between groups , in high-risk subgroups , and across treatment assignment ( rivaroxaban or warfarin ) . Of 14 062 patients , 11 548 ( 82 % ) had persistent AF and 2514 ( 18 % ) had paroxysmal AF . Patients with persistent AF were marginally older ( 73 vs. 72 , P = 0.03 ) , less likely female ( 39 vs. 45 % , P < 0.0001 ) , and more likely to have previously used vitamin K antagonists ( 64 vs. 56 % , P < 0.0001 ) compared with patients with paroxysmal AF . In patients r and omized to warfarin , time in therapeutic range was similar ( 58 vs. 57 % , P = 0.94 ) . Patients with persistent AF had higher adjusted rates of stroke or systemic embolism ( 2.18 vs. 1.73 events per 100-patient-years , P = 0.048 ) and all-cause mortality ( 4.78 vs. 3.52 , P = 0.006 ) . Rates of major bleeding were similar ( 3.55 vs. 3.31 , P = 0.77 ) . Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment ( rivaroxaban vs. warfarin , Pinteraction = 0.6 ) . Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation , those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF Aims Uncertainty exists over the importance of device-detected short- duration atrial arrhythmias . Continuous atrial diagnostics , through home monitoring ( HM ) technology ( BIOTRONIK , Berlin , Germany ) , provides a unique opportunity to assess frequency and quantity of atrial fibrillation ( AF ) episodes defined as atrial high-rate events ( AHRE ) . Methods and results Prospect i ve data from 560 heart failure ( HF ) patients ( age 67 ± 10 years , median ejection fraction 27 % ) patients with a cardiac resynchronization therapy ( CRT ) device capable of HM from two multi-centre studies were analysed . Atrial high-rate events burden was defined as the duration of mode switch in a 24-h period with atrial rates of > 180 beats for at least 1 % or total of 14 min per day . The primary endpoint was incidence of a thromboembolic ( TE ) event . Secondary endpoints were cardiovascular death , hospitalization because of AF , or worsening HF . Over a median 370-day follow-up AHRE occurred in 40 % of patients with 11 ( 2 % ) patients developing TE complications and mortality rate of 4.3 % ( 24 deaths , 16 with cardiovascular aetiology ) . Compared with patients without detected AHRE , patients with detected AHRE>3.8 h over a day were nine times more likely to develop TE complications ( P= 0.006 ) . The majority of patients ( 73 % ) did not show a temporal association with the detected atrial episode and their adverse event , with a mean interval of 46.7 ± 71.9 days ( range 0–194 ) before the TE complication . Conclusion In a high-risk cohort of HF patients , device-detected atrial arrhythmias are associated with an increased incidence of TE events . A cut-off point of 3.8 h over 24 h was associated with significant increase in the event rate . Routine assessment of AHRE should be considered with other data when assessing stroke risk and considering anti-coagulation initiation and should also prompt the optimization of cardioprotective HF therapy in CRT patients OBJECTIVE This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation ( AF ) . BACKGROUND Although intermittent AF is common , relatively little is known about the attendant risk of stroke . METHODS A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years . Independent risk factors for ischemic stroke were identified by multivariate analysis . RESULTS Patients with intermittent AF were , on average , younger ( 66 vs. 70 years , p < 0.001 ) , were more often women ( 37 % vs. 26 % p < 0.001 ) and less often had heart failure ( 11 % vs. 21 % , p < 0.001 ) than those with sustained AF . The annualized rate of ischemic stroke was similar for those with intermittent ( 3.2 % ) and sustained AF ( 3.3 % ) . In patients with intermittent AF , independent predictors of ischemic stroke were advancing age ( relative risk [ RR ] = 2.1 per decade , p < 0.001 ) , hypertension ( RR = 3.4 , p = 0.003 ) and prior stroke ( RR = 4.1 , p = 0.01 ) . Of those with intermittent AF predicted to be high risk ( 24 % ) , the observed stroke rate was 7.8 % per year ( 95 % confidence interval 4.5 to 14 ) . CONCLUSIONS In this large cohort of AF patients given aspirin , those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors . Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation . High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF Background —It is unknown if brief episodes of device-detected atrial fibrillation ( AF ) increase thromboembolic event ( TE ) risk . Methods and Results —TRENDS was a prospect i ve , observational study enrolling patients with ≥1 stroke risk factor ( heart failure , hypertension , age ≥65 years , diabetes , or prior TE ) receiving pacemakers or defibrillators that monitor atrial tachycardia (AT)/AF burden ( defined as the longest total AT/AF duration on any given day during the prior 30-day period ) . This time-varying exposure was up date d daily during follow-up and related to TE risk . Annualized TE rates were determined according to AT/AF burden subsets : zero , low ( < 5.5 hours [ median duration of subsets with nonzero burden ] ) , and high ( ≥5.5 hours ) . A multivariate Cox model provided hazard ratios including terms for stroke risk factors and time-varying AT/AF burden and antithrombotic therapy . Patients ( n=2486 ) had at least 30 days of device data for analysis . During a mean follow-up of 1.4 years , annualized TE risk ( including transient ischemic attacks ) was 1.1 % for zero , 1.1 % for low , and 2.4 % for high burden subsets of 30-day windows . Compared with zero burden , adjusted hazard ratios ( 95 % CIs ) in the low and high burden subsets were 0.98 ( 0.34 to 2.82 , P=0.97 ) and 2.20 ( 0.96 to 5.05 , P=0.06 ) , respectively . Conclusions —The TE rate was low compared with patients with traditional AF with similar risk profiles . The data suggest that TE risk is a quantitative function of AT/AF burden . AT/AF burden ≥5.5 hours on any of 30 prior days appeared to double TE risk . Additional studies are needed to more precisely investigate the relationship between stroke risk and AT/AF burden Background —Some current pacing systems can automatically detect and record atrial tachyarrhythmias that may be asymptomatic . We prospect ively studied a 312-patient ( pt ) subgroup of MOST ( MOde Selection Trial ) , a 2010-patient , 6-year r and omized trial of DDDR versus VVIR pacing in sinus node dysfunction ( SND ) . The purpose of the study was to correlate atrial high rate events ( AHREs ) detected by pacemaker diagnostics with clinical outcomes . Methods and Results —Pacemakers were programmed to log an AHRE when the atrial rate was > 220 bpm for 10 consecutive beats . Analysis was confined to patients with at least 1 AHRE duration exceeding 5 minutes . The 312 patients were median age 74 years , 55 % female , and 60 % had a history of SVT . 160 of 312 ( 51.3 % ) patients enrolled had at least 1 AHRE > 5 minutes duration over median follow-up of 27 months . Cox proportional hazards analysis assessed the relationship of AHREs with clinical events , adjusting for prognostic variables and baseline covariates . The presence of any AHRE was an independent predictor of the following : total mortality ( hazard ratio AHRE versus no AHRE and 95 % confidence intervals=2.48 [ 1.25 , 4.91 ] , P = 0.0092 ) ; death or nonfatal stroke ( 2.79 [ 1.51 , 5.15 ] , P = 0.0011 ) ; and atrial fibrillation ( 5.93 [ 2.88 , 12.2 ] , P = 0.0001 ) . There was no significant effect of pacing mode on the presence or absence of AHREs . Conclusions —AHRE detected by pacemakers in patients with SND identify patients that are more than twice as likely to die or have a stroke , and 6 times as likely to develop atrial fibrillation as similar patients without AHRE Aim To investigate whether diagnostic data from implanted cardiac resynchronization therapy defibrillators ( CRT-Ds ) retrieved automatically at 24 h intervals via a Home Monitoring function can enable dynamic prediction of cardiovascular hospitalization and death . Methods and results Three hundred and seventy-seven heart failure patients received CRT-Ds with Home Monitoring option .  Data on all deaths and hospitalizations due to cardiovascular reasons and Home Monitoring data were collected prospect ively during 1-year follow-up to develop a predictive algorithm with a predefined specificity of 99.5 % . Seven parameters were included in the algorithm : mean heart rate over 24 h , heart rate at rest , patient activity , frequency of ventricular extrasystoles , atrial – atrial intervals ( heart rate variability ) , right ventricular pacing impedance , and painless shock impedance . The algorithm was developed using a 25-day monitoring window ending 3 days before hospitalization or death . While the retrospective sensitivities of the individual parameters ranged from 23.6 to 50.0 % , the combination of all parameters was 65.4 % sensitive in detecting cardiovascular hospitalizations and deaths with 99.5 % specificity ( corresponding to 1.83 false-positive detections per patient-year of follow-up ) . The estimated relative risk of an event was 7.15-fold higher after a positive predictor finding than after a negative predictor finding . Conclusion We developed an automated algorithm for dynamic prediction of cardiovascular events in patients treated with CRT-D devices capable of daily transmission of their diagnostic data via Home Monitoring . This tool may increase patients ’ quality of life and reduce morbidity , mortality , and health economic burden , it now warrants prospect i ve studies . Clinical Trials.gov NCT00376116 Background Oral anticoagulation prevents ischemic strokes in patients with atrial fibrillation ( AF ) . Early detection of AF and subsequent initiation of oral anticoagulation help to prevent strokes in AF patients . Implanted cardiac pacemakers and defibrillators allow seamless detection of atrial high rate episodes ( AHRE ) , but the best antithrombotic therapy in patients with AHRE is not known . Rationale Stroke risk is higher in pacemaker patients with AHRE than in those without , but the available data also show that stroke risk in patients with AHRE is lower than in patients with AF . Furthermore , only a minority of patients with AHRE will develop AF , many strokes occur without a temporal relation to AHRE , and AHRE can reflect other arrhythmias than AF or artifacts . An adequately powered controlled trial of oral anticoagulation in patients with AHRE is needed . Design The Non – vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes ( NOAH – AFNET 6 ) trial tests whether oral anticoagulation with edoxaban is superior to prevent the primary efficacy outcome of stroke or cardiovascular death compared with aspirin or no antithrombotic therapy based on evidence ‐based indications . The primary safety outcome will be major bleeding . NOAH – AFNET 6 will r and omize 3,400 patients with AHRE , but without documented AF , aged ≥65 years with at least 1 other stroke risk factor , to oral anticoagulation therapy ( edoxaban ) or no anticoagulation . All patients will be followed until the end of this investigator‐driven , prospect i ve , parallel‐group , r and omized , event‐driven , double‐blind , multicenter phase IIIb trial . Patients will be censored when they develop AF and offered open‐label anticoagulation . The sponsor is the Atrial Fibrillation NETwork ( AFNET ) . The trial is supported by the DZHK ( German Centre for Cardiovascular Research ) , the BMBF ( German Ministry of Education and Research ) , and Daiichi Sankyo Europe . Conclusion NOAH – AFNET 6 will provide robust information on the effect of oral anticoagulation in patients with atrial high rate episodes detected by implanted devices . Graphical abstract Figure . No Caption available AIMS Atrial tachyarrhythmias ( ATs ) detected by implanted devices are often atrial fibrillation or flutter ( AF ) associated with stroke . We hypothesized that introduction and termination of anticoagulation based upon AT monitoring would reduce both stroke and bleeding . METHODS AND RESULTS We r and omized 2718 patients with dual-chamber and biventricular defibrillators to start and stop anticoagulation based on remote rhythm monitoring vs. usual office-based follow-up with anticoagulation determined by st and ard clinical criteria .  The primary analysis compared the composite endpoint of stroke , systemic embolism , and major bleeding with the two strategies . The trial was stopped after 2 years median follow-up based on futility of finding a difference in primary endpoints between groups . A total of 945 patients ( 34.8 % ) developed AT , 264 meeting study anticoagulation criteria . Adjudicated atrial electrograms confirmed AF in 91 % ; median time to initiate anticoagulation was 3 vs. 54 days in the intervention and control groups , respectively ( P < 0.001 ) . Primary events ( 2.4 vs. 2.3 per 100 patient-years ) did not differ between groups ( HR 1.06 ; 95 % CI 0.75 - 1.51 ; P = 0.732 ) . Major bleeding occurred at 1.6 vs. 1.2 per 100 patient-years ( HR 1.39 ; 95 % CI 0.89 - 2.17 ; P = 0.145 ) . In patients with AT , thromboembolism rates were 1.0 vs. 1.6 per 100 patient-years ( relative risk -35.3 % ; 95 % CI -70.8 to 35.3 % ; P = 0.251 ) . Although AT burden was associated with thromboembolism , there was no temporal relationship between AT and stroke . CONCLUSION In patients with implanted defibrillators , the strategy of early initiation and interruption of anticoagulation based on remotely detected AT did not prevent thromboembolism and bleeding . CLINICAL TRIAL REGISTRATION IMPACT Clinical Trials.gov identifier : NCT00559988 ( http:// clinical trials.gov/ct2/show/NCT00559988?term=NCT00559988&rank=1 ) Background —Current methods for detecting atrial fibrillation ( AF ) have limited diagnostic yield . Continuous monitoring with automatic arrhythmia detection and classification may improve detection of symptomatic and asymptomatic AF and subsequent patient treatment . The study purpose was to quantify the performance of the first implantable leadless cardiac monitor ( ICM ) with dedicated AF detection capabilities . Methods and Results — Patients ( n=247 ) with an implanted ICM ( Reveal XT , Medtronic Inc , Minneapolis , Minn ) who were likely to present with paroxysmal AF were selected . A special Holter device stored 46 hours of subcutaneously recorded ECG , ICM markers , and 2 surface ECG leads . The ICM  automatic arrhythmia classification was compared with the core laboratory classification of the surface ECG . Of the 206 analyzable Holter recordings collected , 76 ( 37 % ) contained at least 1 episode of core laboratory classified AF . The sensitivity , specificity , positive predictive value , and negative predictive value for identifying patients with any AF were 96.1 % , 85.4 % , 79.3 % , and 97.4 % , respectively . The AF burden measured with the ICM was very well correlated with the reference value derived from the Holter ( Pearson coefficient=0.97 ) . The overall accuracy of the ICM for detecting AF was 98.5 % . Conclusions —In this ICM validation study , the dedicated AF detection algorithm reliably detected the presence or absence of AF and the AF burden was accurately quantified . The ICM is a promising new diagnostic and monitoring tool for the clinician to treat AF patients independently of symptoms . Long-term studies are needed to evaluate the clinical benefits of the technology . Clinical Trial Registration — clinical trials.gov Identifier NCT00680927 Background Device‐detected sub clinical atrial fibrillation ( AF ) refers to infrequent , short‐lasting , asymptomatic AF that is detected only with long‐term continuous monitoring . Sub clinical AF is common and associated with an increased risk of stroke ; however , the risk of stroke with sub clinical AF is lower than for clinical AF , and very few patients with sub clinical AF alone have been included in large AF anticoagulation trials . The net benefit of anticoagulation in patients with sub clinical AF is unknown . Design ARTESiA is a prospect i ve , multicenter , double‐blind , r and omized controlled trial , recruiting patients with sub clinical AF detected by an implanted pacemaker , defibrillator , or cardiac monitor , and who have additional risk factors for stroke . Patients with clinical AF documented by surface electrocardiogram will be excluded from the study . Participants will be r and omized to receive either apixaban ( according to st and ard AF dosing ) or aspirin 81 mg daily . The primary outcome is the composite of stroke , transient ischemic attack with diffusion‐weighted magnetic resonance imaging evidence of cerebral infa rct ion , and systemic embolism . Approximately 4,000 patients will be enrolled from around 230 clinical sites , with an anticipated mean follow‐up of 36 months until 248 adjudicated primary outcome events have occurred . Summary ARTESiA will determine whether oral anticoagulation therapy with apixaban compared with aspirin reduces the risk of stroke or systemic embolism in patients with sub clinical AF and additional risk factors Atrial fibrillation and atrial flutter are common cardiac arrhythmias associated with an increased risk of stroke in patients with additional risk factors .  Anticoagulation ameliorates stroke risk , but because these arrhythmias may occur intermittently without symptoms , initiation of prophylactic therapy is often delayed until electrocardiographic documentation is obtained . The IMPACT study is a multicenter , r and omized trial of remote surveillance technology in patients with implanted dual-chamber cardiac resynchronization therapy defibrillator ( CRT-D ) devices design ed to test the hypothesis that initiation and withdrawal of oral anticoagulant therapy guided by continuous ambulatory monitoring of the atrial electrogram improve clinical outcomes by reducing the combined rate of stroke , systemic embolism , and major bleeding compared with conventional clinical management . For those in the intervention group , early detection of atrial high-rate episodes ( AHRE ) generates an automatic alert to initiate anticoagulation based on patient-specific stroke risk stratification . Subsequently , freedom from AHRE for predefined periods prompts withdrawal of anticoagulation to avoid bleeding . Patients in the control arm are managed conventionally , the anticoagulation decision prompted by incidental detection of atrial fibrillation or atrial flutter during routine clinical follow-up . The results will help define the clinical utility of wireless remote cardiac rhythm surveillance and help establish the critical threshold of AHRE burden warranting anticoagulant therapy in patients at risk of stroke . In this report , we describe the study design and baseline demographic and clinical features of the initial cohort ( 227 patients ) Importance In approximately 20 % of atrial fibrillation (AF)–related ischemic strokes , stroke is the first clinical manifestation of AF . Strategies are needed to identify and therapeutically address previously undetected AF . Objective To quantify the incidence of AF in patients at high risk for but without previously known AF using an insertable cardiac monitor .  Design , Setting , and Participants This prospect i ve , single-arm , multicenter study was conducted from November 2012 to January 2017 . Visits took place at 57 centers in the United States and Europe . Patients with a CHADS2 score of 3 or greater ( or 2 with at least 1 additional risk factor ) were enrolled . Approximately 90 % had nonspecific symptoms potentially compatible with AF , such as fatigue , dyspnea , and /or palpitations . Exposures Patients underwent monitoring with an insertable cardiac monitor for 18 to 30 months . Main Outcomes and Measures The primary end point was adjudicated AF lasting 6 or more minutes and was assessed at 18 months . Other analyses included detection rates at points from 30 days to 30 months and among CHADS2 score subgroups . Median time from insertion to detection and the percentage of patients subsequently prescribed oral anticoagulation therapy was also determined . Results A total of 446 patients were enrolled ; 233 ( 52.2 % ) were male , and the mean ( SD ) age was 71.5 ( 9.9 ) years . A total of 385 patients ( 86.3 % ) received an insertable cardiac monitor , met the primary analysis cohort definition , and were observed for a mean ( SD ) period of 22.5 ( 7.7 ) months . The detection rate of AF lasting 6 or more minutes at 18 months was 29.3 % . Detection rates at 30 days and 6 , 12 , 24 , and 30 months were 6.2 % , 20.4 % , 27.1 % , 33.6 % , and 40.0 % , respectively . At 18 months , AF incidence was similar among patients with CHADS2 scores of 2 ( 24.7 % ; 95 % CI , 17.3 - 31.4 ) , 3 ( 32.7 % ; 95 % CI , 23.8 - 40.7 ) , and 4 or greater ( 31.7 % ; 95 % CI , 22.0 - 40.3 ) ( P = .23 ) . Median ( interquartile ) time from device insertion to first AF episode detection was 123 ( 41 - 330 ) days . Of patients meeting the primary end point , 13 ( 10.2 % ) had 1 or more episodes lasting 24 hours or longer , and oral anticoagulation therapy was prescribed for 72 patients ( 56.3 % ) . Conclusions and Relevance The incidence of previously undiagnosed AF may be substantial in patients with risk factors for AF and stroke . Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days . Further trials regarding the value of detecting sub clinical AF and of prophylactic therapies are warranted . Trial Registration clinical trials.gov Identifier :
target: Conclusion Patients with an AHRE burden over 6 min have an increased risk for stroke .
background: Aims Atrial fibrillation ( AF ) patients have increased risk of stroke .
  In paroxysmal AF , the combination of duration and frequency of episodes defines AF burden .
  In patients with cardiac implantable electronic devices ( CIEDs ) , atrial high-rate episodes ( AHREs ) can be monitored continuously and are considered as a proxy for AF .
  This systematic review aims to determine the relationship between AF burden and risk of thrombo-embolic events ( TBEs ) .