Heart Failure Events After Long-term Continuous Screening for Atrial Fibrillation: Results From the Randomized LOOP Study.

BACKGROUND: Mounting evidence indicates that even device-detected subclinical atrial fibrillation is associated with a higher risk of heart failure (HF). However, the potential impact of atrial fibrillation screening on HF remains unknown. METHODS: The LOOP Study (Atrial Fibrillation detected by Continuous ECG Monitoring using Implantable Loop Recorder to prevent Stroke in High-risk Individuals) evaluated the effects of atrial fibrillation screening on stroke prevention using an implantable loop recorder (ILR) versus usual care in elderly individuals with additional stroke risk factors. In this secondary analysis, we explored the following HF end points: (1) HF event or cardiovascular death; (2) HF event; (3) event with HF with reduced ejection fraction (HFrEF); and (4) HFrEF event or cardiovascular death. Outcomes were assessed in a Cox model both as time-to-first events and as total (first and recurrent) events analyzed using the Andersen-and-Gill method. RESULTS: Of 6004 participants (mean age 74.7 and 52.7% men), 1501 were randomized to ILR screening and 4503 to the control group. In total, 77 (5.1%) in the ILR group versus 295 (6.6%) in the control group experienced the primary outcome of an HF event or cardiovascular death. Compared with usual care, ILR screening was associated with a nonsignificant reduction in the primary outcome for the time-to-first event analysis (hazard ratio, 0.78 [95% CI, 0.61-1.01]) and the total event analysis (hazard ratio, 0.77 [95% CI, 0.59-1.01]). Similar results were obtained for the HF event. A significant risk reduction in total events was observed in the ILR group for the composite of HFrEF event or cardiovascular death and for HFrEF event (hazard ratio, 0.74 [95% CI, 0.56-0.98] and 0.65 [95% CI, 0.44-0.97], respectively). CONCLUSIONS: In an elderly population with stroke risk factors, ILR screening for atrial fibrillation tended to be associated with a lower rate of total HF events and cardiovascular death, particularly those related to HFrEF. These findings should be considered hypothesis-generating and warrant further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450.

The ABC-Stroke Risk Score and Effects of Atrial Fibrillation Screening on Stroke Prevention: Results From the Randomized LOOP Study.

BACKGROUND: The ABC-stroke score is a risk scheme for prediction of stroke or systemic embolism (SE) in atrial fibrillation (AF). This study sought to examine whether the score could be useful in predicting stroke in AF-naïve individuals and risk stratifying for AF screening. METHODS AND RESULTS: The LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals) study randomized 6004 AF-naïve individuals aged 70 to 90 years with stroke risk factors to either screening with an implantable loop recorder and anticoagulation upon detection of new-onset AF episodes ≥6 minutes, or usual care. A total of 5781 participants had available ABC-stroke score at baseline and were included in this secondary analysis: 4170 (72.1%) with an estimated stroke/SE risk ≤1%/year versus 1611 (27.9%) with an estimated stroke/SE risk >1%/year. Having an annual ABC-stroke risk >1% was associated with stroke/SE, stroke/SE/cardiovascular death, and all-cause death (hazard ratio, 1.82 [95% CI, 1.44-2.21], 2.17 [95% CI, 1.80-2.62], and 2.19 [95% CI, 1.87-2.56], respectively). For screening with implantable loop recorder versus usual care, no significant reduction in these study outcomes was obtained in any ABC-stroke risk groups (P>0.0500 for all), with no signal toward interaction (Pinteraction>0.2500 for all). Similar findings were yielded when assessing the ABC-stroke score as a continuous variable. CONCLUSIONS: In an elderly, AF-naïve population with additional stroke risk factors, a higher ABC-stroke score could identify individuals with increased stroke risk. However, this risk score may not be useful in pinpointing those more likely to benefit from AF screening and subsequent preventive treatment. These findings should be considered as hypothesis generating and warrant further study. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT02036450.

Anticoagulation-Associated Bleeding in Patients Screened for Atrial Fibrillation versus Usual Care-A Post Hoc Analysis from the LOOP Study.

Background Atrial fibrillation (AF) prevalence is rising; however, data on the bleeding risks associated with the detection of subclinical AF are needed. Objective Our objective was to determine the bleeding increment associated with implantable loop recorder (ILR) screening for subclinical AF and subsequent anticoagulation initiation compared with usual care. Methods This post hoc study utilized LOOP trial data from 6,004 elderly patients with stroke risks randomized to either ILR ( n = 1,503) or usual care ( n = 4,503). The mean follow-up time was 64.5 months, and none were lost to follow-up. The primary exposure was the initiation of oral anticoagulation, and the main outcome was the risk of major bleeding events following initiation of oral anticoagulants (OACs), determined by time-dependent cox regression. Second, we investigated antithrombotic prescription patterns and major bleeding events after antiplatelet treatment and in subgroups. Results OAC was initiated in 1,019 participants with a mean age (years) of 78.8 (± 4.67) in control versus 77.0 (± 4.84) in ILR, p < 0.0001. Altogether did 202 participants end or pause OAC treatment. Among AF patients (n = 910) had 40 (28%) completely ended OAC and 105 (72%) temporarily paused OAC during follow-up. Major bleeding events totaled 221 (3.7%). Forty-seven major bleeding events followed an OAC initiation in 1,019 participants (4.6%); 26 versus 21 events in the control and ILR groups, respectively. The hazard ratio (HR) for major bleeding after OAC initiation compared with before initiation was 2.08 (1.50-2.90) p < 0.0001 overall, 2.81 (1.82-4.34) p < 0.0001 for control and 1.32 (0.78-2.23) p = 0.31 for the ILR group ( p = 0.07 for interaction). Antiplatelet treatment resulted in an overall adjusted HR of 1.3 (0.96-1.75) p = 0.09. For OAC users aged ≥75 years in the ILR group, the rate of major bleeding was 1.73 (0.92-2.96) compared with 0.84 (0.36-1.66) for an age <75 years, and the rate of the corresponding control subgroup aged ≥75 years was 2.20 (1.23-3.63) compared with 1.64 (0.82-2.93) for an age <75 years. Conclusion The individual risk of major bleeding increased twofold after initiation of oral anticoagulation for all patients in this study. However, the patients screened for subclinical AF did not have a higher bleeding risk after initiation of anticoagulation compared with those in usual care. Trial Registration: The LOOP study is registered at ClinicalTrials.gov, identifier: NCT020364 50.

Electrocardiographic Morphology-Voltage-P-Wave-Duration (MVP) Score to Select Patients for Continuous Atrial Fibrillation Screening to Prevent Stroke.

Morphology-voltage-P-wave-duration (MVP) score combining P-wave duration (PWD), P-wave voltage in lead I (PWVI), and interatrial block (IAB) has been demonstrated to predict atrial fibrillation (AF). Therefore, this study aimed to examine MVP score and its P-wave components as potential predictors of AF screening effects on stroke prevention. This was a secondary analysis of the LOOP Study (Atrial Fibrillation detected by Continuous ECG Monitoring using Implantable Loop Recorder to prevent Stroke in High-risk Individuals) which randomized older persons (aged 70 to 90 years) with additional stroke risk factors to either continuous monitoring with implantable loop recorder and anticoagulation upon detection of AF episodes ≥6 minutes (the intervention group), or usual care. A total of 5,759 participants were included in the present analysis, where PWD, PWVI, and IAB were determined through a computerized analysis of 12-lead electrocardiogram and further employed to calculate baseline MVP score (0 to 6) for each participant. In total, 305 (5.3%) had stroke or systemic embolism during follow-up, with a higher risk in the group with MVP score 5 to 6 than those having score 0 to 2 (hazard ratio (HR) 1.54 [95% confidence interval (CI) 1.01 to 2.35]). This risk increase was mainly upheld by participants with IAB (HR 1.62 [95% CI 1.11 to 2.36] for IAB vs no IAB) and with longer PWD (HR 1.37 [95% CI 1.07 to 1.75] for >110 vs ≤110 ms). Compared with usual care, implantable loop recorder screening did not significantly reduce the risk of stroke or systemic embolism in any MVP risk categories (HR 0.80 [95% CI 0.60 to 1.08] for MVP score 0 to 2, 0.54 [95% CI 0.16 to 1.85] for MVP score 3 to 4, and 0.89 [95% CI 0.35 to 2.25] for MVP score 5 to 6; pinteraction = 0.78). In conclusion, a higher MVP score was associated with an increased stroke risk, but it did not demonstrate an association with effects of AF screening on stroke prevention. These findings should be considered hypothesis-generating and warrant further study.

Electrocardiographic markers of subclinical atrial fibrillation detected by implantable loop recorder: insights from the LOOP Study.

AIMS: Insights into subclinical atrial fibrillation (AF) development are warranted to inform the strategies of screening and subsequent clinical management upon AF detection. Hence, this study sought to characterize the onset and progression of subclinical AF with respect to 12-lead electrocardiogram (ECG) parameters. METHODS AND RESULTS: We included AF-naïve individuals aged 70-90 years with additional stroke risk factors who underwent implantable loop recorder (ILR) monitoring in the LOOP Study. Using data from daily ILR recordings and the computerized analysis of baseline ECG, we studied empirically selected ECG parameters for AF detection (≥6 min), cumulative AF burden, long-lasting AF (≥24 h), and AF progression. Of 1370 individuals included, 419 (30.6%) developed AF during follow-up, with a mean cumulative AF burden of 1.5% [95% CI: 1.2-1.8]. Several P-wave-related and ventricular ECG parameters were associated with new-onset AF and with cumulative AF burden in AF patients. P-wave duration (PWD), P-wave terminal force in Lead V1, and interatrial block (IAB) further demonstrated significant associations with long-lasting AF. Among AF patients, we observed an overall reduction in cumulative AF burden over time (IRR 0.70 [95% CI: 0.51-0.96]), whereas IAB was related to an increased risk of progression to AF ≥24 h (HR 1.86 [95% CI: 1.02-3.39]). Further spline analysis also revealed longer PWD to be associated with this progression in AF duration. CONCLUSION: We identified several ECG parameters associated with new-onset subclinical AF detected by ILR. Especially PWD and IAB were robustly related to the onset and the burden of AF as well as progression over time.

Effects of Atrial Fibrillation Screening According to N-Terminal Pro-B-Type Natriuretic Peptide: A Secondary Analysis of the Randomized LOOP Study.

BACKGROUND: Research suggests NT-proBNP (N-terminal pro-B-type natriuretic peptide) to be a strong predictor of incident atrial fibrillation (AF) and stroke. However, its utility in AF screening remains unknown. The aim of this study was to investigate NT-proBNP as a potential marker for screening efficacy with respect to AF yield and stroke prevention. METHODS: In the LOOP Study (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals), 6004 AF-naïve individuals at least 70 years old and with additional stroke risk factors were randomized 1:3 to either screening with an implantable loop recorder (ILR) and initiation of anticoagulation upon detection of AF episodes lasting ≥6 minutes or usual care (control). This post hoc analysis included study participants with available NT-proBNP measurement at baseline. RESULTS: A total of 5819 participants (96.9% of the trial population) were included. The mean age was 74.7 years (SD, 4.1 years) and 47.5% were female. The median NT-proBNP level was 15 pmol/L (interquartile range, 9-28 pmol/L) corresponding to 125 pg/mL (interquartile range, 76-233 pg/mL). NT-proBNP above median was associated with an increased risk of AF diagnosis both in the ILR group (hazard ratio, 1.84 [95% CI, 1.51-2.25]) and the control group (hazard ratio, 2.79 [95% CI, 2.30-3.40]). Participants with NT-proBNP above the median were also at higher risk of clinical events compared with those having lower levels (hazard ratio, 1.21 [95% CI, 0.96-1.54] for stroke or systemic embolism [SE], 1.60 [95% CI, 1.32-1.95] for stroke/SE/cardiovascular death, and 1.91 [95% CI, 1.61-2.26] for all-cause death). Compared with usual care, ILR screening was associated with significant reductions in stroke/SE and stroke/SE/cardiovascular death among participants with NT-proBNP above median (hazard ratio, 0.60 [95% CI, 0.40-0.90] and 0.70 [95% CI, 0.53-0.94], respectively) but not among those with lower levels (Pinteraction=0.029 for stroke/SE and 0.045 for stroke/SE/cardiovascular death). No risk reduction in all-cause death was observed in either NT-proBNP subgroup for ILR versus control (Pinteraction=0.68). Analyzing NT-proBNP as a continuous variable yielded similar findings. CONCLUSIONS: In an older population with additional stroke risk factors, ILR screening for AF was associated with a significant reduction in stroke risk among individuals with higher NT-proBNP levels but not among those with lower levels. These findings should be considered hypothesis generating and warrant further study before clinical implementation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02036450.

Prevalence and Prognostic Significance of Bradyarrhythmias in Patients Screened for Atrial Fibrillation vs Usual Care: Post Hoc Analysis of the LOOP Randomized Clinical Trial.

Importance: There is increasing interest in heart rhythm monitoring and technologies to detect subclinical atrial fibrillation (AF), which may lead to incidental diagnosis of bradyarrhythmias. Objective: To assess bradyarrhythmia prevalence and prognostic significance in persons screened for AF using implantable loop recorder (ILR) compared with unscreened persons. Design, Setting, and Participants: This was a post hoc analysis of the Implantable Loop Recorder Detection of Atrial Fibrillation to Prevent Stroke (LOOP) randomized clinical trial, which took place in 4 sites in Denmark. Participants were 70 years or older without known AF but diagnosed with at least 1 of the following: hypertension, diabetes, heart failure, or prior stroke. Participants were recruited by letter invitation between January 31, 2014, and May 17, 2016. The median (IQR) follow-up period was 65 (59-70) months. Analysis took place between February and June 2022. Interventions: ILR screening for AF with treatment of any bradyarrhythmia left to the discretion of the treating physician (ILR group) vs usual care (control group). Main Outcomes and Measures: Adjudicated bradyarrhythmia episodes, pacemaker implantation, syncope, and sudden cardiovascular death. Results: A total of 6004 participants were randomized (mean [SD] age, 75 [4.1] years; 2837 [47.3%] female; 5444 [90.7%] with hypertension; 1224 [20.4%] with prior syncope), 4503 to control and 1501 to ILR. Bradyarrhythmia was diagnosed in 172 participants (3.8%) in the control group vs 312 participants (20.8%) in the ILR group (hazard ratio [HR], 6.21 [95% CI, 5.15-7.48]; P < .001), and these were asymptomatic in 41 participants (23.8%) vs 249 participants (79.8%), respectively. The most common bradyarrhythmia was sinus node dysfunction followed by high-grade atrioventricular block. Risk factors for bradyarrhythmia included higher age, male sex, and prior syncope. A pacemaker was implanted in 132 participants (2.9%) vs 67 (4.5%) (HR, 1.53 [95% CI, 1.14-2.06]; P < .001), syncope occurred in 120 (2.7%) vs 33 (2.2%) (HR, 0.83 [95% CI, 0.56-1.22]; P = .34), and sudden cardiovascular death occurred in 49 (1.1%) vs 18 (1.2%) (HR, 1.11 [95% CI, 0.64-1.90]; P = .71) in the control and ILR groups, respectively. Bradyarrhythmias were associated with subsequent syncope, cardiovascular death, and all-cause death, with no interaction between bradyarrhythmia and randomization group. Conclusions and Relevance: More than 1 in 5 persons older than 70 years with cardiovascular risk factors can be diagnosed with bradyarrhythmias when long-term continous monitoring for AF is applied. In this study, ILR screening led to a 6-fold increase in bradyarrhythmia diagnoses and a significant increase in pacemaker implantations compared with usual care but no change in the risk of syncope or sudden death.

Screening for atrial fibrillation to prevent stroke in elderly individuals with or without preexisting cardiovascular disease: A post hoc analysis of the randomized LOOP Study.

BACKGROUND: An evidence-based approach for risk stratification of subclinical atrial fibrillation (AF) and hereby AF screening is lacking. This study aimed to investigate whether established cardiovascular diseases (CVD) could help to identify the population more likely to benefit from AF screening. METHODS: The LOOP Study randomized AF-naïve individuals aged ≥70 years and with additional stroke risk factors to either screening with implantable loop recorder (ILR) and subsequent anticoagulation upon detection of new-onset AF episodes ≥6 min, or usual care. In this sub-study, all participants were divided into two risk groups according to the presence/absence of CVD (defined as ischemic heart disease, heart failure, previous stroke, valvular heart disease, or peripheral artery disease). RESULTS: A total of 1997 (33.3%) had CVD at baseline and experienced higher incidences of stroke or systemic arterial embolism (SAE), ischemic stroke, stroke/SAE/cardiovascular death, and all-cause death (adjusted HR 1.34 [1.06-1.69], 1.31 [1.02-1.69], 1.49 [1.23-1.79], and 1.59 [1.36-1.85], respectively) than those without. For ILR screening versus usual care, there was no decrease in stroke/SAE, ischemic stroke, or stroke/SAE/cardiovascular death among participants with CVD (adjusted p-values >0.05), whereas significant reductions in these outcomes were obtained by screening among those without CVD (adjusted HR 0.64 [0.44-0.93], 0.54 [0.35-0.82], 0.64 [0.46-0.87], respectively); adjusted p-values for interaction ≤0.05. CONCLUSIONS: In an elderly, at-risk population, ILR screening did not prevent stroke significantly in individuals with CVD, whereas screening was associated with approximately 40% stroke risk reduction among those without CVD. However, these findings should be considered as hypothesis-generating and warrant further study.

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.

Importance: Atrial fibrillation (AF) screening trials have failed to demonstrate a significant reduction in stroke risk. The impact on stroke severity and the importance of prior strokes are unknown. Objective: To assess stroke characteristics in patients undergoing implantable loop recorder (ILR) screening for AF vs usual care and assess the importance of prior stroke. Design, Setting, and Participants: This was a post hoc analysis of the Atrial Fibrillation Detected by Continuous Electrocardiogram Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals (LOOP) randomized clinical trial. Persons 70 years or older without known AF but diagnosed with 1 or more of the following, hypertension, diabetes, heart failure, or prior stroke, were screened for inclusion. Four sites in Denmark recruited participants by letter between January 31, 2014, and May 17, 2016. The median (IQR) follow-up period was 65 (59-70) months. Data were analyzed from April 1 to May 31, 2022. Interventions: ILR screening for AF and anticoagulation initiation if AF duration of 6 minutes or longer was detected (ILR group) vs usual care (control group). Main Outcomes and Measures: Adjudicated stroke, classified according to the modified Rankin Scale (mRS) using a score of 3 or more as a cutoff for severe (disabling or lethal) stroke, and according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification for ischemic strokes. Results: A total of 6205 individuals were screened for inclusion, and 6004 were randomized and included in the analysis; 4503 participants (75%; mean [SD] age, 74.7 [4.1] years; 2375 male [52.7%]) were assigned to the control group and 1501 participants (25%; mean [SD] age, 74.7 [4.1] years; 792 male [52.8%]) were assigned to the ILR group. A total of 794 of 4503 participants (17.6%) in the control group had a history of prior stroke compared with 262 of 1501 participants (17.5%) in the ILR group. During follow-up, AF was diagnosed in 1027 participants (control group, 550 [12%] vs ILR group, 477 [32%]), and anticoagulation was initiated in 89% of these (910). A total of 315 participants (5.2%) had a stroke (control group, 249 [5.5%] vs ILR group, 66 [4.4%]), and the median (IQR) mRS score was 2 (1-3) with no difference across the groups. A total of 272 participants (4.5%) had ischemic stroke (control group, 217 [4.8%] vs ILR group, 55 [3.7%]), and 123 (2.0%) had severe stroke (control group, 100 [2.2%] vs ILR group, 23 [1.5%]), and the hazard ratios comparing the control and ILR groups were 0.76 (95% CI, 0.57-1.03; P = .07) and 0.69 (95% CI, 0.44-1.09; P = .11), respectively. For participants without prior stroke, the hazard ratios were 0.68 (95% CI, 0.48-0.97; P = .04) and 0.54 (95% CI, 0.30-0.97; P = .04), respectively. Conclusions and Relevance: This post hoc analysis of the LOOP randomized clinical trial found that ILR screening for AF did not result in a significant decrease in ischemic or severe strokes compared with usual care. Exploratory subgroup analyses indicated a possible reduction of these outcomes among participants without prior stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02036450.

Systolic Blood Pressure and Effects of Screening for Atrial Fibrillation With Long-Term Continuous Monitoring (a LOOP Substudy).

BACKGROUND: Hypertension is a well-known risk factor for atrial fibrillation (AF) and stoke, but data on the interaction between systolic blood pressure (SBP) and effects of AF screening are lacking. METHODS: The LOOP Study randomized AF-naïve individuals aged 70 to 90 years with additional stroke risk factors to either screening with implantable loop recorder (ILR) and anticoagulation initiation upon detection of AF episodes ≥6 minutes, or usual care. In total, 5997 participants with available baseline SBP measurements were included in this substudy. Outcomes were analyzed according to the time-to-first-event principle using cause-specific Cox models. RESULTS: The hazard ratio of stroke or systemic arterial embolism for ILR versus control decreased with increasing SBP. ILR screening yielded a 44% risk reduction of stroke or systemic arterial embolism among participants with SBP ≥150 mm Hg (adjusted hazard ratio, 0.56 [0.37-0.83]). Within the ILR group, SBP≥150 mm Hg was associated with a higher incidence of AF episodes ≥24 hours than lower SBP (adjusted hazard ratio, 1.70 [1.08-2.69]) but not with the overall occurrence of AF (adjusted P>0.05). CONCLUSIONS: The impact of AF screening on thromboembolic events increased with increasing blood pressure. SBP≥150 mm Hg was associated with a >1.5-fold increased risk of AF episodes ≥24 hours, along with an almost 50% risk reduction of stroke or systemic arterial embolism by ILR screening compared to lower blood pressure. These findings should be considered hypothesis-generating and warrant further study. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT02036450.

Dose reduction of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: A Danish nationwide cohort study.

INTRODUCTION: To investigate the patterns of dose reduction of non-vitamin K antagonist oral anticoagulants (NOAC) in patients with atrial fibrillation (AF). MATERIALS AND METHODS: Using Danish nationwide registries, we identified all non-valvular AF patients initiated on standard-dose NOAC during 2011-2017 who were followed until dose reduction. The absolute risk of dose reduction was presented as cumulative incidence both overall and according to baseline characteristics. Moreover, to assess baseline comorbidities related to dose reduction, adjusted Cox regression models were used. In subgroup analysis, we investigated dose reduction following acute myocardial infarction and/or percutaneous coronary intervention (MI/PCI), chronic kidney disease (CKD), turned 80 years, intracranial hemorrhage, peripheral bleeding, ischemic stroke, cancer, bone fracture, and antiplatelet treatment start. RESULTS: Of 24,489 patients included, 12.2% experienced dose reduction during the study period. Dabigatran treatment, higher age at inclusion, high CHA2DS2-VASc score, and high HAS-BLED score were related to higher risk of dose reduction. Baseline ischemic heart disease (IHD), heart failure, cancer, CKD, chronic obstructive pulmonale disease (COPD), and hypertension were independent predictors of dose reduction. In subgroup analysis with six-month follow-up, MI/PCI, CKD, intracranial hemorrhage, peripheral bleeding, and antiplatelet treatment therapy were strongly associated with dose reduction. CONCLUSIONS: Dose reduction of NOACs was observed in 12.2% of AF patients during 2011-2017 and was associated with dabigatran treatment, advanced age at baseline, high CHA2DS2-VASc score, and high HAS-BLED score. Among comorbidities, IHD, heart failure, cancer, CKD, COPD, and hypertension predicted dose reduction independently. During six-month follow-up, MI/PCI showed the strongest association with dose reduction.