Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients. This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and electrocardiogram (ECG)-diagnosed atrial fibrillation. Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE ≥24 h were present at baseline in 259/2389 patients (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE ≥24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .001). This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk. Anticoagulation with edoxaban in patients with long AHRE ≥24 h. AHRE, atrial high-rate episodes; CI, confidence interval; ECG, electrocardiogram; HR, hazard ratio.

The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation. These pre-specified analyses of the NOAH-AFNET 6 (n=2534 patients) and ARTESiA (n=4012 patients) trials compared anticoagulation to no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death. In patients with vascular disease (NOAH-AFNET 6 56%, ARTESiA 46.0%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6 2.7%/patient-year, ARTESiA 2.3%/patient-year in both randomised groups). Meta-analysis found consistent results across both trials (I²_{heterogeneity}=6%) with a trend for interaction with randomised therapy (p_interaction=0.08). Stroke/SE behaved similarly. Anticoagulation increased major bleeding in vascular disease patients (edoxaban 2.1%/patient-year, no anticoagulation 1.3%/patient-year; apixaban 1.7%/patient-year; no anticoagulation 1.1%/patient-year; incidence rate ratio 1.55 [1.10-2.20]) and without vascular disease (edoxaban 2.2%/patient-year; no anticoagulation 0.6%/patient-year; apixaban 1.4%/patient-year; no anticoagulation 1.1%/patient-year, incidence rate ratio 1.93 [0.72-5.20]). Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.

Background: Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device‐detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device‐detected AF but with no ECG‐documented AF is unclear. Methods and Results: This prespecified analysis of the NOAH‐AFNET 6 (Non‐Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) trial with post hoc elements assessed the effect of oral anticoagulation in patients with device‐detected AF with and without a prior stroke or TIA in the randomized, double‐blind, double‐dummy NOAH‐AFNET 6 trial. Outcomes were stroke, systemic embolism, and cardiovascular death (primary outcome) and major bleeding and death (safety outcome). A prior stroke or TIA was found in 253 patients with device‐detected AF randomized in the NOAH‐AFNET 6 (mean age, 78 years; 36.4% women). There was no treatment interaction with prior stroke or TIA for any of the primary and secondary time‐to‐event outcomes. In patients with a prior stroke or TIA, 14 out of 122 patients experienced a primary outcome event with anticoagulation (5.7% per patient‐year). Without anticoagulation, there were 16 out of 131 patients with an event (6.3% per patient‐year). The rate of stroke was lower than expected (anticoagulation: 4 out of 122 [1.6% per patient‐year]; no anticoagulation: 6 out of 131 [2.3% per patient‐year]). Numerically, there were more major bleeding events with anticoagulation in patients with prior stroke or TIA (8 out of 122 patients) than without anticoagulation (2 out of 131 patients). Conclusions: Anticoagulation appears to have ambiguous effects in patients with device‐detected AF and a prior stroke or TIA in this hypothesis‐generating analysis of the NOAH‐AFNET 6 in the absence of ECG‐documented AF, partially due to a low rate of stroke without anticoagulation.

Screening for depression in primary care alone is not sufficient to improve clinical outcomes. However, targeted feedback of the screening results to patients might result in beneficial effects. The GET.FEEDBACK.GP trial investigated whether targeted feedback of the depression screening result to patients, in addition to feedback to general practitioners (GPs), leads to greater reductions in depression severity than GP feedback alone or no feedback. The GET.FEEDBACK.GP trial was an investigator-initiated, multicentre, three-arm, observer-blinded, randomised controlled trial. Depression screening was conducted electronically using the Patient Health Questionnaire-9 (PHQ-9) in 64 GP practices across five regions in Germany while patients were waiting to see their GP. Currently undiagnosed patients (aged ≥18 years) who screened positive for depression (PHQ-9 score ≥10), were proficient in the German language, and had a personal consultation with a GP were randomly assigned (1:1:1) into a group that received no feedback on their depression screening result, a group in which only the GP received feedback, or a group in which both GP and patient received feedback. Randomisation was stratified by treating GP and PHQ-9 depression severity. Trial staff were masked to patient enrolment and study group allocation and GPs were masked to the feedback recieved by the patient. Written feedback, including the screening result and information on depression, was provided to the relevant groups before the consultation. The primary outcome was PHQ-9-measured depression severity at 6 months after randomisation. An intention-to-treat analysis was conducted for patients who had at least one follow-up visit. This study is registered at ClinicalTrials.gov (NCT03988985) and is complete. Between July 17, 2019, and Jan 31, 2022, 25 279 patients were approached for eligibility screening, 17 150 were excluded, and 8129 patients completed screening, of whom 1030 (12·7%) screened positive for depression. 344 patients were randomly assigned to receive no feedback, 344 were assigned to receive GP-targeted feedback, and 339 were assigned to receive GP-targeted plus patient-targeted feedback. 252 (73%) patients in the no feedback group, 252 (73%) in the GP-targeted feedback group, and 256 (76%) in the GP-targeted and patient-targeted feedback group were included in the analysis of the primary outcome at 6 months, which reflected a follow-up rate of 74%. Gender was reported as female by 637 (62·1%) of 1025 participants, male by 384 (37·5%), and diverse by four (0·4%). 169 (16%) of 1026 patients with available migration data had a migration background. Mean age was 39·5 years (SD 15·2). PHQ-9 scores improved for each group between baseline and 6 months by -4·15 (95% CI -4·99 to -3·30) in the no feedback group, -4·19 (-5·04 to -3·33) in the GP feedback group, and -4·91 (-5·76 to -4·07) in the GP plus patient feedback group, with no significant difference between the three groups (global p=0·13). The difference in PHQ-9 scores when comparing the GP plus patient feedback group with the no feedback group was -0·77 (-1·60 to 0·07, d=-0·16) and when comparing with the GP-only feedback group was -0·73 (-1·56 to 0·11, d=-0·15). No increase in suicidality was observed as an adverse event in either group. Providing targeted feedback to patients and GPs after depression screening does not significantly reduce depression severity compared with GP feedback alone or no feedback. Further research is required to investigate the potential specific effectiveness of depression screening with systematic feedback for selected subgroups. German Innovation Fund. For the German translation of the abstract see Supplementary Materials section.

Implanted pacemakers, defibrillators, and loop recorders detect short and rare episodes of device-detected atrial fibrillation [DDAF, previously also called atrial high-rate episodes or subclinical atrial fibrillation (AF)] in ∼30% of patients. Device-detected atrial fibrillation rarely has therapeutic consequences in patients with ECG-documented AF. Device-detected atrial fibrillation without ECG-documented AF can lead to consideration of oral anticoagulation in clinical practice, especially in older patients with multiple stroke risk factors and/or very long DDAF episodes, largely based on observational data.¹ Two recent controlled trials, NOAH-AFNET 6² and ARTESiA,³ observed a low rate of ischaemic stroke without anticoagulation (1.1%–1.2%/patient-year) in patients with DDAF and stroke risk factors, including in patients with very long DDAF episodes in NOAH-AFNET 6.⁴ Current guidelines leave the decision to anticoagulate to clinical judgement, balancing the expected stroke risk, typically estimated by using stroke risk scores developed in patients with ECG-documented AF, and the stroke risk reduction induced by anticoagulation, with the increase in bleeding associated with anticoagulation therapy.¹

Since the introduction of the estimand in therapeutical studies, several adaptions have been developed. This short article highlights the important aspects of the estimand concept. A literature research was conducted to identify different extensions to this framework. Different modified strategies for intercurrent events are presented, as well as examples of methods to implement the estimand in clinical studies. The article reflects that the estimand is an ongoing research field with further exploration.