BACKGROUND:Direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). However, limited accessibility in resource-constrained settings makes it important to identify patient subgroups in whom VKAs may achieve comparable net clinical outcomes (NCOs). OBJECTIVES:The purpose of this study was to identify AF patient subgroups and explore potential predictors of differential treatment benefit to inform anticoagulant selection where DOAC access is limited. METHODS:Individual patient data from the COMBINE-AF data set pooling 4 pivotal randomized trials of DOACs vs VKAs in AF were analyzed. Model-based clustering identified patient subgroups. Heterogeneity of treatment effects for the NCO-a composite of all-cause death, disabling or fatal stroke, and intracranial or fatal bleeding- was explored using Cox regression and gradient boosting analyses adapted for time-to-event data. RESULTS:A total of 58,634 patients were included (29,272 warfarin; 29,362 standard dose DOACs). Two subgroups were identified: a high-risk cluster (mean creatinine clearance 55.1 mL/min, age 75.6 years, body mass index [BMI] 26.6 kg/m2) and a low-risk cluster (mean creatinine clearance 101 mL/min, age 64.2 years, BMI 32.3 kg/m2). DOACs significantly reduced NCOs in the high-risk cluster (HR: 0.86; 95% CI: 0.81-0.92; P < 0.001), but not in the low-risk cluster (HR: 0.93; 95% CI: 0.85-1.03; P = 0.154, p-interaction = 0.115). Primary predictors of treatment heterogeneity were renal function, age, and BMI; no statistically significant treatment-by-subgroup interactions were identified. CONCLUSIONS:Renal function, age, and BMI are key determinants of anticoagulant treatment benefit in AF. In regions with limited access to DOACs, these findings suggest that some lower-risk patient profiles may derive similar outcomes with VKAs, although differences were not statistically significant.

BACKGROUND:Atrial fibrillation (AF) can lead to significant cardiovascular events and health care utilization. Continuous monitoring via insertable cardiac monitors (ICMs) and data analytics have the potential to improve care delivery. OBJECTIVE:The DEFINE Atrial Fibrillation (DEFINE AFib) study was designed to develop and evaluate novel algorithms using ICM data to predict AF-associated clinical actions (AFCAs) and guide AF management. METHODS:DEFINE AFib enrolled patients with an ICM (Reveal LINQ/LINQ II; Medtronic) and a history of AF. An Apple iPhone application collected AF-related quality of life (AFEQT) and EQ-5D data. ICM daily AF burden and Apple Watch (AW) irregular rhythm notification (IRN) data were also collected. AFCA was defined as an AF-related procedure or initiation of rate/rhythm control medication. Mutivariable logistic regression was used to identify ICM features in the last 30 days associated with first occurrence of AFCA in the next 30 days in a train and test approach (70%/30%). RESULTS:Among 864 patients (mean 69 ± 10 years; 56% male) meeting inclusion criteria, there were 8963 30-day evaluation windows that included 151 AFCAs. Area under the receiver operating characteristic curve (AUC) was 76% (train) and 70% (test). The model placed participants into high- vs low-risk AFCA groups. At the patient-level, 21% of participants crossing the high-risk threshold for their first time experienced an AFCA at a mean time of 195 ± 164 days compared with 5% in the low-risk group (AUC 65%). Increasing daily mean AF burden was associated with lower quality of life: <6 minutes (reference), 6 minutes to 5.5 hours (AFEQT -7.69; P < .001), and 5.5-12 hours (AFETQ -13.97, P < .001; ≥5.5 hours EQ-5D -0.03, P = .007). In a subanalysis of individuals with smart watch data (n = 53), the ICM model signaled high risk before AFCAs 85% of the time (AUC 57%) compared with 23% for AW IRN (P = .005; AUC 55%). CONCLUSION:DEFINE AFib transformed ICM diagnostic data to predict risk of AFCA with good discrimination, particularly compared with wearable data. These results highlight the potential advantages of ICM-based continuous monitoring for AF management and the utility of ICM prediction models that could help inform pre-emptive therapeutic strategies.

BACKGROUND:Warfarin remains widely used for stroke prevention in atrial fibrillation (AF), particularly where access to direct oral anticoagulants (DOACs) is limited. Updated outcome data across clinical risk groups are needed. OBJECTIVES:The objectives of the study were to identify predictors of adverse outcomes with warfarin, evaluate the TIMI-AF risk score, and assess the benefit of standard-dose (SD) DOACs vs warfarin across risk strata. METHODS:Individual patient-level data from 58,634 patients (29,272 warfarin and 29,362 DOAC) enrolled in 4 pivotal randomized trials were analyzed. The net clinical outcome (NCO), defined as all-cause death, disabling or fatal stroke, or intracranial/fatal bleeding, was assessed using trial-stratified Cox models across key clinical subgroups and TIMI-AF risk score categories. Outcomes with SD-DOACs vs warfarin were compared across risk strata. RESULTS:Older age (adjusted HR [aHR]: 1.55; 95% CI: 1.31-1.83), male sex (aHR: 1.30; 95% CI: 1.20-1.40), impaired kidney function (aHR: 2.21; 95% CI: 1.90-2.56), lower body mass index (aHR: 1.25; 95% CI: 1.15-1.36), vitamin K antagonist-naïve status (aHR: 1.17; 95% CI: 1.08-1.27), and nonparoxysmal AF (aHR: 1.31; 95% CI: 1.19-1.44) were independently associated with increased NCO risk (P < 0.001 for each). Annualized NCO rates were 3.5%, 7.6%, and 12.9% in low-, intermediate-, and high-risk TIMI-AF groups (P trend<0.001). SD-DOACs reduced NCO across all risk strata; however, absolute benefit with DOACs was modest in low-risk patients (0.3%; 95% CI: 0.1% to 0.6%). CONCLUSIONS:Several predictors of poor warfarin outcomes were identified. Although SD-DOACs reduced NCO across the risk spectrum, patients with low TIMI-AF scores derived modest absolute benefit. In settings with limited DOAC access, warfarin may be a reasonable option for lower-risk patients.

BACKGROUND AND AIMS:Oral anticoagulation reduces stroke risk in patients with atrial fibrillation (AF) but increases bleeding. Longer fibrin clot lysis time has been shown to predict adverse cardiovascular outcomes in acute coronary syndromes. This study explored relationships between fibrin clot lysis time at randomization and clinical outcomes in patients with AF enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial. METHODS:Plasma samples were obtained from anticoagulation-naïve participants, before initiation of study medication (n = 1841). Fibrin clot turbidimetry was performed, and lysis time determined. Associations between lysis time and characteristics, biomarkers, and on-treatment bleeding and cardiovascular events were assessed by lysis time quartile (Q1-4, shortest to longest). RESULTS:A shorter lysis time was associated with being older, male, permanent AF, lower body mass index, estimated glomerular filtration rate and C-reactive protein, and higher N-terminal pro-B-type natriuretic peptide. Major and clinically relevant non-major bleeding was significantly more frequent in lysis time Q1 vs. Q4 [6.3%/yr vs. 2.1%/yr; HR, 2.99 (95% CI, 1.75-5.12); P = .001], including after multifactorial adjustment [HR, 2.61 (1.45-4.69); P = .016]. Those in Q2 and Q3 had intermediate bleeding risk vs. Q4 [HR, 2.21 (1.27-3.87); 2.08 (1.18-3.66) respectively], suggesting a graduated effect. Treatment allocation to apixaban vs. warfarin did not affect the relationship between lysis time and bleeding (interaction-P = .80). There was no significant association between lysis time and a composite of cardiovascular death, stroke, systemic embolism or myocardial infarction. CONCLUSIONS:Shorter pre-treatment fibrin clot lysis time independently predicted higher bleeding risk in patients receiving oral anticoagulation for AF.

BACKGROUND: Atrial fibrillation is associated with an increased risk of cardiovascular hospitalization (CVH), which may be triggered by changes in daily burden. Machine learning of dynamic trends in atrial fibrillation burden, as measured by insertable cardiac monitors (ICMs), may be useful in predicting near-term CVH. METHODS: Using Optum's deidentified Clinformatics Data Mart Database (2007-2019), linked with the Medtronic CareLink ICM database, we identified patients with >1 days of ICM-detected atrial fibrillation. ICM-detected diagnostic parameters were transformed into simple moving averages over different periods for daily follow-up. A diagnostic trend was defined as the comparison of 2 simple moving averages of different periods for each diagnostic parameter. CVH was defined as any hospital, emergency department, or ambulatory surgical center encounter with a cardiovascular diagnosis-related group or diagnosis code. Machine learning was used to determine which diagnostic trends could best predict patient risk 5 days before CVH. RESULTS: A total of 2616 patients with ICMs met the inclusion criteria (71 +/- 11 years; 55% male). Among them, 1998 (76%) had a planned or unplanned CVH over 605 363 days. Machine learning revealed distinct groups: (A) sinus rhythm (reference), (B) below-average burden, (C) above-average burden, and (D) above-average burden with decreasing patient activity. The relative risk was increased in all groups versus the reference (B, 4.49 [95% CI, 3.74-5.40]; C, 8.41 [95% CI, 7.00-10.11]; D, 11.15 [95% CI, 9.10-13.65]), including a 21% increase in CVH detection over prespecified burden thresholds of duration (>= 1 hour) and quantity (>= 5%). The area under the receiver operating characteristic curve increased from 0.55 when using hourly burden amounts to 0.66 when using burden trends and decreasing patient activity (P<0.001), a 20% increase in predictive power. CONCLUSIONS: Trends in atrial fibrillation were strongly associated with near-term CVH, especially above-average burden coupled with low patient activity. This approach could provide actionable information to guide treatment and reduce CVH.

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of stroke, yet the limitations of conventional monitoring have restricted our understanding of AF burden risk thresholds. Predictive algorithms incorporating continuous AF burden measures may be useful for predicting stroke. This study evaluated the performance of temporal AF burden trends as predictors of stroke from a large cohort with insertable cardiac monitors. METHODS: Using deidentified data from Optum Clinformatics Data Mart (2007-2019) linked with the Medtronic CareLink insertable cardiac monitor database, we identified patients with an insertable cardiac monitor for AF management (n=1197), suspected AF (n=1611), and cryptogenic stroke (n=2205). Daily AF burden was transformed into simple moving averages, and temporal AF burden trends were defined as the comparison of unique simple moving average pairs. Classification trees were used to predict ischemic stroke, and AF burden significance was quantified using bootstrapped mean variable importance. RESULTS: Of 5013 patients (age, 69.2 +/- 11.7 years; 50% male; CHA(2)DS(2)-VASc, 3.7 +/- 1.9) who met inclusion criteria, 869 had an ischemic stroke over 2 409 437 days total follow-up. Prior stroke or transient ischemic attack (variable importance, 13.13) was the number 1 predictor of future stroke followed by no prior diagnosis of AF (7.35) and AF burden trends in follow-up (2.59). Temporal proximity of AF and risk of stroke differed by device indication (simple moving averages: AF management, <8 days and suspected AF and cryptogenic stroke, 8-21 days). Together, baseline characteristics and AF burden trends performed optimally for the area under the receiver operating characteristic curve (0.73), specificity (0.70), and relative risk (5.00). CONCLUSIONS: AF burden trends may provide incremental prognostic value as leading indicators of stroke risk compared with conventional schemes.

BACKGROUND:Decisions about stroke prevention strategies in atrial fibrillation (AF) typically balance thromboembolism reduction against increased bleeding from oral anticoagulation therapy (OAC). When determining eligibility for OAC, guidelines recommend calculation of thromboembolic event rates using a validated score such as CHA2DS2-VASc. In contrast, routine calculation of bleeding scores is not recommended, in part because many patient factors associated with an increased risk of bleeding are associated with an even larger increased risk of ischemic stroke. We set out to characterize patients by paired stroke and bleeding risk scores to understand the level of concordance. METHODS:Between 2010 and 2016, we identified 20,451 AF patients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) I and II Registries. We grouped patients by stroke and bleeding risk pairings: low and high stroke risk (CHA2DS2-VASc < and ≥2), low and high bleeding risk (ORBIT < and ≥ 4) and described treatment rates with OAC and antiplatelet (AP) therapy. RESULTS:Most patients (68.6 %) were at high stroke and low bleeding risk. Patients at high bleeding risk (19.4 %) had high stroke risk (98.5 %). Treatment rates differed with combined OAC + AP therapy highest for patients at high stroke and bleeding risks. Ischemic and bleeding events were also highest in this group. CONCLUSIONS:Nearly all AF patients in this cohort with high bleeding risk (ORBIT score ≥ 4) had high stroke risk (CHA2DS2-VASc ≥ 2), supporting that bleeding risk should not obviate the need for stroke prevention. In contrast, most at high stroke risk were at low bleeding risk (ORBIT <4), supporting OAC for the majority. Bleeding scores, in combination with factors that specifically indicate a higher risk of bleeding, may identify patients who might be candidates for alternative stroke prevention such as left atrial appendage occlusion devices or bleeding mitigation strategies such as de-escalation of antiplatelet therapy.

Background Atrial fibrillation (AF) has a significant impact on health and quality of life. The relationship of AF burden and temporal patterns of AF on patient symptoms, outcomes, and healthcare utilization is unknown. Insertable cardiac monitors (ICMs) are a strategic and as yet untapped, tool to investigate these relationships. Objective The DEFINE Atrial Fibrillation (DEFINE AFib) study will evaluate how AF burden and patterns are associated with changes in AF-related healthcare utilization (AFHCU) and patient-reported quality of life. Methods This is a prospective, observational, multicenter study with a unique design that supports a complete method of assessing AF as a multifactorial disease. Patients with AF implanted with an ICM will be enrolled in the study and managed through an app-based research platform on their smartphone. Patients will be remotely monitored and patient-reported outcomes will be collected via the app. AFHCU will be confirmed via the participant’s medical record. Results The primary analysis will evaluate whether summary and episodic measurements collected by ICMs are associated with changes in AFHCU. Secondary analyses will determine the relationship between AF characteristics and quality of life, timing and severity of AF-related complications, patient engagement, reliability of patient-reported outcomes, data from other digital rhythm detectors, and heterogeneity in care quality and AFHCU. Conclusion The DEFINE AFib study will provide valuable insights into the association between dynamic measures of AF and AFHCU in a patient population with known AF. The results may demonstrate the impact of ICM-detected AF on patient outcomes and help isolate novel AF patterns predictive of clinical risk.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Although consumer technologies offer patients an opportunity to view their health metrics directly, cardiovascular implantable electronic device (CIED) data is not shared in this manner. Patient (mis)interpretation of data and the potential negative impact on patient perception of health status is often cited as a reason to limit direct access; however, quantified analysis regarding patient engagement with CIED data is scarce.

BACKGROUND:An unmet need exists to reliably predict the risk of intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs).HYPOTHESIS:An externally validated model improves ICH risk stratification.METHODS:Independent factors associated with ICH were identified by Cox proportional hazard modeling, using pooled data from the GARFIELD-AF (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation) and ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registries. A predictive model was developed and validated by bootstrap sampling and by independent data from the Danish National Patient Register.RESULTS:In the combined training data set, 284 of 53 878 anticoagulated patients had ICH over a 2-year period (0.31 per 100 person-years; 95% confidence interval [CI]: 0.28-0.35). Independent predictors of ICH included: older age, prior stroke or transient ischemic attack, concomitant antiplatelet (AP) use, and moderate-to-severe chronic kidney disease (CKD). Vitamin K antagonists (VKAs) were associated with a significantly higher risk of ICH compared with non-VKA oral anticoagulants (NOACs) (adjusted hazard ratio: 1.61; 95% CI: 1.25-2.08; p = .0002). The ability of the model to discriminate individuals in the training set with and without ICH was fair (optimism-corrected C-statistic: 0.68; 95% CI: 0.65-0.71) and outperformed three previously published methods. Calibration between predicted and observed ICH probabilities was good in both training and validation data sets.CONCLUSIONS:Age, prior ischemic events, concomitant AP therapy, and CKD were important risk factors for ICH in anticoagulated AF patients. Moreover, ICH was more frequent in patients receiving VKA compared to NOAC. The new validated model is a step toward mitigating this potentially lethal complication.

Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data. Methods: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. Results: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74-0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87-0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37-0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74-1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95-1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21-0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83-0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45-0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (P=0.01) and lower creatinine clearance (P=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (P=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01) versus warfarin. Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.

HomeCirculationVol. 146, No. 12Duration of Anticoagulation Interruption Before Invasive Procedures and Outcomes in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBDuration of Anticoagulation Interruption Before Invasive Procedures and Outcomes in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial Sana M. Al-Khatib, Daniel M. Wojdyla, Christopher B. Granger, Lars Wallentin, David A. Garcia, Ziad Hijazi, Claes Held, John H. Alexander, Dragos Vinereanu, Gregory C. Flaker, Elaine M. Hylek and Renato D. Lopes Sana M. Al-KhatibSana M. Al-Khatib Correspondence to: Sana M. Al-Khatib, MD, MHS, Duke Clinical Research Institute, 300 Morgan St, Durham, NC 27701. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3561-0146 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (S.M.Al-K., D.M.W., C.B.G., J.H.A., R.D.L.). , Daniel M. WojdylaDaniel M. Wojdyla Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (S.M.Al-K., D.M.W., C.B.G., J.H.A., R.D.L.). , Christopher B. GrangerChristopher B. Granger https://orcid.org/0000-0002-0045-3291 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (S.M.Al-K., D.M.W., C.B.G., J.H.A., R.D.L.). , Lars WallentinLars Wallentin Uppsala Clinical Research Center and the Department of Medical Sciences, Cardiology, Uppsala University, Sweden (L.W., Z.H., C.H.). , David A. GarciaDavid A. Garcia Hematology Division, University of Washington, Seattle (D.A.G.). , Ziad HijaziZiad Hijazi https://orcid.org/0000-0002-7420-743X Uppsala Clinical Research Center and the Department of Medical Sciences, Cardiology, Uppsala University, Sweden (L.W., Z.H., C.H.). , Claes HeldClaes Held https://orcid.org/0000-0001-9402-7404 Uppsala Clinical Research Center and the Department of Medical Sciences, Cardiology, Uppsala University, Sweden (L.W., Z.H., C.H.). , John H. AlexanderJohn H. Alexander https://orcid.org/0000-0002-1444-2462 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (S.M.Al-K., D.M.W., C.B.G., J.H.A., R.D.L.). , Dragos VinereanuDragos Vinereanu https://orcid.org/0000-0002-9054-8779 University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital, Bucharest, Romania (D.V.). , Gregory C. FlakerGregory C. Flaker Division of Cardiology, University of Missouri, Columbia, MO (G.C.F.). , Elaine M. HylekElaine M. Hylek Boston University School of Medicine, Boston, MA (E.M.H.). and Renato D. LopesRenato D. Lopes https://orcid.org/0000-0003-2999-4961 Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (S.M.Al-K., D.M.W., C.B.G., J.H.A., R.D.L.). Originally published19 Sep 2022https://doi.org/10.1161/CIRCULATIONAHA.122.059438Circulation. 2022;146:958–960Factor Xa inhibitors are the predominant type of oral anticoagulant for stroke prevention in atrial fibrillation.1 Although recommendations exist on holding these medications before procedures with a low, intermediate, or high bleeding risk, whether and for how long to interrupt these medications around the time of a procedure continue to be debated.2In a previous analysis of the ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation), the 30-day postprocedure risk of stroke and major bleeding was similarly low in apixaban- and warfarin-treated patients, regardless of whether or not anticoagulation was interrupted at the time of a procedure.3 Despite these results, many clinicians remain concerned about the risk of stroke when anticoagulation is held and the risk of bleeding when anticoagulation is not held before an invasive procedure. We conducted this subanalysis to examine how the duration of anticoagulation interruption before an invasive procedure in patients with atrial fibrillation is associated with 30-day outcomes.This post hoc descriptive analysis included patients in ARISTOTLE who underwent an invasive procedure with a known procedure date (n=10 674).4 Procedures were not included if study medication was intermittently stopped and restarted in the 7 days before a procedure (n=204) or if no doses of study medication were taken for >7 days before a procedure (n=1210), because such interruptions were assumed not to be related to the procedure. We classified each procedure as "no interruption" (no interruption of study drug or if it was interrupted on the day of the procedure) or "interruption" (interruption 1–7 days before the procedure). Outcomes examined in this analysis include 30-day stroke or systemic embolism, myocardial infarction, all-cause death, major bleeding, a composite of major or clinically relevant nonmajor bleeding (per International Society on Thrombosis and Haemostasis criteria), and a net benefit end point of stroke, systemic embolism, or major bleeding. The study was approved by institutional review committees, and all patients provided informed consent.4 The data that support the findings of this study are available from the corresponding author on reasonable request.Of 18 201 patients enrolled in ARISTOTLE, 5439 (29.9%) had a procedure that met the criteria for this analysis, and 9260 procedures (3468 with no interruption and 5792 with interruption) were identified. Of these, 8994 were nonemergency procedures and 266 were emergency procedures. The most prevalent procedures were tooth extraction/oral surgery (14.6%), colonoscopy (9.9%), eye surgery (8.0%), upper gastrointestinal endoscopy (7.6%), and pacemaker implantation (3.5%). In 11.7% of the procedures, bridging with a parenteral anticoagulant was undertaken either before or after the procedure. In patients who interrupted study drug (n=5792), 38.1% were on study drug 1 day after the procedure, 57.8% were on it 2 days after the procedure, and 17.1% did not restart study drug within 8 days after the procedure. The number of patients stopping study drug 5 to 7 days before the procedure was slightly higher in the warfarin (25.1%) than in the apixaban group (19.1%), the remaining rates were similar between the 2 groups. The rates of stroke/systemic embolism, myocardial infarction, death and major bleeding were <0.5% for patients on study drug 1 or 2 days after the procedure. However, for patients who did not start study drug within 8 days from the procedure, the rates of stroke, myocardial infarction, death, and major bleeding were 1%, 0.8%, 1.3%, and 5.1%, respectively. The death rate ranged from 0.26% for a 3-day interruption to 3.94% for a 1-day interruption. The main results are shown in the Figure.Download figureDownload PowerPointFigure. Associations between the duration of apixaban and warfarin interruption before an invasive procedure in patients with atrial fibrillation and 30-day outcomes.The net benefit end point includes stroke/SE or major bleeding. CRNM indicates clinically relevant nonmajor; and SE, systemic embolism.In this analysis, the risk of stroke or systemic embolism was very low (2/2314; 0.086%) when anticoagulation (with apixaban or warfarin) was interrupted for up to 3 days before a procedure, a finding that is consistent with results from the PAUSE study (Perioperative Anticoagulation Use for Surgery Evaluation).5 The risk of stroke or systemic embolism in the present study increased to 0.61% if anticoagulation was interrupted for 5 days. Major bleeding varied from 1.10% for a 3-day interruption to 2.27% for a 1-day interruption. Although the numbers for 6-day and 7-day interruptions were small, the relatively higher rates of major bleeding in those subgroups likely reflect greater morbidity and higher use of bridging. The higher rate of death in the 1-day interruption group likely conveys the need for urgent procedures on acutely ill patients and major periprocedural bleeding.Our study's strengths include a large sample size and prospective and rigorous data. Key limitations are that the day of interruption before a procedure was not randomized, the number of patients in certain subgroups was too small to allow meaningful inferences, and with how data were collected, we could not discern if the study drug was interrupted for ≤2 consecutive doses. Also, decisions regarding interruption of anticoagulation in clinical practice where the type of anticoagulant is known are different from those made in the context of a double-blind, double-dummy clinical trial like ARISTOTLE.In conclusion, in the context of the ARISTOTLE trial, a 2- to 3-day interruption of apixaban appeared to be associated with the most favorable efficacy and safety profiles, including a low risk of stroke or systemic embolism and a low risk of major bleeding. This observation should be examined in future studies for further validation.Article InformationRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00412984.Sources of FundingThe ARISTOTLE study (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) was funded by Bristol-Myers Squibb and Pfizer, Inc. Dr Al-Khatib has received research grants from the National Institutes of Health. Dr Granger received research grants from the Food and Drug Administration and consulting/speaker fees from the National Institutes of Health. Dr Hijazi received research support from the Swedish Society for Medical Research (S17-0133) and the Swedish Heart-Lung Foundation (20200722). Dr Held received research grants from Swedish Heart and Lung foundation. Dr Alexander received research grants from the Food and Drug Administration and the National Institutes of Health.Disclosures Dr Al-Khatib received research funding from Abbott, Medtronic and Boston Scientific. Dr Granger received research grants and consulting/speaker fees from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Pfizer, AstraZeneca, and Novartis; research grants from Daichii-Sankyo, AKROS, Apple, GlaxoSmithKline; and consulting/speaker fees from Bayer Corp, Boston Scientific Corp, Abbvie, Espero BioPharma, Medscape, Merck, NovoNordisk, Roche Diagnostics, Rho Diagnostics, Sirtex, and Verseon. Dr Wallentin received institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics, Merck & Co; consulting fees from Abbott; holds 2 patents involving GDF-15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2). Dr Hijazi received research support from Uppsala University Hospital, Sweden; lecture and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Roche Diagnostics. Dr Held: received institutional research grants from Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, and Coala Life. Dr Alexander received research grants from Bayer, Bristol-Myers Squibb, CryoLife, CSL Behring, Ferring, GlaxoSmithKline, Humacyte, XaTek; and consulting fees from AbbVie, Akros, Atricure, Bristol Myers Squibb, CryoLife, Ferring, Janssen, Pfizer, Portola Pharmaceuticals, VA Cooperative Studies. Dr Vinereanu received research grants and consulting/ speaker fees from Pfizer, Boehringer Ingelheim, Bayer, Novartis, and Amgen. Dr Hylek received research support from Abbott, Anthos Therapeutics, Bristol-Myers Squibb, CryoLife, Janssen, Medtronic; consulting fees from Bayer, Boston Scientific, Medtronic; and speaker fees from Boehringer Ingelheim and Pfizer. Dr Lopes received institutional research grants and consulting fees from Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and consulting fees from Amgen, Bayer, and Boehringer Ingelheim. The other authors report no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circThis manuscript was sent to Paul Gurbel, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 960.Correspondence to: Sana M. Al-Khatib, MD, MHS, Duke Clinical Research Institute, 300 Morgan St, Durham, NC 27701. Email [email protected]duke.eduReferences1. Luo N, Xu H, Jneid H, Fonarow GC, Lopes RD, Piccini JP, Curtis AB, Russo AM, Lewis WR, Matsouaka RA, et al. Use of oral anticoagulation in eligible patients discharged with heart failure and atrial fibrillation.Circ Heart Fail. 2018; 11:e005356. doi: 10.1161/CIRCHEARTFAILURE.118.005356LinkGoogle Scholar2. Doherty JU, Gluckman TJ, Hucker WJ, JanuzziOrtel JLTL, Saxonhouse SJ, Spinler SA. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force.J Am Coll Cardiol. 2017; 69:871–898. doi: 10.1016/j.jacc.2016.11.024CrossrefMedlineGoogle Scholar3. Garcia D, Alexander JH, Wallentin L, Wojdyla DM, Thomas L, Hanna M, Al-Khatib SM, Dorian P, Ansell J, Commerford P, et al. Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures.Blood. 2014; 124:3692–3698. doi: 10.1182/blood-2014-08-595496CrossrefMedlineGoogle Scholar4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365:981–992. doi: 10.1056/NEJMoa1107039CrossrefMedlineGoogle Scholar5. Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, Vanassche T, Verhamme P, Shivakumar S, Gross PL, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant.JAMA Intern Med. 2019; 179:1469–1478. doi: 10.1001/jamainternmed.2019.2431CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wang L, Zhang Y, Zhou W, Chen J, Li Y, Tang Q, Chen B, Zhang H, Zellmer L, Chen J, Chen Z, Li W, Liu X and Zhou H (2023) Relationship between left atrial appendage peak flow velocity and nonvalvular atrial fibrillation recurrence after cryoablation, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2023.1053102, 10 September 20, 2022Vol 146, Issue 12 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.059438PMID: 36121911 Originally publishedSeptember 19, 2022 Keywordsatrial fibrillationembolism, paradoxicalstrokehemorrhageapixabananticoagulantsPDF download Advertisement SubjectsAtrial Fibrillation

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Atrial fibrillation (AF) is associated with increased risk of healthcare utilization (HCU), which may be triggered by onset of AF or change in burden. Change from baseline of AF burden or other parameters measured by insertable cardiac monitors (ICM) may be useful to predict near-term (HCU).

Biomarkers predict risk for heart failure in patients with atrial fibrillation: Insights from the ARISTOTLE trial

Introduction: Apixaban dosing in atrial fibrillation (AF) is 5 mg BID or 2.5 mg BID in patients with ≥2 dose-reduction criteria: age >80 years, weight <60 kg, or creatinine >1.5 mg/dl. There is a question of whether drug monitoring might be useful to guide dosing, particularly in patients with extremely high or low body weight (BW). Previous work has demonstrated that the effects of apixaban versus warfarin are similar across BWs. We aimed to investigate the relationship between BW and exposure to apixaban in patients with AF. Methods: Exposure to apixaban was assessed as area under the curve steady state (AUC SS ) using population pharmacokinetics (PK) data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. The relationship between BW and AUC SS was assessed continuously and by BW categories of ≤60kg, >60-120kg, or >120kg overall and by apixaban dose. Results: Of patients with PK data (n=2924), 8.9% were ≤60kg, and 5.8% >120kg. Compared to the overall group, patients ≤60kg were more likely to be older (74 vs 70 years), female (67 vs 33%), had lower creatinine (0.92 vs 1.02 mg/dL) and higher CHA 2 DS 2 -VASc scores (3.9 vs 3.4). There was a weak but significant correlation between BW and AUC SS assessed continuously (correlation -0.38, p<0.001) and by BW group: ≤60kg [median AUCSS 4089 (25 th 3073, 75 th 5148 ng•hr/ml)], >60-120kg [3566 (2926, 4286 ng•hr/ml)], and >120kg [2699 (2284, 3226 ng•hr/ml)] (p<0.001) (Figure). This relationship persisted with stratification by apixaban dose (data not shown). Conclusions: There is a significant relationship between body weight and predicted exposure to apixaban, including at the extremes of BW, but with wide variation in exposure at every weight. This variation, and the absence of an association between body weight and apixaban’s observed safety and efficacy compared with warfarin, make it unlikely that routine therapeutic monitoring of apixaban will be clinically useful.