Predictors of intracranial hemorrhage in patients with atrial fibrillation treated with oral anticoagulants: Insights from the GARFIELD-AF and ORBIT-AF registries.

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.

Guideline-directed medical therapies for comorbidities among patients with atrial fibrillation: results from GARFIELD-AF.

Aims: This study aimed to identify relationships in recently diagnosed atrial fibrillation (AF) patients with respect to anticoagulation status, use of guideline-directed medical therapy (GDMT) for comorbid cardiovascular conditions (co-GDMT), and clinical outcomes. The Global Anticoagulant Registry in the FIELD (GARFIELD)-AF is a prospective, international registry of patients with recently diagnosed non-valvular AF at risk of stroke (NCT01090362). Methods and results: Guideline-directed medical therapy was defined according to the European Society of Cardiology guidelines. This study explored co-GDMT use in patients enrolled in GARFIELD-AF (March 2013-August 2016) with CHA2DS2-VASc ≥ 2 (excluding sex) and ≥1 of five comorbidities-coronary artery disease, diabetes mellitus, heart failure, hypertension, and peripheral vascular disease (n = 23 165). Association between co-GDMT and outcome events was evaluated with Cox proportional hazards models, with stratification by all possible combinations of the five comorbidities. Most patients (73.8%) received oral anticoagulants (OACs) as recommended; 15.0% received no recommended co-GDMT, 40.4% received some, and 44.5% received all co-GDMT. At 2 years, comprehensive co-GDMT was associated with a lower risk of all-cause mortality [hazard ratio (HR) 0.89 (0.81-0.99)] and non-cardiovascular mortality [HR 0.85 (0.73-0.99)] compared with inadequate/no GDMT, but cardiovascular mortality was not significantly reduced. Treatment with OACs was beneficial for all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use; only in patients receiving all co-GDMT was OAC associated with a lower risk of non-haemorrhagic stroke/systemic embolism. Conclusion: In this large prospective, international registry on AF, comprehensive co-GDMT was associated with a lower risk of mortality in patients with AF and CHA2DS2-VASc ≥ 2 (excluding sex); OAC therapy was associated with reduced all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use. Clinical Trial Registration: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Clinical outcomes of left atrial appendage occlusion versus direct oral anticoagulation in patients with atrial fibrillation and prior ischemic stroke: A propensity-score matched study.

BACKGROUND: This propensity-score matched study investigated clinical outcomes associated with left atrial appendage occlusion (LAAO) versus direct oral anticoagulation (DOAC) in patients with AF and prior ischemic stroke. METHODS: AF patients enrolled in the Amulet Observational Study with a history of ischemic stroke and successful LAAO (n = 299) were compared with a propensity-score matched cohort of incident AF patients with prior ischemic stroke and treated by DOAC (n = 301). The control cohort was identified through the Danish National Patient Registries. Propensity score matching was based on covariates of the CHA2DS2-VASc and HAS-BLED scores, with a 1:2 ratio and using Greedy 5:1 digit matching with replacement. The analysis included 2-years follow-up, with a primary composite outcome of ischemic stroke, major bleeding (BARC ≥ 3) or all-cause mortality. RESULTS: Mean (SD) CHA2DS2-VASc scores were 5.26 (1.42) and 5.40 (1.31) and HAS-BLED scores were 3.95 (0.91) and 4.03 (0.96), for the LAAO and DOAC group, respectively. Total number of primary composite outcome events were 61 (12.4 events/100 patient-years) and 117 (26.9 events/100 patient-years) in the LAAO and DOAC group, respectively. Risk of the primary composite outcome was significantly lower in the LAAO group, hazard rate ratio [HR] 0.48 (95% CI: 0.35-0.65). Ischemic stroke risk was comparable, HR 0.71 (95% CI: 0.34-1.45), while risk of major bleeding, HR 0.41 (95% CI: 0.25-0.67), and all-cause mortality, HR 0.48 (95% CI: 0.32-0.71), were significantly lower with LAAO. Cardiovascular mortality did not differ statistically between the LAAO and DOAC group, HR 0.75 (95% CI: 0.39-1.42). Results were consistent across sensitivity analyses. CONCLUSION: This study indicated significantly lower risk of the composite outcome of stroke, major bleeding and all-cause mortality with LAAO therapy compared to DOAC, in patients with AF and prior stroke. The stroke prevention effectiveness appeared similar, with a significantly lower risk of major bleeding events with LAAO. The suggested clinical benefit of LAAO over DOAC require confirmation in the ongoing randomized OCCLUSION-AF trial.

Identification of undiagnosed atrial fibrillation using a machine learning risk-prediction algorithm and diagnostic testing (PULsE-AI) in primary care: a multi-centre randomized controlled trial in England.

Aims: The aim of the PULsE-AI trial was to assess the effectiveness of a machine learning risk-prediction algorithm in conjunction with diagnostic testing for identifying undiagnosed atrial fibrillation (AF) in primary care in England. Methods and results: Eligible participants (aged ≥30 years without AF diagnosis; n = 23 745) from six general practices in England were randomized into intervention and control arms. Intervention arm participants, identified by the algorithm as high risk of undiagnosed AF (n = 944), were invited for diagnostic testing (n = 256 consented); those who did not accept the invitation, and all control arm participants, were managed routinely. The primary endpoint was the proportion of AF, atrial flutter, and fast atrial tachycardia diagnoses during the trial (June 2019-February 2021) in high-risk participants. Atrial fibrillation and related arrhythmias were diagnosed in 5.63% and 4.93% of high-risk participants in intervention and control arms, respectively {odds ratio (OR) [95% confidence interval (CI)]: 1.15 (0.77-1.73), P = 0.486}. Among intervention arm participants who underwent diagnostic testing (28.1%), 9.41% received AF and related arrhythmia diagnoses [vs. 4.93% (control); OR (95% CI): 2.24 (1.31-3.73), P = 0.003]. Conclusion: The AF risk-prediction algorithm accurately identified high-risk participants in both arms. While the proportions of AF and related arrhythmia diagnoses were not significantly different between high-risk arms, intervention arm participants who underwent diagnostic testing were twice as likely to receive arrhythmia diagnoses compared with routine care. The algorithm could be a valuable tool to select primary care groups at high risk of undiagnosed AF who may benefit from diagnostic testing.

Clinical Outcomes Associated With Left Atrial Appendage Occlusion Versus Direct Oral Anticoagulation in Atrial Fibrillation.

OBJECTIVES: This study sought to investigate clinical outcomes associated with left atrial appendage occlusion (LAAO) versus direct oral anticoagulants (DOACs) in patients with high-risk atrial fibrillation (AF). BACKGROUND: LAAO has been shown to be noninferior to warfarin for stroke prevention in AF. However, anticoagulation with DOACs is now preferred over warfarin as thromboprophylaxis in AF. METHODS: Patients with AF enrolled in the Amulet Observational Registry (n = 1,088) who had successful LAAO with the Amplatzer Amulet device (n = 1,078) were compared with a propensity score-matched control cohort of incident AF patients (n = 1,184) treated by DOACs identified from Danish national patient registries. Propensity score matching was based on the covariates of the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category) and HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol) scores for predicting stroke and bleeding. The primary outcome was a composite of ischemic stroke, major bleeding (Bleeding Academic Research Consortium ≥3), or all-cause mortality, and follow-up was 2 years. RESULTS: AF patients treated with LAAO had a significantly lower risk of the primary composite outcome as compared with patients treated with DOACs (hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.49 to 0.67). Total events and event rates per 100 patient-years were (LAAO vs. DOACs) 256 vs. 461 and 14.5 vs. 25.7, respectively. The risk of ischemic stroke was comparable between groups (HR: 1.11; 95% CI: 0.71 to 1.75), while risk of major bleeding (HR: 0.62; 95% CI: 0.49 to 0.79) and all-cause mortality (HR: 0.53; 95% CI: 0.43 to 0.64) were significantly lower in patients treated with LAAO. CONCLUSIONS: Among high-risk AF patients, LAAO in comparison with DOACs may have similar stroke prevention efficacy but lower risk of major bleeding and mortality.

The 4S-AF Scheme (Stroke Risk; Symptoms; Severity of Burden; Substrate): A Novel Approach to In-Depth Characterization (Rather than Classification) of Atrial Fibrillation.

Atrial fibrillation (AF) is a complex condition requiring holistic management with multiple treatment decisions about optimal thromboprophylaxis, symptom control (and prevention of AF progression), and identification and management of concomitant cardiovascular risk factors and comorbidity. Sometimes the information needed for treatment decisions is incomplete, as available classifications of AF mostly address a single domain of AF (or patient)-related characteristics. The most widely used classification of AF based on AF episode duration and temporal patterns (that is, the classification to first-diagnosed, paroxysmal, persistent/long-standing persistent, and permanent AF) has contributed to a better understanding of AF prevention and treatment but its limitations and the need for a multidimensional AF classification have been recognized as more complex treatment options became available. We propose a paradigm shift from classification toward a structured characterization of AF, addressing specific domains having treatment and prognostic implications to become a standard in clinical practice, thus aiming to streamline the assessment of AF patients at all health care levels facilitating communication among physicians, treatment decision-making, and optimal risk evaluation and management of AF patients. Specifically, we propose the 4S-AF structured pathophysiology-based characterization (rather than classification) scheme that includes four AF- and patient-related domains-Stroke risk, Symptoms, Severity of AF burden, and Substrate severity-and provide a hypothetical model for the use of 4S-AF characterization scheme to aid treatment decision making concerning the management of patients with AF in clinical practice.

Mortality in Patients With Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants.

BACKGROUND: The recommended doses for direct oral anticoagulants (DOACs) to prevent stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) are described in specific regulatory authority approvals. OBJECTIVES: The impact of DOAC dosing, according to the recommended guidance on all-cause mortality, stroke/SE, and major bleeding, was assessed at 2-year follow-up in patients with newly diagnosed AF. METHODS: Of a total of 34,926 patients enrolled (2013 to 2016) in the prospective GARFIELD-AF (Global Anticoagulant Registry in the FIELD-AF), 10,426 patients received a DOAC. RESULTS: The majority of patients (72.9%) received recommended dosing, 23.2% were underdosed, and 3.8% were overdosed. Nonrecommended dosing (underdosage and overdosage combined) compared with recommended dosing was associated with a higher risk of all-cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.48); HR: 1.25 (95% CI: 1.04 to 1.50) for underdosing, and HR: 1.19 (95% CI: 0.83 to 1.71) for overdosing. The excess deaths were cardiovascular including heart failure and myocardial infarction. The risks of stroke/SE and major bleeding were not significantly different irrespective of the level of dosing, although underdosed patients had a significantly lower risk of bleeding. A nonsignificant trend to higher risks of stroke/SE (HR: 1.51; 95% CI: 0.79 to 2.91) and major bleeding (HR: 1.29; 95% CI: 0.59 to 2.78) was observed in patients with overdosing. CONCLUSIONS: In GARFIELD-AF, most patients received the recommended DOAC doses according to country-specific guidelines. Prescription of nonrecommended doses was associated with an increased risk of death, mostly cardiovascular death, compared with patients on recommended doses, after adjusting for baseline factors. (Global Anticoagulant Registry in the Field-AF [GARFIELD-AF]; NCT01090362).

'Real-world' observational studies in arrhythmia research: data sources, methodology, and interpretation. A position document from European Heart Rhythm Association (EHRA), endorsed by Heart Rhythm Society (HRS), Asia-Pacific HRS (APHRS), and Latin America HRS (LAHRS)

The field of observational studies or "real world studies" is in rapid development with many new techniques introduced and increased understanding of traditional methods. For this reason, the current paper provides an overview of current methods with focus on new techniques. Some highlights can be emphasized: We provide an overview of sources of data for observational studies. There is an overview of sources of bias and confounding. Next There is an overview of causal inference techniques that are increasingly used. The most commonly used techniques for statistical modelling are reviewed with focus on the important distinction of risk versus prediction. The final section provides examples of common problems with reporting observational data.

New artificial intelligence prediction model using serial prothrombin time international normalized ratio measurements in atrial fibrillation patients on vitamin K antagonists: GARFIELD-AF.

AIMS: Most clinical risk stratification models are based on measurement at a single time-point rather than serial measurements. Artificial intelligence (AI) is able to predict one-dimensional outcomes from multi-dimensional datasets. Using data from Global Anticoagulant Registry in the Field (GARFIELD)-AF registry, a new AI model was developed for predicting clinical outcomes in atrial fibrillation (AF) patients up to 1 year based on sequential measures of prothrombin time international normalized ratio (PT-INR) within 30 days of enrolment. METHODS AND RESULTS: Patients with newly diagnosed AF who were treated with vitamin K antagonists (VKAs) and had at least three measurements of PT-INR taken over the first 30 days after prescription were analysed. The AI model was constructed with multilayer neural network including long short-term memory and one-dimensional convolution layers. The neural network was trained using PT-INR measurements within days 0-30 after starting treatment and clinical outcomes over days 31-365 in a derivation cohort (cohorts 1-3; n = 3185). Accuracy of the AI model at predicting major bleed, stroke/systemic embolism (SE), and death was assessed in a validation cohort (cohorts 4-5; n = 1523). The model's c-statistic for predicting major bleed, stroke/SE, and all-cause death was 0.75, 0.70, and 0.61, respectively. CONCLUSIONS: Using serial PT-INR values collected within 1 month after starting VKA, the new AI model performed better than time in therapeutic range at predicting clinical outcomes occurring up to 12 months thereafter. Serial PT-INR values contain important information that can be analysed by computer to help predict adverse clinical outcomes.

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation? The prospective global anticoagulant registry in the FIELD-Atrial Fibrillation.

BACKGROUND: Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using prospective cohort data from a large global population of patients with nonvalvular AF, we sought to identify any differences in the use of anticoagulants for stroke prevention in women and men. METHODS AND RESULTS: This was a prospective multicenter observational registry with 858 randomly selected sites in 30 countries. A total of 17 184 patients with newly diagnosed (≤6 weeks) nonvalvular AF and ≥1 additional investigator-defined stroke risk factor(s) were recruited (March 2010 to June 2013). The main outcome measure was the use of anticoagulants (vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors) for stroke prevention at AF diagnosis. Of 17 184 patients enrolled, 43.8% were women. More women than men were at moderate-to-high risk of stroke (CHADS2 score ≥2: 65.1% versus 54.7%). Rates of anticoagulant use were not different overall (60.9% of men versus 60.8% of women) and in patients with a CHADS2 score ≥2 (adjusted odds ratio for women versus men, 1.00; 95% confidence interval, 0.92-1.09). In patients at low risk (CHA2DS2-VASc of 0 in men and 1 in women), 41.8% of men and 41.1% of women received an anticoagulant. In patients at high risk (CHA2DS2-VASc score ≥2), 35.4% of men and 38.4% of women did not receive an anticoagulant. CONCLUSIONS: These contemporary global data show that anticoagulant use for stroke prevention is no different in men and women with nonvalvular AF. Thromboprophylaxis was, however, suboptimal in substantial proportions of men and women, with underuse in those at moderate-to-high risk of stroke and overuse in those at low risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

A nonparametric approach to QT interval correction for heart rate.

We propose to use generalized additive models to fit the relationship between QT interval and RR (RR = 60/heart rate), and develop two new methods for correcting the QT for heart rate: the linear additive model and log-transformed linear additive model. The proposed methods are compared with six commonly used parametric models that were used in four clinical trial data sets and a simulated data set. The results show that the linear additive models provide the best fit for the vast majority of individual QT-RR profiles. Moreover, the QT correction formula derived from the linear additive model outperforms other correction methods.