Global Anticoagulant Registry Research Articles

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF

BackgroundThe extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition...

Country and health expenditure are major predictors of withholding anticoagulation in atrial fibrillation patients at high risk of stroke

BackgroundGuidelines for patients with atrial fibrillation (AF) at high thromboembolic risk recommend oral anticoagulants (OACs) for preventing stroke and systemic embolism (SE). The reasons for guideline non-adherence are still unclear.AimThe...

Rhythm versus rate control in patients with newly diagnosed atrial fibrillation – Observations from the GARFIELD-AF registry

BackgroundInvestigate real-world outcomes of early rhythm versus rate control in patients with recent onset atrial fibrillation. MethodsThe Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is an international multi-centre, non-interventional prospective registry of newly diagnosed (≤6 weeks’ duration) atrial fibrillation patients at risk for stroke. Patients were stratified according to treatment initiated at baseline (≤48 days post enrolment), and outcome risks evaluated by overlap propensity weighted Cox proportional-hazards models. ResultsOf 45,382 non-permanent atrial fibrillation patients, 23,858 (52.6 %) received rhythm control and 21,524 (47.4 %) rate control. Rhythm-controlled patients had lower median age (68.0 [Q1;Q3: 60.0;76.0] versus 73.0 [65.0;79.0]), fewer histories of stroke/transient ischemic attack/systemic embolism (9.4 % versus 13.0 %), and lower expected probabilities of death (median GARFIELD-AF death score 4.0 [2.3;7.5] versus 5.1 [2.8;9.2]). The two groups had the same median CHA2DS2-VASc scores (3.0 [2.0;4.0]) and similar proportions of anticoagulated patients (rhythm control: 66.0 %, rate control: 65.5 %). The propensity-score-weighted hazard ratios of rhythm vs rate control (reference) were 0.85 (95 % CI: 0.79–0.92, p-value < 0.0001) for all-cause mortality, 0.84 (0.72–0.97, p-value 0.020) for non-haemorrhagic stroke/systemic embolism and 0.90 (0.78–1.04, p-value 0.164) for major bleeding. ConclusionRhythm control strategy was initiated in about half of the patients with newly diagnosed non-valvular non-permanent atrial fibrillation. After balancing confounders, significantly lower risks of all-cause mortality and non-haemorrhagic stroke were observed in patients who received early rhythm control.

Comparing U.S. and Canadian treatment patterns on venous thromboembolism outcomes in the GARFIELD-VTE registry

BackgroundEconomically developed countries continue to find that venous thromboembolism (VTE) is a major cause of morbidity and mortality. ObjectiveTo compare baseline risk profiles and patient workflow patterns between the United States (U.S.) and Canadian management of VTE patients from 2014 to 2017. MethodsThe Global Anticoagulant Registry in the FIELD (GARFIELD-VTE) is a prospective, observational study of 10,679 patients with objectively confirmed VTE, followed for 3 years. In total 1101 patients enrolled in the U.S. and Canada were included in this analysis. ResultsMedian age and body mass index were comparable between the U.S. (60.5; 30.2) and Canadian (59.7; 29) patients. A higher percentage of U.S. patients were black (n = 128, 24.1 %; n = 22, 3.9 %) and had a higher VTE-associated risk profile, including immobilization, hospitalization, and recent surgery. U.S. patients had a higher combined DVT and PE primary diagnoses (20.3 %) and were more likely to be treated in hospitals (77.2 %) than Canadians (13.3 %; 48.1 %). Direct oral anticoagulant therapy (DOAC) was nearly two-fold more frequent in Canadian patients (n = 218, 39.2 %) at the end of 3 years in comparison to the U.S. (n = 118, 23.0 %). Adjusted for sex, recent bleed event, heart failure, chronic immobilization, family history of VTE, history of cancer and prior VTE, and renal insufficiency, the risk of all-cause mortality was 51.9 % higher in patients from the U.S. compared to those in Canada after 3 years. Patients from the U.S. also had a higher likelihood of hospitalization, major bleeding, and recurrent VTE after controlling for prior history and comorbid conditions. ConclusionHigher rates of adverse VTE-associated outcomes in the U.S. may be attributed to different baseline risk profiles, facility care, and distribution of specialists and their subsequent treatment strategies. Type of researchGlobal, multicentre, non-interventional, prospective registry titled Global Anticoagulant Registry in the FIELD – Venous Thromboembolism (GARFIELD-VTE). Key findings531 U.S. and 557 Canadians patients included in study. DOAC use more frequent in Canadian patients after 3 years than U.S. (39.2 % vs. 23.0 %, respectively). Adjusted for sex, recent bleed event, heart failure, chronic immobilization, family history of VTE, history of cancer and prior VTE, and renal insufficiency, all-cause mortality risk remained higher in U.S. patients vs. Canadian patients after 3 years. U.S. patients had higher likelihood of hospitalization, major bleeding, and recurrent VTE. Take-home messageHigher rates of adverse VTE-associated outcomes in the U.S. may be attributed to different baseline risk profiles, facility care, and composition of specialists and their subsequent treatment strategies. Table of contents summaryGlobal, multicentre, non-interventional, prospective registry titled Global Anticoagulant Registry in the FIELD – Venous Thromboembolism (GARFIELD-VTE). Higher rates of adverse VTE-associated outcomes were observed in U.S. patients vs Canadian patients, which may be attributed to different baseline risk profiles, facility care, and distribution of specialists and their subsequent treatment strategies.

Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

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

An unmet need exists to reliably predict the risk of intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs). An externally validated model improves ICH risk stratification. 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. 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. 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.

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). 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. 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-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Determinants and clinical outcomes of patients who refused anticoagulation: findings from the global GARFIELD-AF registry

ObjectiveThere is a substantial incidence of stroke in patients with atrial fibrillation (AF) not receiving anticoagulation. The reasons for not receiving anticoagulation are generally attributed to clinician’s choice, however, a...

Rhythm versus rate control in patients with newly diagnosed atrial fibrillation: observations from the GARFIELD-AF registry

Abstract Background Atrial fibrillation is associated with considerable morbidity and mortality. Real-world reports on the effect of early rhythm control on patient outcomes in patient with recent onset atrial fibrillation are limited. Purpose To assess the effect of early rhythm versus rate control on clinical outcomes in patients with newly diagnosed non-valvular atrial fibrillation. Method The Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is a non-interventional registry of adult (≥18 years) patients with newly diagnosed atrial fibrillation (≤ six weeks' duration) and at least one investigator determined risk factor for stroke. Patients were enrolled in 1317 participating sites in 35 countries between March 2010 and August 2016. Patients with permanent atrial fibrillation were excluded. Stratification to rhythm or rate control was based on treatment strategy initiated at baseline (≤48 days post enrolment). Rhythm control was defined as investigator reported initiation of rhythm control (antiarrhythmic drug(s), cardioversion, or ablation – alone or in combination with rate modifiers). Rate control was defined as investigator reported initiation of rate control and absence of rhythm control therapy. Overlap propensity weighting and Cox proportional-hazards models were used to evaluate effect on outcomes. Results Of 45,382 included patients, 23,858 (52.6%) received rhythm control and 21,524 (47.4%) rate control. Rates of rhythm control were similar throughout the study time period (52.7% in 2010/2011, 54.2% in 2015/2016). Patients in the rhythm control group were younger (median age (Q1; Q3) 68.0 (60.0; 76.0) versus 73.0 (65.0; 79.0)), had lower rates of prior stroke/transitory ischemic attack/systemic embolism (9.4% vs 13.0%), and a lower median GARFIELD death score (4.0 (2.3; 7.5) versus 5.1 (2.8; 9.2)). Median CHA2DS2-VASc Scores were 3.0 (2.0; 4.0) in both groups. Rate of anticoagulation treatment was similar in the rhythm and rate control group (66.0% versus 65.5%). After propensity score overlap weighting, patients of the two groups were well balanced on all observed characteristics. Event rates per 100 person-years (95% confidence interval [CI]) over two years follow-up in the rhythm and rate control group were 2.94 (2.78–3.10) versus 4.43 (4.22–4.64) for mortality, 0.84 (0.75–0.92) versus 1.16 (1.05–1.27) for non-haemorrhagic stroke/systemic embolism and 0.84 (0.76–0.93) versus 1.16 (1.06–1.27) for major bleeding. Adjusted hazard ratios (95% CI) for the same time period were 0.85 (0.79–0.92), 0.84 (0.72–0.97) and 0.9 (0.78–1.04). Conclusion In this large, internation registry, a rhythm control strategy was initiated at baseline in about half of the patients with newly diagnosed non-valvular atrial fibrillation. After adjustment for confounding factors, a significantly lower risk of all-cause mortality and non-haemorrhagic stroke/systemic embolism were observed for patients that received an early rhythm control strategy. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by the Thrombosis Research Institute (London, UK).

On-treatment Comparative Effectiveness of Vitamin K Antagonists and Direct Oral Anticoagulants in GARFIELD-VTE, and Focus on Cancer and Renal Disease.

Background Direct oral anticoagulants (DOACs) provide a safe, effective alternative to vitamin K antagonists (VKAs) for venous thromboembolism (VTE) treatment, as shown via intention-to-treat comparative effectiveness analysis. However, on-treatment analysis is imperative in observational studies because anticoagulation choice and duration are at investigators' discretion. Objectives The aim of the study is to compare the effectiveness of DOACs and VKAs on 12-month outcomes in VTE patients using on-treatment analysis. Methods The Global Anticoagulant Registry in the FIELD - VTE (GARFIELD-VTE) is a world-wide, prospective, non-interventional study observing treatment of VTE in routine clinical practice. Results In total, 8,034 patients received VKAs ( n = 3,043, 37.9%) or DOACs ( n = 4,991, 62.1%). After adjustment for baseline characteristics and follow-up bleeding events, and accounting for possible time-varying confounding, all-cause mortality was significantly lower with DOACs than VKAs (hazard ratio: 0.58 [95% confidence interval 0.42-0.79]). Furthermore, patients receiving VKAs were more likely to die of VTE complications (4.9 vs. 2.2%) or bleeding (4.9 vs. 0.0%). There was no significant difference in rates of recurrent VTE (hazard ratio: 0.74 [0.55-1.01]), major bleeding (hazard ratio: 0.76 [0.47-1.24]), or overall bleeding (hazard ratio: 0.87 [0.72-1.05]) with DOACs or VKAs. Unadjusted analyses suggested that VKA patients with active cancer or renal insufficiency were more likely to die than patients treated with DOAC (52.51 [37.33-73.86] vs. 26.52 [19.37-36.29] and 9.97 [7.51-13.23] vs. 4.70 [3.25-6.81] per 100 person-years, respectively). Conclusion DOACs and VKAs had similar rates of recurrent VTE and major bleeding. However, DOACs were associated with reduced all-cause mortality and a lower likelihood of death from VTE or bleeding compared with VKAs.

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use.

Efficacy and safety of various antithrombotic regimens after left atrial appendage occlusion

Aim. To evaluate the efficacy and safety of various antithrombotic regimens after left atrial appendage occlusion (LAAO) in real clinical practice.Material and methods. This prospective observational study included 90 patients with nonvalvular atrial fibrillation and a high risk of ischemic stroke/systemic embolism who underwent endovascular LAAO using the Watchman device. The primary endpoint was the cumulative incidence of ischemic stroke/transient ischemic attack/systemic embolism, major and clinically relevant bleeding according to the Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD) criteria, and all-cause mortality.Results. Patients were divided into subgroups depending on the antithrombotic therapy carried out after LAAO: 1) direct oral anticoagulants (DOACs) ± antiplatelet agents; 2) warfarin ± antiplatelet agents; 3) dual antiplatelet therapy (aspirin + clopidogrel). Multivariate analysis showed a trend toward a lower incidence of the primary endpoint in the DOAC group compared with both warfarin (hazard ratio, 8,49; 95% confidence interval: 2,0-36,15; p=0,004) and antiplatelet agents (hazard ratio, 4,34; 95% confidence interval: 1,08-17,36; p=0,038). At the same time, there were no significant differences in the prevalence of primary endpoint between the warfarin and antiplatelet groups. There was no relationship between device-related thrombosis and postoperative antithrombotic regimen.Conclusion. Endovascular LAAO is an effective and safe alternative to anticoagulant therapy. The present real-world evidence study revealed that the administration of DOACs after LAAO is associated with a greater efficacy and safety profile compared to warfarin and dual antiplatelet therapy.

Use of anticoagulant drugs in patients with atrial fibrillation. Does adherence to therapy have a prognostic impact?

Anticoagulant therapy represents a pivotal element that strongly influences the thromboembolic risk of non-valvular atrial fibrillation (NVAF) subjects. The main purpose of this review was to identify issues and suggest strategies to improve the oral anticoagulants (OACs) treatment adherence, which is the most important predictor of NVAF outcome. Advantages, efficacy, and impact of these drugs on patients' prognosis were revealed in important clinical trials on large cohorts of patients and are often prescribed nowadays. A real-life data registry, the Global Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) analyzed the profile and outcome of patients diagnosed with NVAF receiving oral antithrombotic treatment. The observations gathered in the registry were crucial for identifying relevant elements that clinicians must improve, such as adherence strategies and predisposing factors that correlated with stroke. Adherence to OACs in AF patients is essential from the viewpoint of clinical efficacy and safety. Major adverse events and negative outcome are correlated with a weak anticoagulation control caused by an ineffective treatment adherence strategy. Solving the issue of oral anticoagulation adherence is possible using new technologies, but future directions should be explored. Mobile phone applications centered on patients' needs, telemedicine programs that evaluate patients' evolution and detect adverse reactions or events, encouraging an adequate management of the event without interruption of OACs, represent perspectives with a major impact on treatment adherence.

A treatment-specific marginal structural Cox model for the effect of treatment discontinuation.

Patients taking a prescribed medication often discontinue their treatment; however, this may negatively impact their health outcomes. If doctors had statistical evidence that discontinuing some prescribed medication shortened, on average, the time to a clinical event (e.g., death), they could use that knowledge to encourage their patients to stay on the prescribed treatment. We describe a treatment‐specific marginal structural Cox model for estimation of the causal effect of treatment discontinuation on a survival endpoint. The effect of treatment discontinuation is quantified by the hazard ratio of the event hazard rate had the population followed the regime “take treatment a until it is discontinued at some time ν,” versus the event hazard rate had the population never discontinued treatment a. Valid causal analysis requires control for treatment confounding, regime confounding, and censoring due to regime violation. We propose new inverse probability of regime compliance weights to address the three issues simultaneously. We apply the framework to data from the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD‐AF) study. Patients from this study are treated with one of two types of oral anticoagulants (OACs). We test whether the causal effect of treatment discontinuation differs by type of OAC, and we also estimate the size and direction of the effect. We find evidence that OAC discontinuation increases the hazard for certain events, but we do not find evidence that this effect differs by treatment.

Impact of a Patient's Baseline Risk on the Relative Benefit and Harm of a Preventive Treatment Strategy: Applying Trial Results in Clinical Decision Making.

BackgroundFor translating an overall trial result into an individual patient’s expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient.Methods and ResultsIn 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE‐LY (Randomized Evaluation of Long‐Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field–Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT (P=0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE‐LY trial (P=0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE‐LY trial (P<0.001) for major bleeding. Quartile‐specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26–0.61) to 1.04 (95% CI, 0.83–1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42–0.88) to 1.20 (95% CI, 0.97–1.50) for dabigatran, 150 mg, compared with warfarin.ConclusionsEffect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Cardioversion in patients with newly diagnosed non-valvular atrial fibrillation: observational study using prospectively collected registry data

ObjectiveTo investigate the clinical outcomes of patients who underwent cardioversion compared with those who did not have cardioverson in a large dataset of patients with recent onset non-valvular atrial fibrillation.DesignObservational...

Comparing rivaroxaban and apixaban in GARFIELD-AF according to ROCKET AF and ARISTOTLE trial selection criteria

Abstract Introduction There is debate on the extent to which differences in selection criteria and outcome definitions used for ARISTOTLE and ROCKET AF – the trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular atrial fibrillation – influenced their differences in outcomes relative to vitamin K antagonists (VKAs). In absence of randomized trials comparing the two non-vitamin K oral antagonists (NOACs) directly, this question can be addressed using data from the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) registry, a large, high-quality prospective observational study of newly diagnosed AF patients. Purpose To assess the influence of the ARISTOTLE and ROCKET AF inclusion and exclusion criteria on results for safety and efficacy of apixaban and rivaroxaban versus VKA using uniform endpoints in GARFIELD-AF. Methods We selected patients treated with apixaban, rivaroxaban or VKA from GARFIELD-AF who were eligible for ARISTOTLE or ROCKET AF as per the original trial criteria. We replicated the inclusion criteria in the GARFIELD-AF population and derived those eligible for each trial. We calculated the adjusted hazard ratios (HRs) for stroke or systemic embolism, major bleeding and all-cause mortality within 2 years of enrolment for apixaban as well as rivaroxaban versus VKA (reference) in those eligible for each trial. We used a propensity score overlap weighted Cox model to emulate trial randomization between NOAC and VKA. Results Among patients on apixaban, rivaroxaban and VKA, 2570/3615 (71%), 3560/4914 (72%) and 8005/11734 (71%) were eligible for ARISTOTLE, respectively, and 1612/3615 (45%), 2005/4914 (41%) and 4368/11734 (37%), respectively, were eligible for ROCKET AF. Cardiovascular co-morbidity was greater in those eligible for ROCKET AF than in those eligible for ARISTOTLE. In patients selected using the more restrictive ROCKET AF criteria, apixaban and rivaroxaban users showed similar results when compared with VKA (see Figure). The two sets of comparisons remained non-significant in difference when applying the less restrictive ARISTOTLE criteria, but there were trends for less similarity. Conclusion Apixaban showed similar results to rivaroxaban when selecting for higher-risk patients using the ROCKET AF criteria. In patients selected using ARISTOTLE criteria the similarity was less pronounced. Our results underline the problems faced in comparing treatments across rather than within clinical trials. For instance, co-morbidities were substantially different for patients recruited into the original ARISTOTLE and ROCKET AF trials. The current work points to the need for high-quality observational data for assessment of relative drug performance in absence of direct drug comparisons through randomized trials. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the GARFIELD-AF registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Safety and efficacy of apixaban and rivaroxaban versus warfarin in real-world atrial fibrillation patients are similar to their randomized trials: insights from GARFIELD-AF registry

Abstract Introduction Generalisability of patient selection in the landmark trials for the approval of apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF) for use in non-valvular atrial fibrillation (AF) is limited. Although observational data have confirmed the safety and efficacy of these non-vitamin K oral anticoagulants (NOACs) in unselected AF populations, robust replication of randomized trials in observational studies is warranted. Purpose To investigate the proportion of real-world AF patients who would have been eligible for the landmark trials for ARISTOTLE and ROCKET AF, and to assess reproducibility of these landmark trials in the largest, worldwide, prospective registry of newly diagnosed AF patients. Methods We analysed data from the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) registry. We assessed the eligibility of AF patients treated with apixaban or vitamin K antagonist (VKA) for ARISTOTLE, and those treated with rivaroxaban or VKA for ROCKET AF, using the selection criteria of the original trials. We replicated the inclusion and exclusion criteria of ARISTOTLE and ROCKET AF by deriving the set of patients eligible for each trial and calculating the adjusted hazard ratios (HRs) for stroke or systemic embolism, major bleeding, and all-cause mortality within 2 years of enrolment, using a propensity score overlap weighted Cox model. We compared the results from observational data with those reported in the original ARISTOTLE and ROCKET AF publications. Results Among all patients enrolled in GARFIELD-AF, 67% were eligible for recruitment in ARISTOTLE and 37% in ROCKET AF. The corresponding proportions among anticoagulated patients were 70% and 39%, respectively. Among patients on apixaban and VKA, 2570/3615 (71%) and 8005/11718 (68%), respectively, were eligible for ARISTOTLE. Of patients using rivaroxaban and VKA, 2005/4914 (41%) and 4368/11721 (37%), respectively, were eligible for ROCKET AF. Annual eligibility rates among real-world NOAC users were stable over time (Figure 1). Registry participants on rivaroxaban or VKA eligible for ROCKET AF had a higher burden of cardiovascular co-morbidity than those on apixaban or VKA eligible for ARISTOTLE. The adjusted HRs in observational data were compatible with results of the original trials in all selected outcomes (Figure 2). Conclusion Representativeness of ARISTOTLE and ROCKET AF for real-world AF populations was limited, with ROCKET AF's criteria being more restrictive. Despite inclusion of only incident AF cases in GARFIELD-AF versus mostly prevalent AF cases in the original trials, the results were similar. Our work indicates that the results from ARISTOTLE and ROCKET AF appear robust and reproducible in real-world patients with newly diagnosed AF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the GARFIELD-AF registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Comparative effectiveness of NOAC vs VKA in patients representing common clinical challenges: results from the GARFIELD-AF registry

Abstract Introduction Large phase III trials of non-valvular atrial fibrillation (AF) patients have shown a favourable risk-to-benefit ratio with Non-Vitamin K antagonist oral anticoagulants (NOAC) compared to Vitamin K antagonists (VKA). Although the results of these trials are directly applicable to many AF patients, important subsets of patients were under-represented. Thus, there remains uncertainty about the safety and effectiveness of NOAC therapy in common challenging scenarios. Purpose The main purpose of this study is to quantify and compare the impact of NOAC vs VKA in settings where clinical uncertainty still exists and represents a considerable proportion of AF patients in clinical practice. Methods The analysis was conducted in patients enrolled in the largest AF multinational prospective registry (the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation, GARFIELD-AF). We evaluated the effectiveness and safety of NOAC compared to VKA in three groups of patients representing common clinical challenges (CCC): 1) elderly patients (i.e. age ≥75), 2) increased bleeding risk (i.e. HAS-BLED ≥3 or prior bleeding), and 3) renal impairment (i.e. CKD stages II to IV). We applied a propensity score using an overlap weighting scheme to obtain unbiased estimates of the treatment effect within each CCC group. Weights were applied to Cox proportional hazards models to estimate the effects of the NOAC vs VKA comparison on the occurrence of death, non-haemorrhagic stroke/SE and major bleeding within 2 years of enrolment. Results Comparative effectiveness of NOAC vs VKA was assessed in 8607 elderly patients, 1711 with increased bleeding risk, and 4460 with renal impairment. The proportion of anticoagulated patients was low in patients with increased bleeding risk (59%), while in the other two CCC groups the corresponding proportion was close to the one in the overall population (72%). Among anticoagulated patients, NOAC were prescribed to 50–55% of patients in the CCC groups. Patients with a high risk of bleeding and impaired kidney function were less likely to be prescribed NOAC instead of VKA compared with the overall anticoagulated population (−5.4% and −4.7%, respectively). Propensity-weighted hazard ratios for all-cause mortality favored NOAC (vs VKA) in all three CCC groups: 0.86 (95% CI: 0.74–0.99) for elderly patients, 0.73 (0.53–1.00) for patients with increased bleeding risk, and 0.80 (0.65–0.98) for patients with renal impairment (Figure). Conclusion In the selected common challenging scenarios of AF patients, there were significant mortality reductions in favor of NOACs compared to VKAs. These observations suggest that NOACs are safe and effective in patients who are elderly, at increased bleeding risk, or renally impaired. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the GARFIELD-AF registry. The work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

Risks associated with discontinuation of oral anticoagulation in newly diagnosed patients with atrial fibrillation: Results from the GARFIELD‐AF Registry

BackgroundOral anticoagulation (OAC) in atrial fibrillation (AF) reduces the risk of stroke/systemic embolism (SE). The impact of OAC discontinuation is less well documented. ObjectiveInvestigate outcomes of patients prospectively enrolled in the Global Anticoagulant Registry in the Field‐Atrial Fibrillation study who discontinued OAC. MethodsOral anticoagulation discontinuation was defined as cessation of treatment for ≥7 consecutive days. Adjusted outcome risks were assessed in 23 882 patients with 511 days of median follow‐up after discontinuation. ResultsPatients who discontinued (n = 3114, 13.0%) had a higher risk (hazard ratio [95% CI]) of all‐cause death (1.62 [1.25–2.09]), stroke/systemic embolism (SE) (2.21 [1.42–3.44]) and myocardial infarction (MI) (1.85 [1.09–3.13]) than patients who did not, whether OAC was restarted or not. This higher risk of outcomes after discontinuation was similar for patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) (p for interactions range = 0.145–0.778). Bleeding history (1.43 [1.14–1.80]), paroxysmal vs. persistent AF (1.15 [1.02–1.29]), emergency room care setting vs. office (1.37 [1.18–1.59]), major, clinically relevant nonmajor, and minor bleeding (10.02 [7.19–13.98], 2.70 [2.24–3.25] and 1.90 [1.61–2.23]), stroke/SE (4.09 [2.55–6.56]), MI (2.74 [1.69–4.43]), and left atrial appendage procedures (4.99 [1.82–13.70]) were predictors of discontinuation. Age (0.84 [0.81–0.88], per 10‐year increase), history of stroke/transient ischemic attack (0.81 [0.71–0.93]), diabetes (0.88 [0.80–0.97]), weeks from AF onset to treatment (0.96 [0.93–0.99] per week), and permanent vs. persistent AF (0.73 [0.63–0.86]) were predictors of lower discontinuation rates. ConclusionsIn GARFIELD‐AF, the rate of discontinuation was 13.0%. Discontinuation for ≥7 consecutive days was associated with significantly higher all‐cause mortality, stroke/SE, and MI risk. Caution should be exerted when considering any OAC discontinuation beyond 7 days.