Emulation of ARISTOTLE and ROCKET AF trials in real-world atrial fibrillation patients results in similar efficacy and safety as original landmark trials: insights from the GARFIELD-AF registry

Abstract

Aims: This study aimed to determine the robustness, reproducibility and representativeness of the landmark Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (AF) (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF (ROCKET AF) randomised trials through replication in an observational AF patient registry.

Methods and results: Patients from the Global Anticoagulant Registry in the FIELD (GARFIELD)-AF registry treated with apixaban, rivaroxaban or vitamin K antagonist (VKA) were assessed for eligibility for the ARISTOTLE and ROCKET AF trials. HRs of apixaban and rivaroxaban versus comparator for stroke/systemic embolism, major bleeding and all-cause mortality within 2 years follow-up were calculated using propensity score overlap-weighted Cox models. Among GARFIELD-AF patients on apixaban, 2570/3615 (71%) would have been eligible for ARISTOTLE. Among patients using rivaroxaban, 2005/4914 (41%) would have been eligible for ROCKET AF. Eligibility rates were steady over time, with minor differences across medical specialties. Real-world AF patients selected according to trial criteria had lower cardiovascular burden than the original trial participants, especially compared with ROCKET AF. HRs (95% CI) for apixaban versus VKA among ARISTOTLE-eligible users were 0.57 (0.34 to 0.94) for stroke/systemic embolism, 0.76 (0.48 to 1.20) for major bleeding and 0.89 (0.70 to 1.12) for all-cause mortality. Among ROCKET AF-eligible rivaroxaban users, HRs for rivaroxaban versus VKA were 0.90 (0.57 to 1.43), 0.92 (0.59 to 1.43) and 0.86 (0.69 to 1.08), respectively. All safety and efficacy estimates were similar to those in the original trials.

Conclusion: Real-world representativeness of the selection criteria was greater for ARISTOTLE than ROCKET AF. The pivotal randomised trials of apixaban and rivaroxaban versus warfarin can be successfully emulated in real-world AF patients by applying trial-specific selection criteria and appropriate methodology for non-randomised treatment allocation.

Trial registration number: NCT01090362.

Keywords: Atrial Fibrillation; Outcome Assessment, Health Care; Pharmacology, Clinical.

Figure 1. Flow chart for the selection of study population. AF, atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events; GARFIELD, Global Anticoagulant Registry in the FIELD; ROCKET, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial; VKA, vitamin K antagonist.

Figure 2. Comparison of key clinical characteristics of trial-eligible patients in GARFIELD-AF and participants in the original trials. Since no relevant differences in characteristics were seen between study arms in either ARISTOTLE or ROCKET AF trial, data from treatment groups in the original trials are presented as the mean. Definitions of some characteristics differed slightly between the trials as explained in the footnotes. CHADS₂ scores were applied as in the respective original ARISTOTLE and ROCKET AF trials. ¹Granger et al., 2011. ²Patel et al., 2011. ³Defined in ARISTOTLE as a history of heart failure or left ventricular ejection fraction ≤40% and in ROCKET AF as a history of heart failure or left ventricular ejection fraction ≤35%. ⁴Defined in ARISTOTLE as hypertension requiring pharmacological treatment and in ROCKET AF as a history of hypertension or hypertension treatment. ⁵Defined in ARISTOTLE as a history of diabetes mellitus, and in ROCKET AF as a history of diabetes mellitus or use of antidiabetic medication. ⁶Using the CHADS₂ element definitions as applied in the respective original ARISTOTLE and ROCKET AF trials. AF, atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF; CHADS₂, Congestive heart failure, Hypertension, Age≥75 years, Diabetes, previous Stroke score; GARFIELD, Global Anticoagulant Registry in the FIELD; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF; SE, systemic embolism; TIA, transient ischaemic attack; VKA, vitamin K antagonist.

Figure 3. Adjusted HRs comparing NOAC versus VKA. Shown are selected outcomes at 2 years of follow-up in apixaban users eligible for ARISTOTLE (top) and rivaroxaban users eligible for ROCKET AF (bottom), using the VKA users in each group as reference. HRs were obtained using an overlap-weighted Cox model. Variables included in the weighting scheme were country and cohort enrolment, sex, age, ethnicity, type of AF, care setting specialty and location, congestive heart failure, acute coronary syndromes, vascular disease, carotid occlusive disease, prior stroke/transient ischaemic attack/SE, prior bleeding, VTE, hypertension, hypercholesterolaemia, diabetes, moderate to severe chronic kidney disease, hyperthyroidism, hypothyroidism, current smoking, heavy alcohol consumption, body mass index, heart rate, systolic and diastolic blood pressure at diagnosis, and baseline antiplatelet use. AF, atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events; GARFIELD, Global Anticoagulant Registry in the FIELD; NOAC, non-vitamin K antagonist; ROCKET, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial; SE, systemic embolism; VKA, vitamin K antagonist.