Anticoagulation in device-detected atrial fibrillation with or without vascular disease: a combined analysis of the NOAH-AFNET 6 and ARTESiA trials

Abstract

Background and aims: The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation.

Methods: These pre-specified analyses of the NOAH-AFNET 6 (n = 2534 patients) and ARTESiA (n = 4012 patients) trials compared anticoagulation with no anticoagulation in patients with DDAF with or without vascular disease, defined as prior stroke/transient ischaemic attack, coronary or peripheral artery disease. Efficacy outcomes were the primary outcomes of both trials, a composite of stroke, systemic arterial embolism (SE), myocardial infarction, pulmonary embolism or cardiovascular death, and stroke or SE. Safety outcomes were major bleeding or major bleeding and death.

Results: In patients with vascular disease (NOAH-AFNET 6, 56%; ARTESiA, 46%), stroke, myocardial infarction, systemic or pulmonary embolism, or cardiovascular death occurred at 3.9%/patient-year with and 5.0%/patient-year without anticoagulation (NOAH-AFNET 6), and 3.2%/patient-year with and 4.4%/patient-year without anticoagulation (ARTESiA). Without vascular disease, outcomes were equal with and without anticoagulation (NOAH-AFNET 6, 2.7%/patient-year; ARTESiA, 2.3%/patient-year in both randomized groups). Meta-analysis found consistent results across both trials (I2heterogeneity = 6%) with a trend for interaction with randomized therapy (pinteraction = .08). Stroke/SE behaved similarly. Anticoagulation equally increased major bleeding in vascular disease patients [edoxaban, 2.1%/patient-year; no anticoagulation, 1.3%/patient-year; apixaban, 1.7%/patient-years; no anticoagulation, 1.1%/patient-year; incidence rate ratio 1.55 (1.10-2.20)] and without vascular disease [edoxaban, 2.2%/patient-year; no anticoagulation, 0.6%/patient-year; apixaban, 1.4%/patient-year; no anticoagulation, 1.1%/patient-year; incidence rate ratio 1.93 (0.72-5.20)].

Conclusions: Patients with DDAF and vascular disease are at higher risk of stroke and cardiovascular events and may derive a greater benefit from anticoagulation than patients with DDAF without vascular disease.

Keywords: Atrial fibrillation; Device-detected atrial fibrillation; Oral anticoagulation; Stroke; Trial.

Structured Graphical Abstract

Summary of findings in the NOAH-AFNET 6 and ARTESiA sub-analysis and meta-analysis in patients with and without vascular disease. Orange and blue curves are NOAH-AFNET 6 data with (orange) and without (blue) anticoagulation, red and black curves ARTESiA data with (black) and without (red) anticoagulation. CV, cardiovascular; DDAF, device-detected atrial fibrillation; DOAC, direct oral anticoagulant; MI, myocardial infarction; OAC, oral anticoagulation; PE, pulmonary embolism; SE, systemic arterial embolism; TIA, transient ischemic attack

Figure 1

CONSORT flow chart of this secondary pre-specified sub-analysis. Shown is the analysis population in the intention to treat analysis for patients with and without vascular disease at baseline. The number of efficacy and safety outcomes used in this analysis is shown

Figure 2

Aalen–Johansen cumulative incidence curves considering death as a competing event in the groups with and without vascular disease for the effect of anticoagulation vs. aspirin/placebo (NOAH-AFNET 6) or aspirin (ARTESiA) by vascular disease status. Orange and blue curves are NOAH-AFNET 6 data with (orange) and without (blue) anticoagulation, red and black curves ARTESiA data with (black) and without (red) anticoagulation. (A) Composite of stroke, systemic arterial embolism, myocardial infarction, pulmonary embolism, and cardiovascular death in patients with vascular disease (left panel) and in patients without vascular disease (right panel, shaded curves). (B) Stroke and systemic arterial embolism in patients with vascular disease (left panel) and in patients without vascular disease (right panel, shaded curves)

Figure 3

Random-effects meta-analysis for the effects of anticoagulation vs. aspirin/placebo (NOAH-AFNET 6) or aspirin (ARTESiA) by vascular disease status (A) for the combined outcome of stroke, systemic arterial embolism, myocardial infarction, pulmonary embolism, and cardiovascular death (p_interaction = .08 and B) for the combined outcome of stroke and systemic arterial embolism. Incidence rate ratios were combined (p_interaction = .11)

Figure 4

Cumulative incidence of the safety outcome major bleeding shown as Aalen–Johansen cumulative incidence curves considering death as a competing event for the effect of anticoagulation vs. aspirin/placebo (NOAH-AFNET 6) or aspirin (ARTESiA) by vascular disease status. Orange and blue curves are NOAH-AFNET 6 data with (orange) and without (blue) anticoagulation, red and black curves ARTESiA data with (black) and without (red) anticoagulation. (A) Major bleeding in patients with vascular disease (left panel) and in patients without vascular disease (right panel, shaded curves). (B) Major bleeding or death in patients with vascular disease (left panel) and in patients without vascular disease (right panel, shaded curves)

Figure 5

Random-effects meta-analysis for the effects of anticoagulation vs. aspirin/placebo (NOAH-AFNET 6) or aspirin (ARTESiA) by vascular disease status (A) for the safety outcome of major bleeding and (B) for the combined safety outcome of major bleeding and death. Incidence rate ratios were combined