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.
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.
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 (
=0.01) and lower creatinine clearance (
=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (
=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction
=0.02) and lower-dose DOACs (interaction
=0.01) versus warfarin.
Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.
Device-detected atrial fibrillation (also known as subclinical atrial fibrillation or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is ...associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear.
We performed a systematic review of MEDLINE and Embase for randomized trials comparing oral anticoagulation with antiplatelet or no antithrombotic therapy in adults with device-detected atrial fibrillation recorded by a pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy device, or implanted cardiac monitor. We used random-effects models for meta-analysis and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). The review was preregistered (PROSPERO CRD42023463212).
From 785 citations, we identified 2 randomized trials with relevant clinical outcome data: NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes; 2536 participants) evaluated edoxaban, and ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; 4012 participants) evaluated apixaban. Meta-analysis demonstrated that oral anticoagulation with these agents reduced ischemic stroke (relative risk RR, 0.68 95% CI, 0.50-0.92; high-quality evidence). The results from the 2 trials were consistent (I
statistic for heterogeneity=0%). Oral anticoagulation also reduced a composite of cardiovascular death, all-cause stroke, peripheral arterial embolism, myocardial infarction, or pulmonary embolism (RR, 0.85 95% CI, 0.73-0.99; I
=0%; moderate-quality evidence). There was no reduction in cardiovascular death (RR, 0.95 95% CI, 0.76-1.17; I
=0%; moderate-quality evidence) or all-cause mortality (RR, 1.08 95% CI, 0.96-1.21; I
=0%; moderate-quality evidence). Oral anticoagulation increased major bleeding (RR, 1.62 95% CI, 1.05-2.50; I²=61%; high-quality evidence).
The results of the NOAH-AFNET 6 and ARTESiA trials are consistent with each other. Meta-analysis of these 2 large randomized trials provides high-quality evidence that oral anticoagulation with edoxaban or apixaban reduces the risk of stroke in patients with device-detected atrial fibrillation and increases the risk of major bleeding.
With increasing life-expectancy and changing demographics, non-valvular atrial fibrillation (AF) is currently the most common indication for long-term oral anticoagulation (OAC) in low and middle ...income countries (LMICs). Due to a decreasing trend in the prevalence of rheumatic heart disease (RHD), valve disease as a primary cause of AF now constitutes a small fraction of all people with AF. Moreover, emerging data also indicate that, patients with significant valve disease and AF may have a risk of stroke similar to, if not lower than, those with non-valvular AF. Previous trials of anticoagulation for AF excluded people from LMICs partly because valvular AF constituted a large proportion of those with AF, and it was thought to confer a prohibitively high risk of stroke. Trialists should therefore be less reluctant to include patients with AF from LMICs in general, and those with valve disease in particular, in future trials of anticoagulation. The quality of vitamin K antagonist based oral anticoagulation remains poor in LMICs to a large extent because of poor monitoring. The widespread use of the direct oral anticoagulants (DOAC) presents a practical approach to improve anticoagulation quality. Randomised trials of DOACs in valvular AF are particularlycriticalto bridge the knowledge gap in this area.
Discussions regarding oral anticoagulation (OAC) use in low and middle income countries (LMICs) have historicallybeendominated by severallong-held beliefs. The first is that the quality of vitamin K antagonist (VKA) based anticoagulation is poor in these countries. The veracity of this assumption is supported by a large number of studies documenting both lower prescription of OACs, and a lower proportion of international normalised ratio (INR) values in the therapeutic range.1The second is that a large proportion of patients receiving OAC in LMICs have atrial fibrillation (AF) related to valvular heart disease, and rheumatic mitral stenosis in particular. This assumption, perhaps valid several decades ago, is no longer supported by the data. Finally, patients with valvular heart disease and AF (specifically those with moderate or severe valve lesions), are thought to be at prohibitively high thromboembolic risk. 2 However, recent evidence suggests that this risk may have been overestimated.34Nevertheless, the aforementioned assumptions continue to contribute to the underrepresentation of patients from LMICs in clinical trials of oral anticoagulation. Knowledge of the characteristics of contemporary patients in LMICs who are eligible for long-term OAC, estimates of their stroke risk, and a better understanding of the drivers of poor anticoagulation quality, may help guide research and clinical practice. In this review, we seek to provide an evidence-based perspective on OAC use in patients with AF living in LMICs and China.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Sodium-glucose co-transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains ...unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty-one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 95% CI, 0.66-0.86; I
=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 95% CI, 0.57-0.85; I
=0%)-similar to the effect estimate for patients without AF,
value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF.
Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone ...morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC).
BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death.
The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF.
In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.
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