{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T04:13:20Z","timestamp":1793852000018,"version":"4.6.1"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,1,25]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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\u2013Thrombolysis 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      A total of 71\u2009683 patients were included (29\u2009362 on standard-dose DOAC, 13\u2009049 on lower-dose DOAC, and 29\u2009272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883\/29\u2009312 [3.01%] versus 1080\/29\u2009229 [3.69%]; HR, 0.81 [95% CI, 0.74\u20130.89]), death (2276\/29\u2009312 [7.76%] versus 2460\/29\u2009229 [8.42%]; HR, 0.92 [95% CI, 0.87\u20130.97]), and intracranial bleeding (184\/29\u2009270 [0.63%] versus 409\/29\u2009187 [1.40%]; HR, 0.45 [95% CI, 0.37\u20130.56]), but no statistically different hazard of major bleeding (1479\/29\u2009270 [5.05%] versus 1733\/29\u2009187 [5.94%]; HR, 0.86 [95% CI, 0.74\u20131.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531\/13\u2009049 [3.96%] versus 1080\/29\u2009229 [3.69%]; HR, 1.06 [95% CI, 0.95\u20131.19]) but a lower hazard of intracranial bleeding (55\/12\u2009985 [0.42%] versus 409\/29\u2009187 [1.40%]; HR, 0.28 [95% CI, 0.21\u20130.37]), death (1082\/13\u2009049 [8.29%] versus 2460\/29\u2009229 [8.42%]; HR, 0.90 [95% CI, 0.83\u20130.97]), and major bleeding (564\/12\u2009985 [4.34%] versus 1733\/29\u2009187 [5.94%]; HR, 0.63 [95% CI, 0.45\u20130.88]). 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 (\n                      <jats:italic>P<\/jats:italic>\n                      =0.01) and lower creatinine clearance (\n                      <jats:italic>P<\/jats:italic>\n                      =0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (\n                      <jats:italic>P<\/jats:italic>\n                      =0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction\n                      <jats:italic>P<\/jats:italic>\n                      =0.02) and lower-dose DOACs (interaction\n                      <jats:italic>P<\/jats:italic>\n                      =0.01) versus warfarin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.121.056355","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T09:25:52Z","timestamp":1641374752000},"page":"242-255","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":388,"title":["Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex"],"prefix":"10.1161","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-4562","authenticated-orcid":true,"given":"Anthony P.","family":"Carnicelli","sequence":"first","affiliation":[{"name":"Division of Cardiology (A.P.C., M.R.P., J.H.A., R.D.L., J.P.P., C.B.G.), Duke University, Durham, NC."},{"name":"Duke Clinical Research Institute (A.P.C., H.H., M.R.P., J.H.A., K.H., R.D.L., J.P.P., D.W., C.B.G.), Duke University, Durham, NC."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwanhee","family":"Hong","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute (A.P.C., H.H., M.R.P., J.H.A., K.H., R.D.L., J.P.P., D.W., C.B.G.), Duke University, Durham, NC."},{"name":"Department of Biostatistics and Bioinformatics (H.H., K.H.), Duke University, Durham, NC."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J.","family":"Connolly","sequence":"additional","affiliation":[{"name":"Department of Medicine, McMaster University, Ontario, Canada (S.J.C., J.E.)."},{"name":"Population Health Research Institute, Hamilton Health Sciences, Ontario, Canada (S.J.C., J.E., A.P.B., L.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Eikelboom","sequence":"additional","affiliation":[{"name":"Department of Medicine, McMaster University, Ontario, Canada (S.J.C., J.E.)."},{"name":"Population Health Research Institute, Hamilton Health Sciences, Ontario, Canada (S.J.C., J.E., A.P.B., L.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4110-7675","authenticated-orcid":true,"given":"Robert P.","family":"Giugliano","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (R.P.G., D.A.M., E.A.B., J.K., C.T.R.)."},{"name":"Thrombolysis in Myocardial Infarction Study Group, Boston, MA (R.P.G., D.A.M., E.A.B., C.T.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9589-5382","authenticated-orcid":true,"given":"David A.","family":"Morrow","sequence":"additional","affiliation":[{"name":"Thrombolysis in Myocardial Infarction Study Group, Boston, MA (R.P.G., D.A.M., E.A.B., C.T.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2393-0855","authenticated-orcid":true,"given":"Manesh R.","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Cardiology (A.P.C., M.R.P., J.H.A., R.D.L., J.P.P., C.B.G.), Duke University, Durham, NC."},{"name":"Duke Clinical Research Institute (A.P.C., H.H., M.R.P., J.H.A., K.H., R.D.L., J.P.P., D.W., C.B.G.), Duke University, Durham, 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