Therapeutics
Review: Novel oral anticoagulants reduce stroke more than ASA in nonvalvular atrial fibrillation
Dogliotti A, Paolasso E, Giugliano RP. Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79 808 patients. Heart. 2013; Sep 5 [Epub ahead of print].
Clinical impact ratings: F ★★★★★★✩ H ★★★★★✩✩ N ★★★★★★✩ Question In patients with nonvalvular atrial fibrillation (AF), what are the relative efficacy and safety of various antithrombotic regimens?
outcomes. None of these comparisons differed qualitatively in sensitivity analyses that were restricted to the 16 large phase 3 trials, or when direct vs indirect comparisons were made.
Review scope
Conclusion
Included studies compared novel oral anticoagulants (NOACs), vitamin K antagonists (VKAs), acetylsalicylic acid (ASA), and clopidogrel in patients who had nonvalvular AF. Studies or study groups in which VKAs were administered at nonstandard doses or in which antiplatelet agents other than clopidogrel or ASA were assessed were excluded. Outcomes included stroke and major bleeding.
In patients with nonvalvular atrial fibrillation, apixaban, dabigatran, and rivaroxaban reduce risk for stroke and may not increase major bleeding compared with acetylsalicylic acid; they do not differ from vitamin K antagonists for stroke or bleeding.
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Database of Systematic Reviews (all to May 2013) were searched for phase 2 or 3 randomized controlled trials (RCTs) that used intention-to-treat analysis and had follow-up > 1 year. Reference lists of published meta-analyses of anticoagulant and antiplatelet treatments to prevent embolic events and stroke in AF were also searched. 20 RCTs (n = 79 808, mean age 63 to 83 y, 46% to 100% men), ranging in size from 75 to 18 201 patients, met the selection criteria. 8 treatments were assessed: apixaban; ASA; ASA plus clopidogrel; dabigatran, 110 mg twice daily; dabigatran, 150 mg twice daily; VKAs; rivaroxaban; and control. 1 RCT directly compared newer anticoagulants (dabigatran, 110 mg vs 150 mg), 2 RCTs assessed apixaban, and 1 RCT assessed rivaroxaban.
Main results Network meta-analyses (NMAs) showed that apixaban, dabigatran (110 mg and 150 mg), and rivaroxaban each reduced risk for stroke more than ASA (Table), but none reduced risk more than VKAs (Table) or other NOACs. None of the NOACs differed from ASA (Table), VKAs (Table), or other NOACs for major bleeding. Statistical heterogeneity was low (I2 < 50%) for both Newer antithrombotics vs ASA or vitamin K antagonists in nonvalvular atrial fibrillation for stroke prevention* Treatment ASA
OR (95% CI) Vitamin K antagonists
Stroke Apixaban
0.42 (0.29 to 0.62)
0.82 (0.58 to 1.18)†
Dabigatran, 110 mg
0.47 (0.28 to 0.78)
0.91 (0.60 to 1.45)†
Dabigatran, 150 mg
0.32 (0.19 to 0.55)
0.63 (0.40 to 1.01)†
Rivaroxaban
0.39 (0.24 to 0.65)
0.78 (0.50 to 1.22)†
Apixaban
1.14 (0.46 to 3.23)†
0.68 (0.25 to 1.72)†
Dabigatran, 110 mg
1.33 (0.36 to 5.88)†
0.79 (0.21 to 2.86)†
Dabigatran, 150 mg
1.54 (0.43 to 7.14)†
0.93 (0.26 to 3.33)†
Rivaroxaban
1.72 (0.45 to 7.69)†
1.02 (0.28 to 3.70)†
Major bleeding
*ASA = acetylsalicylic acid; OR = odds ratio. Other abbreviations defined in Glossary. ORs presented are for the row-defining treatment compared with the column-defining treatment; ORs are calculated as the reciprocals of the ORs presented in the article. †Not statistically significant.
18 February 2014 | ACP Journal Club | Volume 160 • Number 4
Source of funding: No external funding. For correspondence: Dr. R.P. Giugliano, Brigham and Women’s Hospital, Boston, MA, USA. E-mail [email protected]. ■
Commentary The NMA by Dogliotti and colleagues shows the merits and limitations of this novel methodology. This particular NMA has strengths (appropriate eligibility criteria, comprehensive search, assessment of heterogeneity in direct comparisons, presentation of both direct and indirect estimates for paired comparisons) and limitations (no formal assessment of risk for bias and no overall rating of confidence in each paired comparison). However, information in the article (e.g., studies were generally at low risk for bias) did allow us to rate the confidence in estimates using the GRADE methodology (1). The NMA provides a structured summary of what could be deduced from the individual comparisons of NOACs with warfarin: Dabigatran, rivaroxaban, and apixaban are at least as effective as warfarin in reducing risk for stroke in patients with AF and may be superior (moderate confidence in estimates because of imprecision). The benefits in terms of reduced strokes—if present—come without the cost of increased bleeding (moderate confidence in estimates due to imprecision). The authors also offer a ranking of the different antithrombotics, which, typical in NMAs, is of limited use and potentially misleading. Dabigatran, 150 mg twice daily, ranks as the best agent in reducing strokes, but the confidence in estimates compared with other NOACs is low due to indirectness and imprecision. Results of this NMA confirm that, given convenience advantages of NOACs, clinicians who adhere to NOAC dosing and patient restrictions (particularly renal dysfunction) can confidently prescribe apixaban, dabigatran, or rivaroxaban. Ignacio Neumann, MD, MSc Pontificia Universidad Catolica de Chile Santiago, Región Metropolitana, Chile Romina Brignardello-Petersen, DDS, MSc University of Toronto Toronto, Ontario, Canada Gordon Guyatt, MD McMaster University Hamilton, Ontario, Canada Reference 1. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction–J Clin Epidemiol. 2011;64:383-94. © 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929769/ by a University of California San Diego User on 06/01/2017
JC3
Review: Novel oral anticoagulants reduce stroke more than ASA in nonvalvular atrial fibrillation
Dogliotti A, Paolasso E, Giugliano RP. Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79 808 patients. Heart. 2013; Sep 5 [Epub ahead of print].
Clinical impact ratings: F ★★★★★★✩ H ★★★★★✩✩ N ★★★★★★✩ Question In patients with nonvalvular atrial fibrillation (AF), what are the relative efficacy and safety of various antithrombotic regimens?
outcomes. None of these comparisons differed qualitatively in sensitivity analyses that were restricted to the 16 large phase 3 trials, or when direct vs indirect comparisons were made.
Review scope
Conclusion
Included studies compared novel oral anticoagulants (NOACs), vitamin K antagonists (VKAs), acetylsalicylic acid (ASA), and clopidogrel in patients who had nonvalvular AF. Studies or study groups in which VKAs were administered at nonstandard doses or in which antiplatelet agents other than clopidogrel or ASA were assessed were excluded. Outcomes included stroke and major bleeding.
In patients with nonvalvular atrial fibrillation, apixaban, dabigatran, and rivaroxaban reduce risk for stroke and may not increase major bleeding compared with acetylsalicylic acid; they do not differ from vitamin K antagonists for stroke or bleeding.
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Database of Systematic Reviews (all to May 2013) were searched for phase 2 or 3 randomized controlled trials (RCTs) that used intention-to-treat analysis and had follow-up > 1 year. Reference lists of published meta-analyses of anticoagulant and antiplatelet treatments to prevent embolic events and stroke in AF were also searched. 20 RCTs (n = 79 808, mean age 63 to 83 y, 46% to 100% men), ranging in size from 75 to 18 201 patients, met the selection criteria. 8 treatments were assessed: apixaban; ASA; ASA plus clopidogrel; dabigatran, 110 mg twice daily; dabigatran, 150 mg twice daily; VKAs; rivaroxaban; and control. 1 RCT directly compared newer anticoagulants (dabigatran, 110 mg vs 150 mg), 2 RCTs assessed apixaban, and 1 RCT assessed rivaroxaban.
Main results Network meta-analyses (NMAs) showed that apixaban, dabigatran (110 mg and 150 mg), and rivaroxaban each reduced risk for stroke more than ASA (Table), but none reduced risk more than VKAs (Table) or other NOACs. None of the NOACs differed from ASA (Table), VKAs (Table), or other NOACs for major bleeding. Statistical heterogeneity was low (I2 < 50%) for both Newer antithrombotics vs ASA or vitamin K antagonists in nonvalvular atrial fibrillation for stroke prevention* Treatment ASA
OR (95% CI) Vitamin K antagonists
Stroke Apixaban
0.42 (0.29 to 0.62)
0.82 (0.58 to 1.18)†
Dabigatran, 110 mg
0.47 (0.28 to 0.78)
0.91 (0.60 to 1.45)†
Dabigatran, 150 mg
0.32 (0.19 to 0.55)
0.63 (0.40 to 1.01)†
Rivaroxaban
0.39 (0.24 to 0.65)
0.78 (0.50 to 1.22)†
Apixaban
1.14 (0.46 to 3.23)†
0.68 (0.25 to 1.72)†
Dabigatran, 110 mg
1.33 (0.36 to 5.88)†
0.79 (0.21 to 2.86)†
Dabigatran, 150 mg
1.54 (0.43 to 7.14)†
0.93 (0.26 to 3.33)†
Rivaroxaban
1.72 (0.45 to 7.69)†
1.02 (0.28 to 3.70)†
Major bleeding
*ASA = acetylsalicylic acid; OR = odds ratio. Other abbreviations defined in Glossary. ORs presented are for the row-defining treatment compared with the column-defining treatment; ORs are calculated as the reciprocals of the ORs presented in the article. †Not statistically significant.
18 February 2014 | ACP Journal Club | Volume 160 • Number 4
Source of funding: No external funding. For correspondence: Dr. R.P. Giugliano, Brigham and Women’s Hospital, Boston, MA, USA. E-mail [email protected]. ■
Commentary The NMA by Dogliotti and colleagues shows the merits and limitations of this novel methodology. This particular NMA has strengths (appropriate eligibility criteria, comprehensive search, assessment of heterogeneity in direct comparisons, presentation of both direct and indirect estimates for paired comparisons) and limitations (no formal assessment of risk for bias and no overall rating of confidence in each paired comparison). However, information in the article (e.g., studies were generally at low risk for bias) did allow us to rate the confidence in estimates using the GRADE methodology (1). The NMA provides a structured summary of what could be deduced from the individual comparisons of NOACs with warfarin: Dabigatran, rivaroxaban, and apixaban are at least as effective as warfarin in reducing risk for stroke in patients with AF and may be superior (moderate confidence in estimates because of imprecision). The benefits in terms of reduced strokes—if present—come without the cost of increased bleeding (moderate confidence in estimates due to imprecision). The authors also offer a ranking of the different antithrombotics, which, typical in NMAs, is of limited use and potentially misleading. Dabigatran, 150 mg twice daily, ranks as the best agent in reducing strokes, but the confidence in estimates compared with other NOACs is low due to indirectness and imprecision. Results of this NMA confirm that, given convenience advantages of NOACs, clinicians who adhere to NOAC dosing and patient restrictions (particularly renal dysfunction) can confidently prescribe apixaban, dabigatran, or rivaroxaban. Ignacio Neumann, MD, MSc Pontificia Universidad Catolica de Chile Santiago, Región Metropolitana, Chile Romina Brignardello-Petersen, DDS, MSc University of Toronto Toronto, Ontario, Canada Gordon Guyatt, MD McMaster University Hamilton, Ontario, Canada Reference 1. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction–J Clin Epidemiol. 2011;64:383-94. © 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929769/ by a University of California San Diego User on 06/01/2017
JC3
