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Adjusted indirect comparison of new oral anticoagulants for stroke prevention in atrial fibrillation |
Testa L, Agnifili M, Latini RA, Mattioli R, Lanotte S, De Marco F, Oreglia J, Latib A, Pizzocri S, Laudisa ML, Brambilla N, Bedogni F |
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CRD summary The review appeared to conclude that only long-term use of new anticoagulants in a real-world setting would demonstrate how they compared with vitamin K antagonists. Although the high levels of statistical variation in some analyses and limitations with indirect comparisons should be considered when interpreting the evidence, the authors’ conclusions reflect the evidence and seem reasonable. Authors' objectives To determine the effectiveness of new oral anticoagulants for the treatment of non-valvular atrial fibrillation. Searching PubMed, SCOPUS, and the Cochrane Library were searched up to March 2012 for articles in any language. Search terms were reported. Conference proceedings from three international conferences were searched from 2008 to 2011. Google Scholar and the reference lists of retrieved studies were also searched. Study selection Randomised controlled trials (RCTs) of new oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation were eligible for inclusion. Trials had to have a follow-up of at least one year and provide an intention-to-treat analysis. The primary endpoints were cumulative thromboembolic stroke, systemic embolism and haemorrhagic stroke at the longest available follow-up. Secondary outcomes included rates of extracranial major bleeding, all-cause mortality and myocardial infarction. The included trials studied dabigatran (110mg or 150mg twice daily), rivaroxaban (20mg), and apixaban (5mg twice daily). The age of patients ranged from 70 to 73 years; the proportion of men ranged from 35.5 to 64.3%. Most patients had persistent/permanent atrial fibrillation, but from 15.1 to 32.6% of patients had paroxysmal/new onset atrial fibrillation. The previous use of aspirin varied from 31.3 to 40%. The proportion of previous myocardial infarction ranged from 14.5 to 16.9%. Some patients received previous vitamin K antagonists, some had a previous stroke and some had diabetes. The authors did not state how many reviewers undertook study selection. Assessment of study quality Trial quality was assessed using the Cochrane Risk of Bias tool, which appraised randomisation, allocation concealment, blinding, incomplete outcome data, similarity of concurrent therapies, and other biases. The authors did not state how many reviewers assessed quality. Data extraction Data were extracted on primary and secondary outcomes, and used to calculate odds ratios and 95% confidence intervals. The authors did not state how many reviewers extracted the data. Methods of synthesis Fixed-effect meta-analysis was used to calculate pooled odds ratios with 95% confidence intervals. Ι² was used to assess statistical heterogeneity. Where there was evidence of statistical heterogeneity, a random-effects meta-analysis was used. Adjusted indirect comparisons were calculated for head-to-head comparisons. The number needed to treat and the number needed to harm were also calculated. Results of the review Three RCTs (providing four comparisons) were included in the review (50,578 patients). All of the trials were deemed low risk of bias. Compared with vitamin K antagonists, new anticoagulants were associated with a statistically significant decrease in systemic embolism (OR 0.64, 95% CI 0.44 to 0.94; Ι²=50%; three RCTs), haemorrhagic stroke (OR 0.43, 95% CI 0.34 to 0.55; Ι²=48%; three RCTs; NNT=153), and all-cause death (OR 0.90, 95% CI 0.84 to 0.96; Ι²=0%; three RCTs). There were no statistically significant differences between vitamin K antagonists and new anticoagulants for thromboembolic stroke (Ι²=37%; three RCTs), thromboembolic stroke plus systemic embolism (Ι²=22%; three RCTs), myocardial infarction (Ι²=73%; three RCTs) or extracranial bleeding (Ι²=73%; three RCTs). Adjusted indirect comparison showed that dabigatran 150mg/twice daily was associated with further reductions in haemorrhagic stroke compared with rivaroxaban. They also showed that rivaroxaban was superior to other drugs in preventing systemic embolism and that apixaban showed a reduced risk of extracranial major bleeding compared with dabigatran 150mg/twice daily and rivaroxaban. Mortality was comparable across treatments, but the risk of myocardial infarction was higher with both doses of dabigatran. Authors' conclusions The authors appeared to conclude that only long-term use of the new anticoagulants in a real-world setting would demonstrate how they compared with vitamin K antagonists. CRD commentary Inclusion criteria for the review were defined and three relevant data sources were searched. However, it was not always clear whether the review aimed to specifically look at warfarin (search strategy) or any vitamin K antagonist (inclusion criteria). Publication bias was not assessed and could be ruled out. It was not clear if any attempts were made to reduce reviewer error and bias during the review. Quality assessment was undertaken using a standard checklist, which indicated that the quality of the evidence base was high. Data were combined using meta-analysis. Statistical heterogeneity was assessed, which was appropriate. However, there was evidence of high statistical heterogeneity in some analyses, which may have indicated that the trials were too dissimilar for pooling. Adjusted indirect meta-analysis was also undertaken using standard methods. However, these methods do have limitations, which the authors acknowledged. The high levels of statistical heterogeneity in some analyses and limitations with indirect comparisons should be considered when interpreting the evidence. The authors’ conclusions were based on the evidence and seem reasonable. Implications of the review for practice and research Practice: The authors stated that dabigatran 150mg/twice daily may have the best risk/benefit profile. Research: The authors stated that direct head-to-head comparison trials of new oral anticoagulants were unlikely to be undertaken, but long-term real-world data would prove useful. Bibliographic details Testa L, Agnifili M, Latini RA, Mattioli R, Lanotte S, De Marco F, Oreglia J, Latib A, Pizzocri S, Laudisa ML, Brambilla N, Bedogni F. Adjusted indirect comparison of new oral anticoagulants for stroke prevention in atrial fibrillation. QJM 2012; 105(10): 949-957 Indexing Status Subject indexing assigned by NLM MeSH Aged; Aged, 80 and over; Anticoagulants /administration & Atrial Fibrillation /complications /drug therapy; Benzimidazoles /administration & Biological Availability; Comparative Effectiveness Research /methods /statistics & Dabigatran; Drug Monitoring /methods; Embolism /etiology /mortality /prevention & Female; Humans; Male; Middle Aged; Morpholines /administration & Outcome and Process Assessment (Health Care); Pharmacovigilance; Pyrazoles /administration & Pyridones /administration & Randomized Controlled Trials as Topic; Risk Assessment /methods /statistics & Rivaroxaban; Stroke /etiology /mortality /prevention & Thiophenes /administration & Warfarin /administration & beta-Alanine /administration & control; control; derivatives; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects; dosage /adverse effects /analogs & dosage /adverse effects /classification; numerical data; numerical data AccessionNumber 12012048316 Date bibliographic record published 09/01/2013 Date abstract record published 09/04/2013 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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