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Adam SS, McDuffie JR, Lachiewicz PF, et al. Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement [Internet]. Washington (DC): Department of Veterans Affairs (US); 2012 Dec.

METHODS

TOPIC DEVELOPMENT

This review was commissioned by the VA’s Evidence-based Synthesis Program. The topic was nominated after a topic refinement process that included a preliminary review of published peer-reviewed literature, consultation with internal partners and investigators, and consultation with key stakeholders. We further developed and refined the key questions (KQs) based on a preliminary review of published peer-reviewed literature in consultation with VA and non-VA experts.

The final KQs were:

KQ 1.

For patients undergoing total hip or total knee replacement, what is the comparative effectiveness of newer oral anticoagulants and standard drug classes (low molecular weight heparin, injectable factor Xa inhibitors, unfractionated heparin, warfarin, aspirin) on the incidence of symptomatic, objectively confirmed venous thromboembolism (VTE), other VTE events, total mortality, and bleeding outcomes?

KQ 2.

For patients undergoing total hip or total knee replacement, what are the effects of combined pharmacological and mechanical modalities versus pharmacological treatment alone on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

KQ 3.

For patients undergoing total hip or total knee replacement, what is the comparative efficacy of individual newer oral anticoagulants on the incidence of symptomatic, objectively confirmed VTE, other VTE events, total mortality, and bleeding outcomes?

ANALYTIC FRAMEWORK

We followed a standard protocol for all steps of this review; certain methods map to the PRISMA checklist.17 Our approach was guided by the analytic framework shown in Figure 1.

Figure 1. Analytic framework for the comparative effectiveness of newer oral anticoagulants.

Figure 1

Analytic framework for the comparative effectiveness of newer oral anticoagulants. Abbreviations: FXa=factor Xa; KQs=key questions; LMWH=low molecular weight heparin

SEARCH STRATEGY

During the topic development phase of this study, we identified a number of published high-quality systematic reviews that addressed our KQs. We concluded that a synthesis of these reviews as they pertained to the KQs and the Veteran population would be the most effective approach to summarizing the evidence. This approach is particularly useful when different intervention options or outcomes are evaluated in multiple recent reviews and when the audience is policymakers. We searched MEDLINE® (via PubMed®), Embase®, and the Cochrane Database of Systematic Reviews for systematic review publications comparing the newer oral anticoagulants to other types of anticoagulation (aspirin, warfarin, LMWH, unfractionated heparin, etc.) from January 1, 2009, through May 30, 2012. Our search strategy used the National Library of Medicine’s medical subject headings (MeSH) keyword nomenclature and text words for newer oral anticoagulants, the conditions of interest, and validated search terms for systematic reviews.18,19

Our final search terms included new or novel oral anticoagulants; DTIs, including dabigatran, FXa inhibitors, including edoxaban, rivaroxaban, apixaban, betrixaban, YM150; the MeSH descriptor “orthopedic procedures”; and terms for the specific procedures of interest, total knee replacement or total hip replacement surgery. We limited the search to systematic reviews and meta-analyses and articles published in the English language involving human subjects 18 years of age and older. The full search strategy is provided in Appendix A. We supplemented the electronic searches with a manual search of citations from a set of key systematic reviews2023 and clinical guidelines.1,24 We developed our search strategy in consultation with an experienced search librarian and updated the search during the course of analysis so as not to miss any recent, pertinent reviews; the last update was conducted September 2012. A supplementary search of the primary literature was conducted in September 2012 to identify relevant trials published since May 2012. All citations were imported into an electronic database (DistillerSR; Evidence Partners, Inc., Manotick, ON, Canada) for citation screening.

STUDY SELECTION

Using prespecified inclusion and exclusion criteria, two reviewers assessed titles and abstracts for relevance to the KQs. Full-text systematic reviews identified by either reviewer as potentially relevant were retrieved for further review. Each article retrieved was examined by two reviewers against the eligibility criteria. Disagreements on inclusion, exclusion, or major reason for exclusion were resolved by discussion or by a third reviewer.

The criteria to screen articles for inclusion or exclusion at both the title-and-abstract and full-text screening stages are detailed in Table 4. Studies excluded at the full-text review stage are listed with the reasons for exclusion in Appendix B.

Table 4. Summary of inclusion and exclusion criteria.

Table 4

Summary of inclusion and exclusion criteria.

DATA ABSTRACTION

Before general use, the abstraction form templates designed specifically for this report were pilot-tested on a sample of included articles and revised to ensure that all relevant data elements were captured and that there was consistency and reproducibility between abstractors. Select data from published reports were then abstracted into the final abstraction form by a trained reviewer (Appendix C). All data abstractions were confirmed by a second reviewer. Disagreements were resolved by consensus or by obtaining a third reviewer’s opinion when consensus could not be reached. We abstracted the following key information for each included study:

  • Systematic review design features
    • Databases used in searches and dates of searches
    • Number of primary studies that apply to each KQ
    • Method of analysis
    • Types of comparisons
    • Tests for heterogeneity
    • Assessment of publication bias
  • Characteristics of the included studies
    • Average or range of ages included
    • Average or range of sex distribution
    • Inclusion of Veteran Health Care Facilities
    • Indication for anticoagulation
    • Baseline bleeding risk or factors associated with increased risk (e.g., creatinine >1.5, history of gastrointestinal bleeding), if given
    • Countries included in primary studies
    • Study drug and comparator, route of administration, and dosage
    • Length of treatment and followup duration
    • Funding source
  • Results of the systematic review
    • Number of studies and subjects and completion rates
    • Quality of the primary literature and strength of evidence, if given
    • Outcomes (including definition of outcome, if given)
    • Results from subgroup or sensitivity analyses
    • Author conclusions

In addition, we examined included articles for subgroup analyses of particular relevance to the population served by Veterans Health Administration. Data on the inclusion of Veteran Health Care Facilities was not provided at the systematic review level; therefore, we returned to the primary literature to abstract this information.

QUALITY ASSESSMENT

We also abstracted data necessary for assessing the quality of systematic reviews, adapted from the AMSTAR criteria.2527 These key quality criteria consist of (1) search methods are adequate for replication and are comprehensive, (2) selection bias is avoided, (3) data are abstracted reliably, (4) characteristics of primary literature are reported and quality is assessed appropriately, (5) results are synthesized using appropriate methods, (6) publication bias is assessed, (7) conflict of interest is reported, and (8) conclusions are supported by results. We supplemented these criteria for studies that used multiple treatment comparisons based on the guidance by Mills et al.28 Based on these criteria, systematic reviews were categorized as good, fair, or poor quality (Appendix D). Poor-quality reviews were excluded. The criteria were applied for each study by the reviewer abstracting the article; this initial assessment was then overread by a second reviewer. Disagreements were resolved between the two reviewers or, when needed, by arbitration from a third reviewer.

DATA SYNTHESIS

We categorized each systematic review by the key research questions they addressed and critically analyzed them to compare their characteristics, methods, and findings. We summarized the key findings and conclusions from each included review and produced summary tables for comparison across reviews. We prioritized the evidence from these reviews by higher quality of methodological designs, more complete drug comparisons (e.g., by class and drug rather than by drug only), and more detailed information about population, specific drug intervention (e.g., dosage), and definitions of outcomes. In addition to summary measures of relative effects (e.g., risk ratios), we report absolute risk differences in the summary strength of evidence tables. For FXa inhibitors, we used the risk differences reported by Neumann et al.20 To standardize the reporting of risk differences, which are dependent on the baseline risk of events, we adopted the approach used by Neumann et al. for other drugs. Risk difference was estimated by using the baseline risk from the control group and the risk ratio from the relevant meta-analysis. Baseline risk for patients treated with LMWH, the common comparator for newer anticoagulants, was estimated for each major outcome as symptomatic deep vein thrombosis (DVT), 9 per 1000 patients; nonfatal pulmonary embolism (PE), 3 per 1000 patients; mortality, 3 per 1000 patients; and major bleeding, 7 per 1000 patients.20

Our synthesis focused on documenting and identifying patterns in efficacy and safety of the different drugs. To determine the consistency of results and conclusions, we then compared each additional review that addressed the same key question. If findings or conclusions differed importantly across reviews, we analyzed potential reasons for discrepancies such as the primary literature included (both the type of studies and the dates of the searches), review inclusion/exclusion criteria, differences in outcome definition, analytic approach, and conflict of interest.

In the event that our supplemental search of the primary literature identified additional eligible studies, we planned a qualitative summary of these studies to determine if the outcomes observed were consistent with the results from the systematic reviews. However, our search did not identify any additional relevant RCTs.

RATING THE BODY OF EVIDENCE

In addition to rating the quality of individual studies, we evaluated the overall quality of the evidence for each KQ as described in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews.29 In brief, this approach requires assessment of four domains: risk of bias, consistency, directness, and precision. For risk of bias, we considered basic (e.g., RCT) and detailed study design (e.g., adequate randomization) using the quality assessments of the primary literature reported in the systematic reviews. We used results from meta-analyses when evaluating consistency (forest plots, tests for heterogeneity), precision (confidence intervals), strength of association (odds ratio), and whether publication bias was detected (e.g., funnel plots or Begg’s test). Optimal information size and consideration of whether the confidence interval crossed the clinical decision threshold for a therapy were also used when evaluating precision.30

These domains were considered qualitatively, and a summary rating of high, moderate, low, or insufficient strength of evidence was assigned after discussion by two reviewers. This four-level rating scale consists of the following definitions:

  • High—Further research is very unlikely to change our confidence on the estimate of effect.
  • Moderate—Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
  • Low—Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
  • Insufficient—Evidence on an outcome is absent or too weak, sparse, or inconsistent to estimate an effect.

When a rating of high, moderate, or low was not possible or was imprudent to make, a grade of insufficient was assigned.31

PEER REVIEW

A draft version of the report was reviewed by technical experts and clinical leadership. A transcript of their comments can be found in Appendix E, which elucidates how each comment was considered in the final report.

Cover of Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement
Comparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement [Internet].
Adam SS, McDuffie JR, Lachiewicz PF, et al.
Washington (DC): Department of Veterans Affairs (US); 2012 Dec.

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