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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.


Question 1: Are the objectives, scope, and methods for this review clearly described?
1Yes. Objectives are clear and KQs relevant to current clinical practice in VA. Scope as defined by KQs is appropriate and clinically relevant. Methods are rigorous, transparent, and accomplished according to latest accepted principles of evidence based medicine.Thank you for your confidence in our process.
2Yes, and no comments from reviewer 2.Thank you.
3Yes, and no comments from reviewer 3.Thank you.
Question 2: Is there any indication of bias in our synthesis of the evidence?
1No. No bias detected. Transparency of methods allows for an open assessment of bias and allows reader to assess validity and accept results as valid for use in informing clinical practice.Thank you again for your confidence in our process.
2No, and no comments from reviewer 2.Thank you.
3No. No bias detected.Thank you.
Question 3: Are there any published or unpublished studies that we may have overlooked?
1No. No additional references to suggest.Thank you.
2No, and no comments from reviewer 2.Thank you.
3No – Not that I am aware ofThank you.
Question 4: Please write additional suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.
11) Could improve transparency regarding conflict of interest
if: a. Drugs in this report made by manufacturers Dr Ortel has potential conflicts of interest with are identified and b. The sections Dr Ortel worked on were listed. Reader would be better able to assess bias.
We added a description of Dr. Ortel’s role in the project.
12) Page 1 executive summary, 3rd paragraph, last sentence discussing ‘Disadvantages of newer oral anticoagulants…’ From a clinical standpoint we are most concerned with veteran safety and the lack of specific antidote is a primary concern. Would edit that sentence to place this concern first.The recommended change has been made.
13) The contemporary 35-day rate of symptomatic VTE w/o prophylaxis of 4.3% (page 1); Baseline risk estimates for LMWH of 9 per 1000 symptomatic DVT, nonfatal PE 3 per 1000, mortality 3 per 1000 and major bleeding of 7 per 1000 (page 2) are extremely useful numbers for the busy clinician to know for counseling patients, comparing with treatment with NOACs (pg 4) and for making treatment decisions. Would include these numbers in the conclusions section on page 9.We added data on the rate of VTE to the conclusion section. We did not repeat the absolute risk reductions as this information is already contained in two locations: in the bullet points and in the summary of evidence table. We will be sure that this information is contained in the VA e-brief.
14) Page 9 Conclusion section: a). first paragraph, as noted above in #3 would put in reduced risk or increase risk numbers and b). Last paragraph…’Based on current evidence, newer anticoagulants—particularly Xa inhibitors—are a reasonable option for thromboprophylaxis…’ Agree from this evidence synthesis that Xa inhibitors are a reasonable option. Any suggested sequence of treatment? LMWH first then Xa? Or is Xa first just as reasonable as LMWH? Is there a way to assess the value of 4 per 1000 decrease in symptomatic DVT vs an increase of 2 major bleeds per 1000 treated with a Xa?Although there are formal methods to consider multiple outcomes to develop a rank order of interventions, none of these methods are robust. The decision whether to use thromboprophylaxis, and the particular mode, is one that involves tradeoffs between potential benefits and harms. Clinicians must consider the patient’s particular risks, values, and preferences when making this decision. Our data inform this decision.
15) 5 Page 12 3rd paragraph: ‘Dabigatran etexilate is an oral reversible DTI…’ Reversible seems to imply there is an antidote for reversal and there is no antidote (other than stopping the medication and letting it wear off). Recommend striking word ‘reversible’.The recommended change has been made.
16) Page 14 Search Strategy first paragraph: Might be more explicit as why a synthesis of high quality reviews would be more effective approach to summarizing the evidence than a perhaps a ‘more standard’ approach of searching the literature for RCTs and combining those in an evidence synthesis. Also, why limit the search only as far back as 1 Jan 2009. What is the rationale for the search timeframe?We added a justification for this approach as follows: “This approach is particularly useful when different intervention options or outcomes are evaluated in multiple recent reviews and when the audience is policymakers.”
17) Page 24 Participant Characteristics: Discussion regarding no Veterans studied in the trials and the participants were predominantly female 50–75%. Given the available evidence is there or are there any reason(s) to believe Veterans would respond differently to these treatments or wouldn’t be applicable to Veterans patients? If so why? If not why not?The applicability of the results to Veteran patients is discussion in the Applicability section of the Discussion.
18) Page 26 Oral Xa Inhibitors compared to LMWH: a reader might assume that all of these drugs are available in the US. While we are considering all the individual drugs, would improve transparency if drugs not available in the US were identified.This detail has been added. Only rivaroxaban is currently available in the United States.
19) Page 27, paragraph 3, first sentence “In subgroup analysis, higher doses of Xa inhibitors, but not intermediate or lower doses, …’ would list the doses considered high, intermediate or low in parentheses like on page 32.The authors did not report the doses categorized as high, intermediate, or low. However, they do give the doses studied in the individual trials and we have added the dosing ranges for apixaban and rivaroxaban, drugs approved in Canada and the United States, respectively.
110) Page 29 Other Comparisons of Interest section, 2nd paragraph ‘Low molecular weight heparin vs vitamin K antagonists, 3rd line, would put in dose regimen of enoxaparin (logiparin not available in US, so could omit dose). Same page, section immediately below ‘Oral FXa inhibitors vs unfractionated heparin would list doses of fondaparinux and unfractionated heparin.We added the dose of enoxaparin (30 mg subcutaneously every 12 hours). Fondaparinux and unfractionated heparin were evaluated in an observational study that did not report doses.
111) Page 31 paragraph under ‘Key Points’ discussion of SRs and quality notes the industry sponsored network meta-analysis (Cohen 2012, ref 36) was rated fair quality. Then notes “The latter review did not provide an adequate description or quality assessment of the included trials and did not test the assumption of a constant treatment effect across different study populations---an assumption inherent to network meta-analysis.” Page 32 same meta-analysis is being discussed and notes ‘the composite outcomes are suspect because they combine events (composite VTE[any DVT, PE, death] and major bleeding[major, clinically relevant and minor bleeding) that have very different clinical importance’. These seem to be fatal deficiencies but the rating is fair. Appendix D pg 54 notes the quality rating scale and Pg 55 notes the individual trial assessments. Item 12 for the study in question (Cohen 2012, ref 36) is answered “Can’t Tell” for which there is no provision in the scoring system which notes if item 12 is ‘Yes’ then study could be rated good or fair and if ‘No’ then Poor. A poor rating would have been excluded this trial from the analysis. The summary Table D-1 lists no answers for 6 of the remaining 11 items including critical items 7 and 8 which the text notes that the review is likely to have major flaws. Should the rating really be ‘poor’ and this analysis excluded?We re-reviewed our quality rating for the Cohen study. We agree that it is poor quality and have excluded it from the final report.
112) Page 37 ‘Guidelines’ section, First paragraph, end o paragraph notes ACCP recommends LMWH in absence of bleeding risk. Does ACCP suggest any sequence if there is an elevated bleeding risk?We have added the ACCP recommendation for patients at increased bleeding risk: “For patients with increased bleeding risk, ACCP recommends intermittent pneumatic compression device or no prophylaxis.”
113) Page 39 ‘Applicability’. End of paragraph notes private sector vs VA patients potential differences 9 (see comment #7 above). What should the reader conclude? This is a solid evidence synthesis but not applicable to VA patients? Or is applicable to VA patients?We revised this section to state that the results likely apply to Veteran populations. We add a specific caution about higher comorbidities in Veterans, increasing the risk of bleeding.
114) Page 40 ‘Conclusion’: Same comments as #4 above as this section also appears on page 9 in the Executive Summary.As stated above, we think these data should be used to make individualized decisions with patients about the choice and mode of thromboprophylaxis.
115) Page 53 Appendix D, item 8, 2nd to last line ‘…If only qualitative analyses are completed, the study show describe…’ Change ‘show’ to ‘should’.Thank you for noting this error. It has been corrected.
116) Glossary: Fantastic descriptions of confidence interval and statistical significance!Thank you.
2I was somewhat surprised to see the evidence that newer anticoagulants did not offer much advantage other than ease of administration and less monitoring but also troubled to see the incidence of side effectsAcknowledged
3Not the focus of this review, but might note that earlier this month the FDA approved rivaroxaban for treatment of deep vein thrombosis or pulmonary embolism, and to reduce the risk of recurrent DVT and PE following initial treatment. These are 2 other important clinical scenarios.The role of newer anticoagulants for treatment of DVT and PE was reviewed in an earlier VA ESP report.
Question 5: Are there any VA clinical performance measures, programs, quality improvement measures, patient care services, or conferences that will be directly affected by this report? If so, please provide detail?
1There may be some inpatient performance measure for DVT prophylaxis that could be affected. Performance measure Technical Manual would need to be checkedWe will ask that this report be sent to the VA clinical guideline and performance measure groups.
2Not that I know ofThank you.
3No Comment???Thank you.
Question 6: Please provide any recommendations on how this report can be revised to more directly address or assist implementation needs.
1See comments noted above.Thank you.
2N/AThank you.
3It seems, at least from my perspective, that most VA providers are unaware of these reports, and fewer actually take the time to read them. However, I find that they are a valuable resource and reference tool.Thank you.
Question 7: Please provide us with contact details of any additional individuals/stakeholders who should be made aware of this report.
1Lisa Longo PharmD who is PBM contact for these medications. vog.av@ognol.asiL based at VA PittsburgThank you; the report has been sent to Dr. Longo, and she is one of our stakeholders in the product.
2PBM; Chiefs of Medicine; Chief Medical Officers; Chiefs of StaffThank you.
3No comments??Thank you.
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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