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Bloomfield HE, Taylor BC, Krause A, et al. Safe and Effective Anticoagulation in the Outpatient Setting: A Systematic Review of the Evidence [Internet]. Washington (DC): Department of Veterans Affairs (US); 2011 Feb.

APPENDIX APEER REVIEW COMMENTS AND RESPONSES

Reviewer CommentAuthor Response
Overall
You exhaustively synthesize the literature related to the questions you sought to answer. This was extremely professional and the product is truly authoritative.Thank you
Re: the repeated messages about how warfarin is due to be replaced at any moment
  1. I'm not sure this really belongs in an ESP because this is not part of the evidence base you were synthesizing.
  2. I suspect we will still be using warfarin, at least for some patients, for at least the next 10 years, if not more. No alternative agent has received FDA approval.
We have deleted many of the messages about potential alternatives to warfarin (see additional responses below).
The report is a comprehensive review of anticoagulation management in the outpatient setting.Thank you
Objectives, Scope, and Methods Clearly Described
Each of these areas is clearly described.NR*
YesNR
YesNR
  1. Yes. Overall, this is a very thoughtful, thorough, and well written report that provides a comprehensive summary of three decades of research on management of oral anticoagulation.
  2. Although the questions addressed by the review are clinically quite relevant, in certain respects, however, it forces the analysis to address the clinical circumstances in a somewhat unrealistic manner. The management of oral anticoagulation is simplistically divided into two phases: initiation and maintenance. As the authors of this review have found, the highest risk of complications is during this period [initiation]. Once stability is achieved, the maintenance is oriented toward minimizing variation in the INR related to intercurrent illness, administration of drugs, changes in diet, etc. Research suggests the inherent variability during this latter phase also predicts likelihood of complications. The analytic framework adopted in this review treats these phases as one continuous process. It is likely that interventions studies, i.e., AC clinics and PST, and the risk factors for complications might be different according to the phase studied.
  3. It does not appear that the confounding effects of computerized dosing programs, protocols, or nomograms were considered. My bias is that much of any beneficial effect of ACCs reflect the standard use of protocols. Can you ascertain if some of the “control” clinics related to Question #1 were using such tools?
Thank you.
b. We have reviewed the studies cited in the report and have added information about initiation and maintenance phases in the Overview of Included Studies sections for KQ1 and KQ2.
c. We have added information about possible processes of care that might have accounted for observed differences under KQ1a.
Bias
I believe there is significant bias shown in support of the direct thrombin inhibitors class and specially dabigatran which is yet to be approved for release to the US market (see pages iii, iv, and vi of the Executive Summary for example); these statements are all speculative and biased and should not be included in an evidence based report. A more benign and accurate statement to be considered that could be used once in the Executive Summary: “New anticoagulants which may offer the same clinical efficacy and safety profile as warfarin with considerable less monitoring are currently being evaluated for the US market. Final FDA approval of these products may significantly alter the standard for anticoagulation therapy and subsequent monitoring”.Thank you for the suggested wording. We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.
NoNR
There is no evidence in the report to support the conclusions regarding direct thrombin inhibitors and specifically dabigatran (see pages iii, iv, vi, and 46). This drug has not been approved by the FDA for use in the US and the report does not draw on any FDA documents surrounding this drug. There have been several drugs that showed exceptional promise in pre-marketing trials that have either been withdrawn from the market or had their use severely limited due to problems found during post-marketing surveillance. Stating that direct thrombin inhibitors are “poised to become the preferred treatment for long term anticoagulation” shows bias towards this class of drugs that is not supported by evidence in the report. The statement on page 46 (“The long term safety of these new agents is not yet established”) is not included in the executive summary. I would recommend removing references to direct thrombin inhibitors from the report. If it is included, I would recommend just stating this class of drugs is currently in clinical trials and the role in therapy has not been defined but may impact the usage of warfarin.We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.
NoNR
Other Published or Unpublished Studies
Not that I am aware ofNR
NoNR
None to my knowledgeNR
It is not clear that all studies have been included specifically:
  1. Fihn SD et al. Ann Intern Med 1993;118:511-520 (addresses several risk factors presented in Table 12 including variability in INR)
  2. Van Leeuwen Y et al. Thromb Haemost 2008;6:451-460 (addresses variability in INR as a risk factor)
  3. LeTourneau T. Chest 2009;136:1503-1513 (addressed variability in INR as a risk factor) There is evidence that variability in INR Is important during the maintenance phase and should be acknowledged in the review.
Fihn 1993 was excluded, because it was outside of the search window (1996 or later).
Information for both Van Leeuwen 2008 and LeTourneau 2009 has now been added to the KQ3 section.
Additional Comments
Page 23, paragraph 2 - change THIINRS to THINRSNR
There are multiple statements diminishing the usefulness of this review with the assumption that direct thrombin inhibitors will replace warfarin for anticoagulation since they do not require intensive monitoring. It seems premature to make this assumption based on recently published RCTs. While these studies report the efficacy of the new drug in clinical trial populations, the effectiveness (or cost-effectiveness) of these therapies in non-clinical trial settings remains to be seen.We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.
The THINRS final analyses have been completed and the main study paper is planned for submission in February 2010. An inquiry on whether the unpublished results can be included in the tables and meta-analysis could be sent to the CSPCC in Palo Alto.We have been in contact with the CSPCC and including unpublished data is not an option.
  1. Although the literature synthesis showed insufficient evidence to conclude that ACC care leads to fewer deaths, thromboembolic events, or major bleeding events than usual care, several expert reviews have concluded that better quality anticoagulation control typically seen within an ACC can infer better outcomes. This is discussed in Philips and Ansell (2008) and the ACCP Guidelines (2008). This review does discuss other reviews (pg. 46) but this disparity is not discussed in the Executive Summary.
  2. Other organizations that have focused on quality and safety have supported AC clinics (Joint Commission Sentinel Event Alert Issue 41; AHRQ Report #43, Part III, Chpt. 9).
  3. For the conclusion on page iv that states “there is insufficient evidence for the VA to actively promote the implementation of ACCs” I would recommend stating further that this has not been the conclusion of other organizations or expand on how the conclusion of the systematic review differs from conclusions of other organizations and experts in the field.
  4. I would recommend adding that this synthesis of the literature did not consider the cost-effectiveness of ACCs or resource utilization and therefore the conclusion that there is insufficient evidence is based solely on evidence regarding clinical outcomes and does not factor in patient satisfaction, costs, and resource utilization. As the VA does manage a large portion of their patients within AC clinics HSR&D may want to consider a study that looks at AC clinic patient management within the VA system and include these factors.
  1. We have chosen to present the results from our review in the Executive Summary leaving comparisons to other studies in the Discussion section. In agreement with the ACCP Guidelines, we have noted the limited nature of the evidence in the Executive Summary.
  2. We have reviewed these documents. The Joint Commission Alert is based on a few studies (not a comprehensive review). The AHRQ Report was completed in 2001 and therefore does not include many of the studies cited in our review.
  3. We are limited to reaching conclusions based on the evidence.
  4. Cost-effectiveness was outside the scope of the report as defined by the Key Questions. We searched for but were unable to identify evidence-based data on resource utilization. Patient satisfaction results are included in our review. We agree that a study that includes costs and resource utilization would be worthwhile and we have added a statement to that effect in the Conclusions and Recommendations for Key Question 1.
In a couple of places, the authors indicate that the review may be of limited value because of the imminent introduction of direct thrombin inhibitors. Although this may well be true, reports of demise of vit K antagonists have been prevalent for 3 decades. Although these drugs have a narrow therapeutic ratio, they have an efficacy in preventing stroke of nearly 75%, higher, perhaps, than almost any other drug in regular therapeutic use. Given the fact that the drug itself is relatively inexpensive, must typically be taken for many years, and has a long track record, it may not be dislodged all that soon.We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.
*

No Response Needed

Cover of Safe and Effective Anticoagulation in the Outpatient Setting
Safe and Effective Anticoagulation in the Outpatient Setting: A Systematic Review of the Evidence [Internet].
Bloomfield HE, Taylor BC, Krause A, et al.
Washington (DC): Department of Veterans Affairs (US); 2011 Feb.

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