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Adam SS, McDuffie JR, Ortel TL, et al. Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism [Internet]. Washington (DC): Department of Veterans Affairs; 2012 Apr.

APPENDIX EPEER REVIEW COMMENTS

ReviewerCommentResponse
Question 1: Are the objectives, scope, and methods for this review clearly described?
1Yes, and no comments from reviewer 1.Thank you.
2Yes, and no comments from reviewer 2.Thank you.
3Yes, and comment was “Methods, scope, and objectives are sufficiently described.”Thank you.
4Yes, and comment was “Very clear, comprehensive report of the current literature.”Thank you.
Question 2: Is there any indication of bias in our synthesis of the evidence?
1No, and no comments from reviewer 1.Thank you.
2No, and no comments from reviewer 2.Thank you.
3Search methods identified all relevant studies (published and unpublished), the identified studies are of good quality, and author’s analysis of the data does not appear to be influenced by any obvious source of bias. However, the analysis is potentially misleading by combining together the findings from clinical trials for all new anticoagulants - thus obfuscating any differences (in efficacy or safety) that might exist between these new agents (for example – figure 14 suggests there are significant differences in medication discontinuation rates)... or diminishing the effect a medication or class of medication may have had on outcomes relative to warfarin. At the very least, the reader should be alerted to this potential flaw in the analytical methods (e.g. the analysis, as constructed, assumes that “new anticoagulants” are substantially similar and were treated as a single class of medications).We conducted additional analyses and presented results by drug class. However, these analyses consist of indirect comparisons (across studies that may differ in other ways, such as differences in the patient population or quality of adjusted-dose warfarin) and should be considered hypothesis generating.
We added statements in the Discussion section and both the global Summary and Strengths and Limitations sections.
4While the report is a comprehensive review of the current literature with sound results, the text is currently written in a biased manner favoring the newer anticoagulants without equally balancing the disadvantages and unknowns. Recommend revising to be more balanced in describing the findings and including disadvantages and unknowns. Examples provided below:
Exec Summary, p. 1: potential benefits of newer anticoagulants are over-stated, and clinical limitations are not included (i.e., dabigatran is associated with higher GI bleeding than warfarin; downside is that there is not a readily available means of quantifying anticoag effect of newer agents in cases of emergency such as bleeding or emergent procedure/surgery needed). There is also more recent concern raised by FDA as well as other agencies outside of US about serious bleeding events with dabigatran, particularly in the elderly and renally impaired.
We have performed a secondary search of the observational literature and the FDA Web site looking specifically for reports of adverse events. These data are included under KQ 4 and in the Executive Summary.
4Page 5, page 36: “In the trial of dabigatran for chronic AF, myocardial infarction was increased, but the enrolled sample had higher CHADS2 scores than other trials.” First, this statement is incorrect; mean CHADS2 score for RE-LY ~2.1; mean CHADS2 score ROCKET ~3.5. Second, the “but…” phrase does not explain the increase in MI. CHADS2 score is an assessment of stroke risk in patients with AF.Thank you for pointing out this factual error that was an artifact of editing. The ROCKET study did have a higher mean CHADS score, and this factual error has been corrected.
While it is true that the CHADS2 score is an assessment of stroke risk in patients with AF, many of the risk factors used in this assessment (e.g., HTN, DM, history of vascular disease) are risk factors for myocardial infarction too. We have clarified this point in the discussion.
4Intro and Page 10: It is misleading to state that the newer agents are free from monitoring. It is more accurate, fair and balanced to state that there is not a need for “routine anticoagulant monitoring”. All patients on anticoagulants should be monitored for s/sx bleeding, stroke, AEs, medication adherence. In addition, certain newer anticoagulants require monitoring of renal function (i.e., dabigatran, rivaroxaban).Agreed. We have modified this statement to state: “These drugs characteristically have a predictable anticoagulant effect, eliminating the need for routine monitoring. However, patients on newer anticoagulants should still be monitored for any adverse events, including bleeding. Bleeding risk is increased with concurrent use of antiplatelet medications, older age, and renal impairment since most of these drugs are eliminated through the kidneys. (Harder 2011)”
4GI bleeding and GI related adverse events were not included in KQ4; these events were reported more often with dabigatran.We have now addressed GI bleeding and GI-related events in KQ 4.
4Page 39, summary of KQ1: only the favorable outcomes of the newer anticoagulants are discussed. It may be stated that there was no significant difference found in VTE related mortality and ischemic stroke.Agreed. The following statement was added to the paragraph: “However, VTE-related mortality and ischemic stroke were not significantly lower with newer oral anticoagulants.”
4Page 39, summary of KQ1: bleeding outcomes and INR control – “The difference in bleeding related outcomes are dependent in part upon the quality of adjusted- dose warfarin treatment; these studies reported rates of time in therapeutic range that were similar to those observed in the VHA.” Statement is misleading and an oversimplification as is. First, it would be more accurate to state that it is the MEAN or AVERAGE TTR from the clinical trials. Second, VHA national data show that ~70% of INRs are between 1.8 and 3.3. The method used to calculate TTR in the clinical trials differed and therefore limits the ability to directly compare numbers. The take home message to me is that outcomes with dabigatran vs. warfarin were similar when INR control was good. Further, outcomes with dabigatran were better when INR control was poor. INR control in the rivaroxaban study was poorer than typical standard. Suggest revision of the statement to include these limitations. Also suggest adding that anticoagulation control in VHA appears to be at least as good as the mean TTR in clinical trials.The discussion of bleeding rates has been revised to: “While anticoagulation control in the VHA appears to be at least as good as that found in clinical trials, the ROCKET-AF study had a mean TTR that was worse than typical standards. In the RE-LY study, the advantages of dabigatran were greater at sites with poor INR control than at those with good INR control for all vascular events, nonhemorrhagic events, and mortality. Warfarin and dabigatran showed comparable outcomes in centers with good mean TTR.”
4Page 39, summary of KQ1: “Except for discontinuations due to adverse effects, other outcomes also favored newer anticoagulants but were not statistically significant.” The MI outcome did not favor newer anticoagulants and should be stated here.The statement was revised to: “Except for discontinuations due to adverse effects, other outcomes also favored newer anticoagulants; however, they were not statistically significant.”
4Page 40, summary of KQ2: Agree with conclusion; however similarly as for KQ1, only the positive effects of newer anticoagulants is included. It should also be stated that rate of DC due to AEs was higher with newer anticoagulants, though not statistically significant.We have added this text: “When the study examining ximelagatran was included, results were similar except that drug discontinuation due to adverse effects was significantly higher than rates with adjusted-dose warfarin.”
4Page 41, summary of KQ4: same incorrect statement about the dabigatran, higher CHADS2 – see comment above.ROCKET-AF had a higher mean CHADS2, and the text has been corrected to reflect this.
4Page 41, summary of KQ4: “Fatal bleeding was significantly lower for newer anticoagulants in the chronic AF studies, and the point estimate favored these drugs for fatal bleeding in patients with VTE and major bleeding in both groups.” For the VTE AEs, these were not statistically significant. Statement currently is unbalanced, showing bias in reporting to the newer anticoagulants.We agree and have changed the statement to: “The newer oral anticoagulants were associated with a consistent decrease in mortality (0.88; 95% CI, 0.82 to 0.95), without significant variability across studies or differences between drug classes. Similarly, rates of fatal bleeding were consistently lower with newer oral anticoagulants (Table 9). There was a non–statistically significant reduction in major bleeding, but this effect varied importantly across studies—variability that was not explained by drug class.”
4Page 42, “It is possible that the newer agents may improve patient experience and HRQOL.” Statement is biased; a more balanced statement is that it is unknown whether new agents may improve patient experience and HRQOL.This statement has been rephrased to: “Because no studies reported effects on patient experience and HRQOL, effects on these important outcomes are unknown.”
4Page 42, it states that patients with high bleeding risk were excluded from clinical trials, yet in the next paragraph it goes on to recommend these newer agents in patients at higher than average risk of bleeding. I don’t agree with this statement and it is not supported by evidence.Agreed. We have changed the wording to: “In the RE-LY study, the advantages of dabigatran were greater at sites with poor INR control than at those with good INR control for all vascular events, nonhemorrhagic events, and mortality. Warfarin and dabigatran showed comparable outcomes in centers with good mean TTR.”
4Page 42, including only part of the recommendation from ACCP/AHA on dabigatran is biased. The update also states that: because of BID dosing and greater risk of nonhemorrhagic AEs with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran.The discussion has been updated to include the point that patients already taking warfarin and who have excellent INR control may have little to gain by switching.
4Page 42 – Clinical and Policy Implications: It is not balanced in that this section currently omits discussion of the unknowns or disadvantages of newer anticoagulants. 1) unknown outcomes in the setting of lower adherence – Adherence in clinical trials was very high and likely to be lower in real-world setting. Given the short half-life of the newer agents and the fact that patients discontinue them more frequently, the clinical implications of lower adherence rates are unknown (but potentially important, increased stroke risk).; 2) Higher GI bleeds, GI adverse effects with dabigatran; 3) higher bleeding rates with the newer anticoagulants vs. warfarin in the elderly–this is important and extremely applicable to the VA population; 4) higher MI with dabigatranWe have added the following text: “In a prespecified subgroup analysis, Wallentin et al.99 found that the advantage of dabigatran over warfarin in terms of major bleeding rates was evident only at sites with poor-quality anticoagulation (TTR <57.1%), while rates of major bleeding were not significantly different at sites with higher quality anticoagulation. Hence, better INR control led to similar bleeding rates between both groups. In the VHA, time in treatment exceeds this threshold, but newer oral anticoagulants could have important advantages for individual patients who have difficulty maintaining a therapeutic INR. However, since newer oral anticoagulants are dosed twice daily, compared with once daily dosing of warfarin, better outcomes would not be expected if poor medication adherence were the cause of the subtherapeutic INR.”
Also: “Although newer oral anticoagulants are associated with a lower risk of fatal bleeding compared with warfarin, this advantage may be tempered by the increased risk of gastrointestinal bleeding with dabigatran. 70,84,91,99 The FDA is currently evaluating reports of high rates of serious bleeding. The reports of bleeding appear to be concentrated in older adults and those with impaired renal function. Another worrisome finding is elevated rates of myocardial infarction with dabigatran, although the strength of evidence for this finding is low.”
And: “VA should carefully consider the potential benefits and harms, along with patients at higher risk for adverse effects when establishing eligibility criteria for newer oral anticoagulants.”
4Page 42, “In a prespecified subgroup analysis, Wallentin et al.22 found that major bleeding rates with dabigatran were lower than warfarin at sites where time in therapeutic range was low (<57.1%); rates were not significantly different at sites with higher quality anticoagulation.” This statement is somewhat misleading by not also including that major GI bleeding was significantly HIGHER with dabigatran vs. warfarin when INR control was good. Also, for the primary endpoint of stroke or systemic embolism, outcomes were similar with dabigatran and warfarin when INR control was good. In other words, dabigatran was not superior to warfarin when INR control was good.Agreed. We have rephrased the statement to: “In a prespecified subgroup analysis, Wallentin et al.99 found that the advantage of dabigatran over warfarin in terms of major bleeding rates was evident only at sites with poor-quality anticoagulation (TTR <57.1%), while rates of major bleeding were not significantly different at sites with higher quality anticoagulation. Hence, better INR control led to similar bleeding rates between both groups. In the VHA, time in treatment exceeds this threshold, but newer oral anticoagulants could have important advantages for individual patients who have difficulty maintaining a therapeutic INR. However, since newer oral anticoagulants are dosed twice daily, compared with once daily dosing of warfarin, better outcomes would not be expected if poor medication adherence were the cause of the subtherapeutic INR.”
Question 3: Are there any published or unpublished studies that we may have overlooked?
1No, and no comments from reviewer 1.Thank you.
2 The cited articles were published after our draft report was submitted. However, in response to peer review, we conducted a secondary search for observational studies and recent meta-analyses that address adverse effects of the newer anticoagulants.
The updated data on myocardial ischemic events (Hohnloser et al.) are included in a newly conducted sensitivity analysis. The meta-analysis by Uchino et al. is cited in the Discussion section. The article by Jacobs et al was reviewed but is an editorial and not eligible for inclusion.
3No – none that I am aware.Thank you.
4No, and no comments from reviewer 4.Thank you.
Question 4: Please write additional suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.
1Make it clear early on that the review covers warfarin and newer oral anticoagulants.This has been clarified throughout the document.
1Define ‘patient treatment experience.’Patient experience is a more inclusive set of outcomes than patient satisfaction. It has been defined as: The sum of all interactions, shaped by an organization’s culture that influence patient perceptions across a continuum of care.
1KQ4: Where there differences in bleeding when stratifying data based on age or indication (e.g., age ≥ 80 vs. < 80)?From Eikelboom et al. 2011: 18113 patients in RE-LY study randomized to 110 mg, 150 mg dabigatran BID, or warfarin for a median followup of 2 years:
  • Risk of major bleeding with 150 mg dabigatran was lower than warfarin in those <75 years of age (2.12% vs. 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those ≥ 75 (4.37%; P=0.07; P for 5.10 % vs. interaction <0.001).
  • In patients with AF, both doses of dabigatran are associated with lower risk of major bleeding in patients <75 years of age. In those ≥75, intracranial bleeding risk is lower, but extracranial bleeding risk is the same or higher in both doses of dabigatran.
1KQ2: No data are presented on LMWHs. Remove this from KQ or reword to indicate heparins overlapped with warfarin. Also, how many VTEs were DVTs versus PEs? Are results applicable to DVTs and PEs?Agreed. It may be confusing although it is common practice to overlap warfarin with LMWH or other parenteral anticoagulants. We have changed the wording of KQ 2 to:
“For patients with venous thromboembolism, are there differential effects of newer oral anticoagulants versus warfarin on recurrent thromboembolism, mortality, HRQOL, and patient treatment experience?”
1Future research: CEAs could help address uncertain effects on health care systems in addition to BIAs. CEAs involving dabigatran noted, but none involving other agents.In the literature search performed for the Budget Impact Analysis we plan to conduct, we did not find any CEAs on new oral anticoagulants other than Dabigatran.
1Page 10: Warfarin has significant interactions with herbal supplements in addition to drugs and foods.Agreed. This interaction has been noted in the report.
1Page 10: Physicians are still concerned about inability to reverse effects of newer anticoagulants in patients at higher risk of bleeding even though half-lives are shorter (e.g., patient who is 76 years old and h/o GI bleed).Agreed. We have added the statement: “However, there are valid concerns about the lack of specific antidotes for newer oral anticoagulants that would prevent the timely reversal of their anticoagulant effect in a bleeding patient. This is especially worrisome in elderly patients and those with renal disease, where drug clearance may be longer and the anticoagulant effects prolonged.”
1Contraindications (page 13): What is the data source?We have changed the heading to “Precautions.”
1Objective (page 15): Clarify that data on primary VTE prevention s/p surgery are not presented.We have added a statement that a later report will summarize the data on newer anticoagulants used for primary VTE prevention.
1Figure 1: eliminate or clarify inclusion of LMWHsWe have adjusted Figure 1 as suggested.
1Search strategy: standard of care was usually warfarin, rather than VKAsWarfarin is one of the vitamin K antagonists.
1Clinical implications: The risk of major bleeding is unclear with newer agents in patients at higher risk for a major bleed (e.g., older elderly, h/o major bleed, renal insufficiency, h/o stroke).We have refined the discussion to state: “Gastrointestinal bleeding was significantly increased in patients treated with dabigatran and rivaroxaban compared with warfarin.(Wallentin 2010) The efflux of dabigatran by p-glycoprotein transporters into the gastrointestinal tract may be a mechanism for this finding. (Bovio 2011) The European Society of Cardiology recommends dabigatran at a dose of 150 mg be used in patients with a low risk of bleeding, while the lower dose of 110 mg is reserved for those with a high risk of bleeding.(Camm 2010) In Canada, dabigatran is approved for the prevention of stroke in AF, and dabigatran 110 mg twice daily is recommended for elderly patients 80 years of age or older or those at a high risk of bleeding.(Cairns 2011) In the United States, the FDA has only approved the 150 mg dose and recommends a dose of 75 mg twice daily for patients with CrCl of 15 to 30 mL/min. (Beasley 2011)”
2Page 9 – Therapeutic Options for Anticoagulation, Paragraph 1, Line 6 – additional LMWH advantage includes decreased risk of HIT. Line 8 – additional LMWH disadvantage is that it is not completely reversible by protamine.We have added the following statement: “Unfractionated heparin requires hospital admission and continuous monitoring and carries the risk of heparin-induced thrombocytopenia. The advantages of low molecular weight heparin include longer half-life, better bioavailability, a predictable dose-response that minimizes the need for laboratory monitoring, and a decreased risk of heparin-induced thrombocytopenia.(Key 2010) The disadvantages of low molecular weight heparin include the need for subcutaneous administration once or twice daily, which patients find painful and inconvenient. Further, protamine sulfate only partially reverses heparin’s anticoagulant effect. (Crowther 2002)”
2Page 10 – Line 1 – Point of care INR testing is simple and relatively inexpensive. Paragraph 1, Line 4 and 5 – bridging also with LMWH, generally performed in an outpatient setting, which is more convenient for the patient and less costly to the health plan (compared to admission). Paragraph 2, Line 10 – Although a shorter t1/2 is beneficial compared to warfarin, a lack of antidote for DTI and Xa inhibitors is problematic in acute hemorrhage or emergent surgery, whereas the effect of warfarin may be reversed rapidly with PCC. Paragraph 4 – Line 4 – May consider additional information regarding post-marketing bleeding in Pradaxa and 12/7/2011 FDA Safety Announcement.This FDA Safety Announcement and several others have been addressed under KQ 4.
2Page 11 – Paragraph 1, Line 2 – Consider noting that dabigatran is susceptible to Pgp drug:drug interactions.Thank you. This observation has been added both to the text and the appropriate table.
2Page 12 – Column 6, Row 8 – Typo Should read Ecarin clotting time. Row 10 – PPIs not included in package insert.The reference has been changed to a more recent one that does include PPIs.
2Page 13 – Column 1 – May be worthwhile adding additional row listing precautions.“Contraindications” has been changed to “Precautions.”
2Page 36 – Paragraph 2, Line 7/8 – Do the authors have a citation for the two statements that adverse events are related to # medical conditions and # medications and that duration of treatment may increase absolute rates of adverse events?Oldgren 2011 has been added to the text in the “Metaanalyses for KQ 1” section, 2nd paragraph, 4th sentence.
2Page 36 – Paragraph 3, Line 10 – Is this true? I thought Rocket-AF had higher average CHADS2 score?Agreed. This text has been corrected.
2Page 41 – Paragraph 1, Line 6 – See previous comment regarding CHADS2 score and Rocket-AF vs. RE-LY.We have corrected this text.
2Page 42 – Paragraph 1, Line 5 – Should also add aspirin + clopidogrel. Paragraph 2, Line 3 – For now fewer drug interactions are noted, but new information may emerge. Paragraph 3, Line 11 – The shorter t1/2 life of new anticoagulants may be problematic in patients with non-compliant behavior (ie – increase in death rates after discontinuation of treatment in Rocket-AF).The ACTIVE-W trial of ASA plus clopidogrel was stopped early due to inferiority compared with warfarin. Other studies are ongoing. We decided not to add this detail as it may distract the reader from the main point that warfarin is superior to antiplatelet agents.
3I am troubled by the fact that all of the new anticoagulants are considered as a group – rather than as individual agents (or, at the very least, two distinct classes of medications). Each of these new agents have unique pharmacological and pharmacokinetic properties. While the efficacy of these agents in clinical trials appears to have been similar (for both a-fib and VTE treatment indications), the adverse event and side effect profiles clearly were not (dabigatran had a relatively higher incidence of GI side effects … rivaroxaban was associated with relatively higher rate of GI bleeding … and apixaban was not associate with either of these adverse events). Thus I believe combining, analyzing, and summarizing the results of the clinical trials of these distinct classes of medications (DTIs and direct Xa inhibitors) is not appropriate.Thank you for this comment. Our analysis assumes a class effect. Although each drug has unique pharmacological and pharmacokinetic properties, they are all developed as anticoagulants. However, we have revised our analytic approach to analyze by drug class when there were sufficient studies for meaningful analyses. Further, we have revised the results and discussion to emphasize when the results were variable across drugs or drug class and to point out that our analyses is limited because we cannot reliably detect differences between individual drugs.
3Not sure why the ROCKET-AF study (Patel 2011 – reference 74) is consistently listed as Patel 2010 in the tables and figures; was this a typographical error?The report has been revised to ensure that studies are consistently listed by author/year in the tables and figures.
4Page 9: minor correction to be complete: Though not very commonly used, UFH may be given SC for acute VTE treatment as well as IV: “unfractionated heparin administered intravenously”The statement has been revised to state that UFH is typically given intravenously.
4Page 10: consider adding: warfarin’s interaction with certain disease states in addition to drugs, foods. (e.g., CHF, thyroid, acute infection)Thank you for the suggestion, but we decided to omit this detail as we believe the current text makes it abundantly clear that interindividual and intraindividual variability in warfarin response, along with food and drug interactions, is a disadvantage.
4Page 10–11: consider adding: dabigatran’s advantage over warfarin in the lack of drugfood interaction. Also, while dabigatran doesn’t interact with drugs via CYP enzyme system, there are fewer but significant interactions through P-gp transporter system.Agreed. We have added the following statement: “Dabigatran acts as a substrate for the p-glycoprotein transporter system, which makes it more prone to drugdrug interactions.”
It is also present in the table.
4Page 12, Table 1: ECT time is best measure of anticoagulant effect of dabigatran, although this test is not widely available outside of a research setting at this time.Agreed. This has been added to the report.
4Page 13, Table 1, Contraindications: Warfarin and severe renal impairment – I could not find evidence of this to be true. Reviewed the Harder reference provided where it directs you to UK product information. The link provided in the reference in the Harder article lists renal impairment as a precaution, not contraindication. Also per US PI, severe renal impairment is NOT a contraindication. These patients likely have higher risk of bleeding and need lower doses of warfarin but it is not a contraindication to useAgreed. We have changed the heading to “Precautions.”
Optional Dissemination and Implementation Questions
Question 5: Are there any 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.
1No comment from reviewer 1.NA
2No comment from reviewer 2.NA
3No comment from reviewer 3.NA
4The implications of this report are unclear at this time.Acknowledged
Question 6: Please provide any recommendations on how this report can be revised to more directly address or assist implementation needs.
1No comment from reviewer 1.NA
2While it may be outside of the scope and stated objective of the review, it would be helpful to include a more comprehensive discussion of the major clinical trials including criticism and clinical applicabilityWe feel that it is outside the scope of this review to discuss the major trials separately.
3No comment from reviewer 3.NA
4The report should be revised to read more balanced; it is biased toward the newer agents without describing the potential disadvantages and unknowns.Agreed. We have revised the report to be more balanced, and we highlight the potential disadvantages of the newer oral anticoagulants. For example, we state:
“Wallentin et al. found that the advantage of dabigatran over warfarin in terms of major bleeding rates was only evident at sites with poor-quality anticoagulation (time in therapeutic range <57.1%), while rates of major bleeding were not significantly different at sites with higher quality anticoagulation. Hence, better INR control led to similar bleeding rates between both groups. In the VHA, time in treatment exceeds this threshold, but newer anticoagulants could have important advantages for individual patients who have difficulty maintaining a therapeutic INR. However, since newer anticoagulants are dosed twice daily, compared with once daily dosing warfarin, better outcomes would not be expected if poor medication adherence were the cause of the subtherapeutic INR. A pragmatic concern related to adherence is the FDA notification that dabigatran may lose potency if placed in pill boxes and that it should only be dispensed and stored in the original bottle or blister package.
Although newer anticoagulants are associated with a lower risk of fatal bleeding compared to warfarin, this advantage may be tempered by the increased risk of gastrointestinal bleeding with dabigatran. The FDA is currently, evaluating reports of high rates of serious bleeding. The reports of bleeding appear to be concentrated in older adults and those with impaired renal function. Another worrisome finding is elevated rates of myocardial infarction with dabigatran, although the strength of evidence for this finding is low.”
And we have added a word of caution: “VA should carefully consider the potential benefits and harms, along with patients at higher risk for adverse effects when establishing eligibility criteria for newer anticoagulants.”
Question 7: Please provide us with contact details of any additional individuals/stakeholders who should be made aware of this report.
1No comment from reviewer 1.NA
2No comment from reviewer 2.NA
3No comment from reviewer 3.NA
4No comment from reviewer 4.NA
Cover of Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism [Internet].
Adam SS, McDuffie JR, Ortel TL, et al.
Washington (DC): Department of Veterans Affairs; 2012 Apr.

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