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Kansagara D, Dyer E, Englander H, et al. Treatment of Anemia in Patients with Heart Disease: A Systematic Review [Internet]. Washington (DC): Department of Veterans Affairs (US); 2011 Oct.

Cover of Treatment of Anemia in Patients with Heart Disease: A Systematic Review

Treatment of Anemia in Patients with Heart Disease: A Systematic Review [Internet].

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APPENDIX DPEER REVIEW COMMENTS AND RESPONSES

ReviewerCommentResponse
Question 1: Are the objectives, scope, and methods for this review clearly described?
1No: I am worried about a few things in the current iteration of the review: 1) defining the population upfront; 2) defining the outcomes upfront; 3) justification of the inclusion of observational data. Defining the population – the document refers to patients with “CHF” and “CHD” but does not drill down and define these. CHF can include those with asymptomatic low LVEF or those with symptoms of CHF but with normal LVEF. Similarly, CHD can include acute coronary syndrome, PCI, or those with stable angina. I think these clinical entities need to be defined upfront.We've clarified these definitions in the “study selection” section of Methods. The entities had been defined (fairly broadly) up front, but we agree this was not well-reported in the manuscript.
1If the studies are heterogeneous in their inclusion of these populations, then this should be specifically mentioned.We've added more detail to the “data abstraction” section of Methods to clarify that we've collected and reported the clinical characteristics of study populations. We also added a sentence to the second paragraph of Discussion clarifying that most ESA studies were in patients with systolic heart failure. The applicability of the evidence review findings to various patient populations is also further delineated in the GRADE table, and in the clinical applications section.
1Also, why examine non-anemic patients with iron deficiency if the primary purpose is to study the treatment of anemia?Clarified this in “study selection” section.
1Defining the outcomes – the document examines several outcomes but no justification is provided for why they were chosen.Clarified that we are defining “health outcome” as those that are patient-centered and apparent to the patient (in contrast to intermediate physiologic outcomes). The list of outcomes was discussed with and approved by the Technical Expert Panel during the topic development phase.
1Justification of observational data – on pages 7 and 8, there is a section on Study Quality, and the answers to all of the questions posed would result in observational data being “low quality.” This is entirely justified, but there are other ways to evaluate observational data like the appropriateness and robustness of the statistical methods. The authors should consider including some measure of observational data quality.We've added a table describing the methodologic characteristics of each of the observational studies. We've added the quality assessment description to “study quality” section of Methods.
2Agree with adding ortho surgery data as large RCT recently completed.The data had not been available, but we will include if enough data available.
3Yes.
Question 2: Is there any indication of bias in our synthesis of the evidence?
1The only bias is in the observational studies that are included (see above).Noted and discussed above.
2Seemed to be more pro-ESA than the data supportsNoted
3No.
Question 3: Are there any published or unpublished studies that we may have overlooked?
1No.Noted.
2The ortho FOCUS trialSee comment 5 rows below regarding the FOCUS trial.
3No.Noted.
Question 4: Please write additional suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.
1The section on iron therapy doesn't seem to have a summary of what the overall findings are. This would be helpful.Thanks – yes, an accidental omission – this was added to the beginning of the iron section.
1Page 39 – MINT is an ongoing trial and likely will not be published for several years. There is a trial that has been presented called FOCUS that will be published soon. (see http://www.theheart.org/article/1024017.do for a report of the presented results).Thanks for the clarification. The results were amended accordingly. We report the FOCUS results available in an abstract and acknowledge the full document has yet to be published.
1Page 40 – an important distinction between the Wu study and the Rao study are that Wu looked at baseline anemia while Rao examined the lowest hct value occurring during hospitalization. In addition, patients with active bleeding were excluded from the Wu study.We've clarified these distinctions in this section of the discussion.
1The section on Clinical Applications should be more prescriptive (see below). It's tough to actually get at what the recommendation is because it is obscured a bit by more description of the data.We've stopped short of providing prescriptive recommendations of what should and should not be done intentionally as we'd feel more comfortable developing clinical recommendations in conjunction with our stakeholders/clinical partners.
2Page 2- need to give number of paper rejectedThank you – we had accidentally omitted this from the executive summary.
2Page 2 – ESA – to me the evidence is clear that ESA are associated with harm and not “may be”. This is especially true in diabetic patientsThe harm of targeting near-normal hemoglobin, especially in diabetic patients, seems clear after trials like TREAT, but these were not exclusively focused on treatment of anemic heart disease patients. The harms of using ESAs in heart disease populations are not as well elucidated. The language is meant to reflect this uncertainty and the fact that it most closely applies to those with chronic kidney disease. However, we did change the language to be a bit more direct (changed “possibility” to “finding,” and “may be” to “is”.
2Page 9 – the hematocrit to hemoglobin correction of 10:1 makes no sense – the Hbg:Hct is 1:3 roughly.Thank you – this was a typo – corrected.
2Page 12 – again I think the case ESA cause harm is provenPlease see response to page 2 comment above.
2Page 16 – would strongly disagree that 6MWT is not influence by blinding – reams of data in the sports medicine literature supports placebo effect!Thank you – yes, we had mis-stated this. Meant to say lack of personnel blinding alone, given that outcome assessors were blinded, shouldn't carry high risk of bias for these outcomes. Patients were blinded, and control patients received placebo injections. We've clarified this in the table.
2Page 21- is there data to support the notion that longer use of ESA is associated with greater harm?It would be hard to determine this from the studies. The two studies mentioned with long follow-up periods also differed in patient population and treatment from the other smaller, shorter duration ESA trials. The mortality curves in Besarab did begin to separate several months into treatment and continued to diverge 1-2 years into treatment.
2Page 26 – any data for increased risk of cancer? Was suggested in TRICK study and certainly seen in the oncology trials…No, not that was reported in these trials. Of note, many excluded patients with malignancy.
2Page 26 – just a comment – are the ongoing trials even ethical given what we know about high Hct goals and bad outcomes with ESA…Interesting point, but outside the scope of our review. It is a different patient population.
2Page 29 – Although old, I have found the discussion in this paper the best framework for understanding the complex interplay of transfusions for cardiac disease: Prudent strategies for elective red blood cell transfusion. Welch HG, Meehan KR, Goodnough LT. Ann Intern Med. 1992 Mar 1;116(5):393-402Thanks for this suggestion.
2Page 32 – any suggestion of confounder of ACS management and risk of transfusion – i.e. if more patients have PCI that did worse with more transfusions??One of the main confounders would be risk of bleeding associated with management – either procedural or med-related. Not all studies accounted for bleeding, but some did and we've added a table clarifying some of the methodologic characteristics of observational transfusion studies, including whether or not they accounted for bleeding complications.
2Page 38 – the FDA ESA recommendation is even more aggressive than stated:
In controlled trials with CKD patients, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL.
No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
ESA labels now recommend:
For patients with CKD, consider starting ESA treatment when the hemoglobin level is less than 10 g/dL. This advice does not define how far below 10 g/dL is appropriate for an individual to initiate. This advice also does not recommend that the goal is to achieve a hemoglobin of 10 g/dL or a hemoglobin above 10 g/dL. Individualize dosing and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions. Adjust dosing as appropriate.
Agree. We've tried to clarify the language further by inserting the phrase “if they are to be used at all”.
2Page 39: - the “10/30” was base on an off the cuff recommendation by a Mayo Anesthesiologist in WWII (Vox Sang. 2010 Jan;98(1):2-11)Thank you. We've inserted this reference.
2Page 40 – given that most ACS patients in the USA get PCI should transfusions be proscribed in them for hbg > 8-9??This is a question for policy- and guideline-makers. The data summarized here are still largely of poor quality because it is mostly observational data.
2Page 41 – The person with the ferritin of 50 is truly iron deficiency and needs some form of iron replacement - also needs a GI work-up – maybe a ferritin of 123 would make the point betterWe felt the data was not as strong for patients with ferritin > 100. The Anker study included patients with higher ferritins, but most had ferritin well below 100 and the applicability of the results of this IV iron trial are strongest for patients with low ferritins.
2Page 42 – I though the trial for ESA for STEMI was distinctly negative - JAMA. 2011 May 11;305(18):1863-72. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial.
Najjar SS, Rao SV, Melloni C, Raman SV, Povsic TJ, Melton L, Barsness GW, Prather K, Heitner JF, Kilaru R, Gruberg L, Hasselblad V, Greenbaum AB, Patel M, Kim RJ, Talan M, Ferrucci L, Longo DL, Lakatta EG, Harrington RA; REVEAL Investigators. – also stroke - Stroke. 2009 Dec;40(12):e647-56
This and 2 other recent trials examined one-time high-dose ESA use in ACS patients but these were not focused on treatment of anemic patients. As such, they fell outside of the scope of our review. Inclusion of the statement alluding to these studies in our discussion is probably confusing and we've deleted it.
3Overall excellent review. The “emerging themes” concept is great as it does not leave the reader hanging in his/her approach to the individual patient.
Love the way you broke out the high quality studies in fig 3 and 4.
Noted. Thanks.
3On page 2- need to fill in # of studies rejected.
Page 11- first box on right needs the N filled in.
Done.
3We can develop practice guidelines around this but would not promulgate quality measures just yet.Noted.
4Overall --very readable, a seemingly transparent, honest assessment of the literature leaving this reader confident in the findings and the interpretations.Noted.
4Never easy to give weight to benefits and harms, or benefits versus harms, the problem was not clearly resolved in this analysis. I've no suggestions and in general thought the balance reached by the authors was reasonable.Noted.
4Except for the one ongoing study of 80 patients, all (or the vast,vast majority) patients apparently had recognized systolic dysfunction. In some CHF series, up to half have normal ejection fractions‥ While I can't think why this would group would fare differently with treatments for anemia, available studies don't apply. . In some clinical trials evaluating arrhythmia patients, a clinical history of CHF was a more powerful predictor of outcome than ejection fraction measurements.Agree. We've added statements to the ESA “summary” paragraph in results, the ESA discussion, and the Future studies sections clarifying that this evidence base applies most directly to those with reduced systolic function.
4No data on influence of very common and potentially important contributors to outcomes‥‥smoking, lung disease, cardiovascular medications, arrhythmias (particularly atrial fibrillation), others‥‥We limited the ESA and iron sections to trials only. We examined each trial for important baseline differences, though most were adequately randomized. This is more of an issue for the observational transfusion studies and we have evaluated the methodologic characteristics – including accounting for important confounders – of these studies.
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.
1Absolutely. The use of blood is high in the VA system as is the use of ESAs. By providing this document, the use of these therapies with limited benefit should be curbed resulting in safer care for veterans at lower cost.Noted.
2Yes – this report has wide implications for multiple areas of careNoted.
3Each individual institution/system will need to assess its use of ESA's, iron and transfusions in these populations.Noted.
Question 6. Please provide any recommendations on how this report can be revised to more directly address or assist implementation needs.
1I think the section on Clinical Applications should be more prescriptive. Also the clinical scenarios are a bit strange. I would prefer to see broader categories, or if this is too difficult, a table with the first column being the clinical situation and the subsequent columns addressing ESAs, Iron, and Blood transfusion. The cells then could have a (+), (-), or “Unk” for whether the evidence supports or refutes use or if there are no data.We intended the GRADE table to show the level of evidence in various broad clinical categories for each of the interventions.
2I think the transfusion part could stand alone as a journal articleNoted.
3Target not only the cardiology and hospitalist leaders, but the P&T and blood bank chairs at system levels.Noted.
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