Economic model to examine the cost-effectiveness of FlowOx home therapy compared to standard care in patients with peripheral artery disease

Victory ‘Segun Ezeofor; Nathan Bray; Lucy Bryning; Farina Hashmi; Henrik Hoel; Daniel Parker; Rhiannon Tudor Edwards

doi:10.1371/journal.pone.0244851

Peer Review History

Original SubmissionJune 1, 2020
7 Aug 2020 Decision Letter - Colin Green, Editor PONE-D-20-16557 Economic model to examine the cost-effectiveness of FlowOx™ home therapy compared to standard care in patients with peripheral artery disease PLOS ONE Dear Dr. Ezeofor, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please do address the Review comments on presentation of results, avoiding the primary presentation of results using negative cost-effectiveness ratios. It would be helpful to clarify the statement made on the cost-effectiveness of the FlowOx in addition to standard care (as Review comments), and to reconsider the appropriateness of the discount rates applied. Whilst I note one of the Reviewers has requested an update to the unit costs (year of cost data), I would be happy for you to retain the current approach if the requested changed involved excessive additional work. However, if you could address that request it would be helpful. Please do ensure any potential conflicts of interest are clearly stated, given at least one of the co-authors has an affiliation to Otivio AS. Please submit your revised manuscript by Aug 31 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). 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We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: A very nice analysis has been presented exploring the potential cost-effectiveness of FlowOx therapy compared to standard care. Congratulations on the submission. I have a few minor comments, which are listed below: - Introduction: A nice background to the condition has been presented, and the financial burden of progressing to end-stage PAD is clear. However, upon presentation of the intervention, I would like you to clearly state at what point in the treatment pathway it is likely to be used, i.e. pre-analgesics/post analgesics/prior to significant progression of the condition and surgical intervention. This would allow me to put use of the intervention in the overall context of progression of the disease right at the beginning of the paper. - Methods: Moloney et al. carried out a systematic review of economic models used to compare methods of diagnosing PAD, which summarises evidence in this area (Systematic Review of Economic Models Used to Compare Techniques for Detecting Peripheral Arterial Disease). Was this identified in your searches and could any of the models outlined here have been used to inform your own analysis? As mentioned previously, you talk about use of the intervention for the purpose of treating PAD patients in your 'Model overview' and 'Decision model' sections, but I am still unclear at this point as to the stage in the treatment pathway at which the intervention would be introduced, beyond knowing it will cover mild/severe stage PAD. Is 5 years a sufficient time horizon to capture all relevant costs and effects? You state in the introduction that the condition is associated with prolonged morbidity. If that's the case and the intervention can potentially reduce associated morbidity, then I would suggest that a longer time horizon should be used. At the very least, if it can be definitively argued that 5 years is a sufficient time horizon, it may still be worth carrying out a lifetime analysis as part of your sensitivity analysis to explore any change in results, even if there is uncertainty surrounding the long-term extrapolation. I suggest you update your costs to a 2018/19 price year given that we are into 2020 now. In your 'Sources of cost data' section I would like to see more detail as to what is actually included in each health state cost, beyond 'community, inpatient and outpatient' costs. When you state that 'expert opinion' was used, please clearly indicate the source of this opinion. - Results: I note that you have presented negative ICERs, which I suggest shouldn't be done. Instead, present these results in terms of 'dominant', 'dominated' etc. In your cost-effectiveness plane, please present the WTP threshold in order to help interpret the scatter-plot. In your CEAC, make it clear that the WTP values are £ sterling, and reduce your prob. cost-effective values to two decimal places. - Discussion: In your discussion and concluding sections, I would like to see some reference to other similar studies that have been conducted, if at all, to help put the results of your own analysis in context. Reviewer #2: I would like to thank the authors for giving me the opportunity to review their article. As they will see most of my comments relate to how the results are presented and some of the assumptions (e.g. discount rates) underpinning their model. Abstract 1) What is nominal care? Is it the same as standard care? 2) In the results, the authors report mean treatment costs. Are these just the costs of the actual treatment, or do these include follow-up healthcare costs. If so, please amend the terminology. 3) The authors report a negative ICER. Although, not incorrect, it might lead to potential confusion, as a negative ICER could be arrived at by different combinations of negative incremental costs or outcomes. Would it be best if the authors reported that FlowOx therapy was dominant? 4) I am very confused by the following: “FlowOx™ therapy in addition to standard care was the least cost-effective scenario at £17,823 per QALY gained.” As opposed to what? In addition, if FlowOx + standard care yielded more QALYs than FlowOx therapy on its own, would FlowOx + SC not be recommended? 5) I missed any probabilistic sensitivity results in the abstract. Methods 6) Source needed for the assertion: Cost data associated with PAD have a wide 237 variance, which has a direct impact on average cost estimates.” 7) More details are required on which costs were derived from the literature and which ones were derived from expert opinion. 8) I am very dubious at the differential discounting rate applied by the authors. The UK’s current recommendation is: “a rate of 3.5% for costs and effects”. As far as I am aware, the only exception to this is: “for therapies with long-term benefits, where differential discounting is recommended with a lower discount rate for health effects of 1.5%.” Results 9) Although I can understand why the authors compare all interventions to SC, interventions should also be compared against each other. Therefore, at one year for e.g., S0 should be compared to S1, SC to S0 and S2 to SC (before removing interventions that are dominated) 10) QALYs should be rounded to the 3rd or 4th decimal point. As results are presented, it implies there is absolutely no difference in QALY gain between the 3 interventions. 11) I found Tables 7 and 8 absolutely redundant as they present all the information in Table 6. 12) Why are CEACs not presented including all four of the interventions assessed? 13) I also missed that no break-up of costs was given. How much of the total costs are due to: FlowOx therapy, amputations, early stages of disease etc… ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes:** Ramon Luengo-Fernandez [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0244851.r001
Revision 1
2 Dec 2020 Author Response Review 1 - Introduction: A nice background to the condition has been presented, and the financial burden of progressing to end-stage PAD is clear. However, upon presentation of the intervention, I would like you to clearly state at what point in the treatment pathway it is likely to be used, i.e. pre-analgesics/post analgesics/prior to significant progression of the condition and surgical intervention. This would allow me to put use of the intervention in the overall context of progression of the disease right at the beginning of the paper. Ans- We have included statements to answer this query in the introduction and decision model section (see Page 6-7, Lines 121-126 and Pages 8-9, Lines 169-173). - As mentioned previously, you talk about use of the intervention for the purpose of treating PAD patients in your 'Model overview' and 'Decision model' sections, but I am still unclear at this point as to the stage in the treatment pathway at which the intervention would be introduced, beyond knowing it will cover mild/severe stage PAD. Ans- We have clarified this in the manuscript (see Page 6-7, Lines 121-126 and Pages 8-9, Lines 169-173) and have also included references to a clinical trial of the FlowOXTM device from another study in the introduction section (Page 6, Lines 116-118). - Methods: Moloney et al. carried out a systematic review of economic models used to compare methods of diagnosing PAD, which summarises evidence in this area (Systematic Review of Economic Models Used to Compare Techniques for Detecting Peripheral Arterial Disease). Was this identified in your searches and could any of the models outlined here have been used to inform your own analysis? Ans- This is a very nice systematic review, though we did not use it in this paper we have pencilled it down for the main trial of the FlowOXTM therapy. -Is 5 years a sufficient time horizon to capture all relevant costs and effects? You state in the introduction that the condition is associated with prolonged morbidity. If that's the case and the intervention can potentially reduce associated morbidity, then I would suggest that a longer time horizon should be used. At the very least, if it can be definitively argued that 5 years is a sufficient time horizon, it may still be worth carrying out a lifetime analysis as part of your sensitivity analysis to explore any change in results, even if there is uncertainty surrounding the long-term extrapolation. Ans- This would be investigated in larger scale trial we are looking into conducting in the future. This study was more like a feasibility trial and with a lot of missing data we have decided not to conduct a lifetime analysis. We feel that it would be a step beyond the available data to extrapolate the findings to a lifetime analysis. We have added a caveat to the discussion to explain our position: “Given these issues, we did not feel that extrapolating the data further, for instance in a lifetime analysis was necessary. Additional robust data is required to draw further conclusions about the cost-effectiveness of FlowOx™ therapy over a lifetime analysis” (see page 27, lines 441-443) -I suggest you update your costs to a 2018/19 price year given that we are into 2020 now. Ans- Yes, agreed. All cost in the study where necessary were inflated to 2018/19 in the computation (lines 258-259). - In your 'Sources of cost data' section I would like to see more detail as to what is actually included in each health state cost, beyond 'community, inpatient and outpatient' costs. Ans- In this study cost were obtained from literature and as noted these costs for PAD have some variance hence expert opinion were used as guidance in choosing which costs and reference were suitable for this study. Tables A, B and D in the appendix gives the breakdown to Table 3 with details to cost applied in the study and the references. - When you state that 'expert opinion' was used, please clearly indicate the source of this opinion. Ans- Expert advice were essential in selecting which cost were necessary to this study from a wide range of cost (see Source of Cost section, Page 14-15, Lines 262 - 264). - Results: I note that you have presented negative ICERs, which I suggest shouldn't be done. Instead, present these results in terms of 'dominant', 'dominated' etc. Ans- Agreed and have been changed (Tables 6-7). - In your cost-effectiveness plane, please present the WTP threshold in order to help interpret the scatter-plot. Ans- This has been added to the scatter plot as suggested (Figure 3). - In your CEAC, make it clear that the WTP values are £ sterling, and reduce your prob. cost-effective values to two decimal places. Ans- Agreed and this has been amended (Figure 4). - Discussion: In your discussion and concluding sections, I would like to see some reference to other similar studies that have been conducted, if at all, to help put the results of your own analysis in context. Ans- Agreed and have been added in the Discussion and conclusion section (see Page 24-25, Lines 408-410; Pages 27, Lines 471 -473). Review 2 1) What is nominal care? Is it the same as standard care? Ans- Nominal care is a reduced standard care, such that there are fewer visit by the nurse and medication is reduced as shown in Table A of the Appendix, while standard care is seen in tables A and D (see Decision model section, Page 9, Lines 181-184). 2) In the results, the authors report mean treatment costs. Are these just the costs of the actual treatment, or do these include follow-up healthcare costs. If so, please amend the terminology. Ans- Agreed and Amended (lines 34-36). 3) The authors report a negative ICER. Although, not incorrect, it might lead to potential confusion, as a negative ICER could be arrived at by different combinations of negative incremental costs or outcomes. Would it be best if the authors reported that FlowOx therapy was dominant? Ans- Yes, Agreed and Amended (Tables 6-7). 4) I am very confused by the following: “FlowOx™ therapy in addition to standard care was the least cost-effective scenario at £17,823 per QALY gained.” As opposed to what? In addition, if FlowOx + standard care yielded more QALYs than FlowOx therapy on its own, would FlowOx + SC not be recommended? Ans- This statement has been taken out 5) I missed any probabilistic sensitivity results in the abstract. Ans- A probabilistic sensitivity result has been included in the abstract (see Abstract, Page 2, Lines 38-39). 6) Source needed for the assertion: Cost data associated with PAD have a wide 237 variance, which has a direct impact on average cost estimates. Ans- We have included cost data in Tables A, B and D of the appendix to show the breakdown of all cost applied in this analysis. 7) More details are required on which costs were derived from the literature and which ones were derived from expert opinion. Ans- Expert advice were essential in selecting which cost were necessary to this study from a wide range of cost (see Source of Cost section, Page 14-15, Lines 262 - 264). In this study cost were obtained from literature and as noted these costs for PAD have some variance hence expert opinion were used as guidance in choosing which costs and reference were suitable for this study. Tables A, B and D in the appendix give details to cost applied in the study and the references. 8) I am very dubious at the differential discounting rate applied by the authors. The UK’s current recommendation is: “a rate of 3.5% for costs and effects”. As far as I am aware, the only exception to this is: “for therapies with long-term benefits, where differential discounting is recommended with a lower discount rate for health effects of 1.5%.” Ans- A rate of 3.5% has now been implemented on the Effect in accordance with the NICE guideline [43] (See Discounting section, Page 15, Line 281 - 284). 9) Although I can understand why the authors compare all interventions to SC, interventions should also be compared against each other. Therefore, at one year for e.g., S0 should be compared to S1, SC to S0 and S2 to SC (before removing interventions that are dominated) Ans- Data for the EQ-5D showed very similar results as shown in Tables 6 and 7, with this the change in effect will be zero and thus it is not particularly useful to report these findings. This will be one of the points we will focus on during the larger scale trial. 10) QALYs should be rounded to the 3rd or 4th decimal point. As results are presented, it implies there is absolutely no difference in QALY gain between the 3 interventions. Ans- All QALYs have been rounded to 2dp as requested (Tables 6 – 8). 11) I found Tables 7 and 8 absolutely redundant as they present all the information in Table 6. Ans- Table 7 has been changed and table 8 removed. 12) Why are CEACs not presented including all four of the interventions assessed? Ans- These have now been included (Figure 4). 13) I also missed that no break-up of costs was given. How much of the total costs are due to: FlowOx therapy, amputations, early stages of disease etc… Ans- In this study cost were obtained from literature and as noted these costs for PAD have some variance hence expert opinion were used as guidance in choosing which costs and reference were suitable for this study. The breakdown of the cost are presented in Tables A, B and D in the appendix. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0244851.r002
18 Dec 2020 Decision Letter - Raffaele Serra, Editor Economic model to examine the cost-effectiveness of FlowOx™ home therapy compared to standard care in patients with peripheral artery disease PONE-D-20-16557R1 Dear Dr. Ezeofor, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: I would like to thank the authors for addressing my comments satisfactorily. I would, however, would like to see QALYs rounded up to the fourth-fifth decimal point not just two (currently showing that three interventions are identical outcomes). ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Eoin Moloney Reviewer #2: Yes:** Ramon Luengo-Fernandez https://doi.org/10.1371/journal.pone.0244851.r003
Formally Accepted
28 Dec 2020 Acceptance Letter - Raffaele Serra, Editor PONE-D-20-16557R1 Economic model to examine the cost-effectiveness of FlowOx home therapy compared to standard care in patients with peripheral artery disease Dear Dr. Ezeofor: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Raffaele Serra Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0244851.r004

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