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Sophie Beese, Tuba S Avşar, Malcolm Price, David Quinn, Hoong S Lim, Janine Dretzke, Chidubem O Ogwulu, Pelham Barton, Louise Jackson & David Moore.

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Sophie Beese ^1,†, Tuba S Avşar ^1,2,†, Malcolm Price ¹, David Quinn ³, Hoong S Lim ³, Janine Dretzke ¹, Chidubem O Ogwulu ¹, Pelham Barton ¹, Louise Jackson ¹, David Moore ^1,*

¹ Institute of Applied Health Research, University of Birmingham, Birmingham, UK
² Institute of Epidemiology and Health, University College London, London, UK
³ Cardiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
^* Corresponding author Email: d.j.moore@bham.ac.uk

^† Joint lead authors

Funding: {{metadata.Funding}}

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https://doi.org/{{metadata.DOI}}

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Responses to this report

Response by Dr David Moore on 4 November 2024 at 10:39 AM
Author response to comments

Thank you for taking the time to read and comment on our report.

1. Our research report was submitted to the NIHR in December 2022.

We were aware of the 5-year MOMENTUM-3 results becoming available towards the end of our study, but well after our final search update for evidence. We specifically mention their existence and their implications in our discussion section:

“Data from the 5-year extended observational follow-up of MOMENTUM 3 were recently presented at the ESC congress.148 While this was outside of our latest search update and therefore not included in the analysis, overall survival was reported at 54.8% in DT HM3 patients at 5 years, compared to 39.4% in those with the HeartMate II. This was higher than any survival figures reported in INTERMACS analyses of multiple device types, though these analyses did not include the HM3.31,46,72 This reiterates the survival benefit of the HM3 over other devices and may be useful in future economic models.” (page 83, Summary of findings)

We agree that it would be beneficial to update the systematic reviews and the economic modelling with this and any more recent evidence, however, this was and is beyond the scope and funding for this commissioned project.

2. At the time of model development, we used the most appropriate available data that we could acquire, which were not always from the most recent devices. Extensive discussions with our clinical specialists were undertaken to make final decisions on which data were most appropriate to be utilised in the base-case analyses. We also note that there are little data available to suggest that “Proportion requiring RVAD placement in patients with LVAD” is different between HVAD and HeartMate 3.

3.We agree that there are limitations with the medical management data available and used within our modelling. We highlight this issue throughout the report and include a research recommendation to overcome this evidence gap, particularly from the UK NHS context:

“One important issue is the uncertain costs for patients with AHF on MM. There are few to no data available on the current costs of MM in the UK, and all recent models have relied upon cost data, which are either very old or from other countries that could be considered to have similar healthcare systems. Alternative value inputs were considered in the deterministic sensitivity analysis and when the mean of all the values identified in the literature were used, ICER per QALY estimates were similar to the base case estimates. However, the true cost of MM in the UK remains unclear and therefore a major audit is recommended to establish these costs and to include them in future economic models.”

We understand that that there are potentially various side effects associated with several of the drugs that may form medical management, however it should also be noted that as per current guidelines, treatment with many of these drugs would be resumed after LVAD implant. This means that these side effects would apply to LVAD patients as well.

Response by Mr Ross Wardle on 18 September 2024 at 5:10 PM
The important limitations of the report on the

We read the article "Clinical and cost-effectiveness of left ventricular assist devices as destination therapy for advanced heart failure: systematic review and economic evaluation" with great interest and would like to congratulate the authors for their important contribution. While we appreciate the research and analyses, we believe there are some limitations to this publication and have outlined these in the three points below:

1. The MOMENTUM3 RCT 5-year study results by Mehra et al., 2022 were published on JAMA in September 2022. We are aware the NIHR search strategy was only until the 11th January 2022 and therefore, the 5-year results did not fall within the search time period. However, with a 2-year gap from the search strategy period to the publication of this HTA report, we believe there was sufficient time to include the 5-year study results of MOMENTUM 3.
The lack of inclusion of this data leads to a key limitation and this is highlighted in the following text from the "limitations" paragraph of this publication on page 80, 
“Another consideration was the lack of mortality data beyond 2 years. This required making an assumption to extrapolate the mortality data. The model used the mortality risk reported for the months between 13 and 24 in the trial for the time points beyond 2 years. The sensitivity analyses showed that this was a conservative assumption and had a modest impact on the cost-effectiveness outcome. Therefore, the model might be underestimating the cost-effectiveness of LVADs if the impact on mortality beyond 2 years is greater than the values used in the model. On the other hand, the model might be overestimating the cost-effectiveness of LVADs if the impact on mortality beyond 2 years is lower than the values used.”
As stated here, we believe the model underestimates the cost-effectiveness of LVADs given that the published HM3 survival beyond two years is greater than the values used in the model. The outcome of this model would be more accurate if the 5-year study results were used instead of the extrapolated 2-year mortality data from MOMENTUM3 RCT, and we recommend that this is done as an update.

2. The Medtronic HVAD RCT ENDURANCE DT was used in the publication section "monthly probabilities" in the base-case analysis for “Proportion of disabling stroke in patients experiencing stroke”, “Proportion requiring RVAD placement in patients with LVAD”, and “Death due to stroke in LVAD patients”. Medtronic’s HVAD was discontinued and removed from the market globally on the 3rd of June 2021.
We do not believe that this analysis should rely on any data from discontinued devices, which are no longer implanted in England today. Relying on data from a device that will never be implanted for destination therapy compromises the validity of the model.
This limitation is further confirmed on page 34 of the publication in the section “Other Trial data” on HeartWare ventricular assist device. In this paragraph it is stated that, “Two RCTs assessed the HeartWare HVAD device. The HVAD was compared to the HeartMate II device in both trials: ENDURANCE DT and ENDURANCE DT Supplemental Trial (an extended study of the HVAD looking at stroke outcomes). The HVAD has now been withdrawn from the market and reporting of results from this device will be of limited value.”
We recommend reviewing the base-case analysis probabilities referencing the ENDURANCE DT study and instead
include the probabilities from, for example, the existing UK LVAD DT vs drug therapy cost-effectiveness analysis by Lim et al., 2022.

3. The complications in the medical management (MM) arm are limited to the risk of stroke in the NIHR report, which is an unrealistic assumption to make. The following is an excerpt from the publication on page 59,
“The major events identified for patients receiving LVADs were stroke, RHF and AR. For the MM group, the major event included was stroke. In addition, complications with no or limited impact on long-term mortality were incorporated in the model for LVAD patients to estimate their QoL impacts and the costs. These conditions are GIB, DI, PI, PE and arrhythmia.”
The 2021 Heart Failure ESC Guidelines state additional complications related to inotropes and diuretics as shown in the introduction section from “Figure 1. ESC Guidelines for the management of patients with HFrEF”. Assuming these are the drugs included in the report’s MM arm, the following complications may occur:
•       Inotropes leads to tachyarrhtymias and myocardial infarction.
•       Patients who fail to respond to diuretics are recommended to receive a renal replacement.
Below are further complications for the listed drugs from several publicly available publications:
•       Ivabradine can cause bradycardia, atrial fibrillation, sinus arrest, and heart block.
•       ARNI adverse events include hypertension, hyperkalemia, renal failure, cough, and angioedema.
•       MRAs can lead to worsening renal function, hypertension, and hyperkalemia.
•       SGLT2i can lead to acute renal injury, ketoacidosis (in diabetic patients), urinary infections, hypotension. The risk of bone fracture and amputation have been found to increase as well.
Similar to LVAD, the MM arm should include complications such as those listed above, even with no or limited impact of long-term mortality on top of the stroke risk, to estimate realistic quality-of-life impacts and costs.
The risk of arrhythmias, myocardial infarction, and renal failure and replacement during drug therapy should be taken into special consideration.