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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

A clinical and cost-effectiveness analysis of the HeartMate 3 left ventricular assist device for transplant-ineligible patients: A United Kingdom perspective

Open AccessPublished:November 23, 2021DOI:https://doi.org/10.1016/j.healun.2021.11.014

      Background

      The clinical and cost-effectiveness of left ventricular assist device (LVAD) therapy for patients with advanced heart failure (HF) who are ineligible for heart transplantation is debated in the UK. This study develops an indirect comparison between the fully magnetically levitated HeartMate 3 (HM 3) LVAD and medical therapy (MT) to evaluate expected clinical and cost-effectiveness in the UK National Health Service (NHS) context.

      Methods

      We performed an economic analysis comparing the HM3 pump against the HeartMate II LVAD (MOMENTUM 3), and then another analysis comparing MT with the first- and second-generation HeartMate XVE pump LVAD and HeartMate II LVAD for the same patient population (REMATCH and ROADMAP, respectively). By bridging those 2 analyses, an indirect comparison between HM3 and MT in the form of a network meta-analysis was developed. A literature search was performed to select the most appropriate pair of studies for this purpose. Outcomes were adjusted to produce Kaplan-Meier curves for the cost-effectiveness evaluation by using a decision-analytic model. Data were extrapolated linearly over a 5-year time horizon. Uncertainty and additional scenarios were addressed by one-way and probabilistic sensitivity analysis. Local costs and health utility were used from England, thereby representing the UK context.

      Results

      The incremental cost-effectiveness ratio (ICER) for LVAD vs MT in transplant ineligible patients with advanced HF was estimated to be £47,361 per quality-adjusted life year gained, with a 97.1% probability of being cost-effective at £50,000. In a subgroup of patients who are inotropic therapy dependent (INTERMACS 1-3 severity profile), the ICER was £45,616, while for a population with less-ill ambulatory HF (INTERMACS profile 4-7) the ICER changed to £64,051.

      Conclusions

      This study provides evidence that HM3 LVAD therapy in advanced HF patients ineligible for heart transplantation may be cost-effective compared to MT in the NHS UK-England context. The ICER is lowest for patients dependent on inotropic support, but exceeds the willingness to pay threshold of £50,000 in ambulatory noninotropic therapy dependent advanced HF patients.

      KEYWORDS

      Abbreviations:

      LVAD (Left Ventricular Assist Device), HF (Heart Failure), MT (Medical Therapy), HM3 (HeartMate 3), NHS (National Health Service), ICER (Incremental Cost-Effectiveness Ratio), QALY (Quality-Adjusted Life Year), NICE (National Institute for Health and Care Excellence), HES (Hospital Episode Statistics), DT (Destination Therapy), BTT (Bridge to Transplant), CHEERS (Consolidated Health Economics Evaluation Reporting Standards), INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), MFF (Market Forces Factor), HRG (Healthcare Resource Group), REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure), ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients), MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3)
      Heart failure (HF) is a major cause of hospitalizations in the UK.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • et al.
      2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

      NICE. Chronic heart failure in adults: diagnosis and management. 2021. Accessed December 10, 2021. https://www.nice.org.uk/guidance/ng106

      National Institute for Health and Care Excellence
      Acute Heart Failure: Diagnosis and Management.
      • Rough E
      • Adcock A
      • baker C
      House of Commons. Quality of life for patients with heart failure.
      According to the National Health Service (NHS) Hospital Admitted Care Activity, the number of emergency HF admissions increased from 81,000 in 2016/17 to 94,185 in 2019/20.

      NHS Digital. Hospital admitted patient care activity, 2016-17. 2021. Accessed December 10, 2021. https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/2016-17

      ,

      NHS Digital. Hospital admitted patient care activity, 2019/20. 2021. Accessed December 10, 2021. https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/2019-20

      The estimated cost of HF hospital readmission ranges from £2,274 to £3,690 for an average length of stay of 6 to 9 days according to a National Institute of Health and Care Excellence (NICE) guidance and Hospital Episode Statistics (HES) database 2019/20.

      Pumping Marvellous, Roche Diagnostics. The heart failure challenge. 2021. Accessed December 10, 2021. https://rochereport.readz.com/the-heart-failurechallenge

      NICE. Resource impact report: chronic heart failure in adults: diagnosis and management (NG106); 2018

      NHS Digital. Hospital episode statistics database. 2021. Accessed December 10, 2021. https://digital.nhs.uk/data-and-information/data-tools-and-services/data-services/hospital-episode-statistics

      As a result, the economic cost of HF is considerable, estimated at £2 billion in 2016. A 2021 report from the House of Commons shows that HF accounts for 2% of the total NHS budget, with 70% of these costs due to hospitalization.
      • Rough E
      • Adcock A
      • baker C
      House of Commons. Quality of life for patients with heart failure.
      Advanced HF (AHF) describes a distinct group of patients with severe limiting symptoms and frequent HF hospitalizations associated with severe cardiac dysfunction despite conventional heart therapies and poor short-term prognosis.
      • Crespo-Leiro MG
      • Metra M
      • Lund LH
      • et al.
      Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology.
      Heart transplantation, limited by the scarcity of donors is an option for only a small subgroup of patients with AHF. Increasingly, LVAD has been used in transplant-ineligible patients with AHF for their remaining lifetime, referred to as destination therapy (DT).
      • Schmier JK
      • Patel JD
      • Leonhard MJ
      • Midha PA
      A systematic review of cost-effectiveness analyses of left ventricular assist devices: issues and challenges.
      ,
      • Teuteberg JJ
      • Cleveland Jr., JC
      • Cowger J
      • et al.
      The society of thoracic surgeons intermacs 2019 annual report: the changing landscape of devices and indications.
      The clinical effectiveness and cost-effectiveness of LVAD therapy for AHF patients ineligible for heart transplantation is debated in the UK as well as worldwide. While Bridge-to-transplant (BTT) has been supported given the evidence available at the time of NHS England service specifications, DT has so far been explicitly excluded on the basis of lack of demonstration of cost-effectiveness

      NHS England. 2013/14 NHS standard contract for ventricular assist devices (VADs) as a bridge to heart transplantation or myocardial recovery (all ages). 2021. Accessed December 10, 2021. https://www.england.nhs.uk/wp-content/uploads/2018/08/Ventricular-assist-devices-as-a-bridge-to-heart-transplantation-or-myocardial-recovery-all-ages.pdf

      and absence of contemporary evidence around cost-effectiveness over Medical Therapy (MT) alone has not allowed for revision of the policy so far. First, direct comparison between LVAD and MT has only been studied with older generation LVADs, most that are no longer in clinical use.
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Stevenson LW
      • Miller LW
      • Desvigne-Nickens P
      • et al.
      Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (randomized evaluation of mechanical assistance in treatment of chronic heart failure).
      Second, existing economic evaluations have shown poor cost-effectiveness owing to the suboptimal performance and decreased durability of the devices available at the time of such analyses,
      • Long EF
      • Swain GW
      • Mangi AA
      Comparative survival and cost-effectiveness of advanced therapies for end-stage heart failure.
      ,
      • Rogers JG
      • Bostic RR
      • Tong KB
      • Adamson R
      • Russo M
      • Slaughter MS
      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      and clinical and cost-effectiveness of LVAD has not been re-evaluated in light of the recent progress in LVAD therapy.
      • Schmier JK
      • Patel JD
      • Leonhard MJ
      • Midha PA
      A systematic review of cost-effectiveness analyses of left ventricular assist devices: issues and challenges.
      The latest advance in technology includes the HeartMate 3 (HM3) centrifugal-flow LVAD (Abbott, Chicago, USA), a fully magnetically levitated rotor pump with a superior clinical outcome compared to older generation devices. As evidence on its better performance and durability continues to grow, it is time to revisit the clinical and cost-effectiveness in the context of a more forgiving device that reduces the rates of hospitalizations and morbidity related to bleeding, stroke and need for surgical pump replacement.
      • Mehra MR
      Evolving disruption in left ventricular assist systems: forgiving but not yet forgettable.
      This evaluation uses patient level evidence derived from robustly conducted clinical trials across various advanced heart failure populations to estimate the cost-effectiveness of LVADs compared to MT in patients with advanced HF, from an NHS UK-England perspective.

      Methods

      Model design

      The economic analysis was performed by using a decision-analytic model to estimate clinical outcomes and costs among advanced HF patients receiving LVADs or MT (Figure 1), similar to previous studies.
      • Rogers JG
      • Bostic RR
      • Tong KB
      • Adamson R
      • Russo M
      • Slaughter MS
      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      ,
      Special report: cost-effectiveness of left-ventricular assist devices as destination therapy for end-stage heart failure.
      A time horizon was 5 years post assessment for transplantation candidacy as this is the timescale used by NHS England Specialised Services and is plausible in terms of life expectancy as seen in outcomes from observational series of LVADs.
      Special report: cost-effectiveness of left-ventricular assist devices as destination therapy for end-stage heart failure.
      ,

      NHS England. Making decisions about new treatments. 2019. Accessed December 10, 2021. https://www.england.nhs.uk/commissioning/spec-services/

      Costs and effects after year one were discounted at 3.5% per year, as recommended by NICE.

      NICE. The guidelines manual. 2021. Accessed December 10, 2021. https://www.nice.org.uk/process/pmg6/chapter/assessing-cost-effectiveness

      The model was constructed using Microsoft Excel. The economic evaluation was appraised using the Consolidated Health Economics Evaluation Reporting Standards (CHEERS) checklist to ensure transparent reporting.
      • Husereau D
      • Drummond M
      • Petrou S
      • et al.
      Consolidated health economic evaluation reporting standards (CHEERS) statement.
      Figure 1
      Figure 1Structure of the economic model. (A) The schematic of the network meta-analysis used to indirectly compare HeartMate 3 with Medical Therapy by mediating a common comparator (HeartMate II / HeartMate XVE). (B) The description of the decision-analytics model: the square represents a decision point and the model is run at a quarterly cycle over the time horizon of 5 years.

      Data sources

      We conducted a literature search using PubMed, which includes citations in MEDLINE, to search for articles about the cost-effectiveness of LVADs, excluding reviews, cost of illness studies and editorials. The search was limited to articles published in English-language journals from 2000 to 2020. Since the search did not yield a study on the HM3 LVAD specifically, we undertook an indirect comparison by utilizing the best available evidence to date for each arm. We first analyzed the HM3 pump against the HeartMate II LVAD (MOMENTUM 3 trial), and then another analysis comparing MT with either the HeartMate II LVAD for the same patient population (ROADMAP trial) or a first generation HeartMate XVE LVAD (REMATCH trial). By bridging those analyses, an indirect comparison is possible in the form of a network meta-analysis.
      • Hutton B
      • Salanti G
      • Caldwell DM
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      A schematic of the indirect comparison is depicted in Figure 1. The outcome values sourced through this step are used as input variables in the decision-analytics model to generate outcomes data for cost-effectiveness. A literature search was performed to select the most appropriate pairing of studies for this purpose.
      HM3 LVAD was selected as the intended device comparator to MT since the overall survival and freedom from major adverse events are reported to be the greatest when compared with other devices in trial-level and real-world analyses.
      • Pagani FD
      • Mehra MR
      • Cowger JA
      • et al.
      Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study.
      • Mehra MR
      • Cleveland Jr., JC
      • Uriel N
      • et al.
      Primary results of long-term outcomes in the MOMENTUM-3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants.
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      The MOMENTUM-3 study was selected as the largest and most recent high-quality RCT to date for HM3, which explicitly pre-specified the examination of sub-group analyses in the DT-cohort compared with an older generation of the device.
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      ,
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      Regarding the MT arm, the REMATCH trial or its sub-group analyses (in those restricted to inotropic therapy dependency) were chosen as were those in the ROADMAP trial because they used clinical endpoints comparable to MOMENTUM-3 and compared MT patients with a comparator, namely older generations of LVAD (HeartMate II in ROADMAP and HeartMate XVE in REMATCH), hence enabling an indirect comparison.
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Stevenson LW
      • Miller LW
      • Desvigne-Nickens P
      • et al.
      Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (randomized evaluation of mechanical assistance in treatment of chronic heart failure).
      While clinical evidence, especially mortality, on the exact patient population was scarce, the validity of outcomes evaluated in the MT arm was verified in view of the current practice. A literature search confirmed that contemporary HF management with MT in the target population has not improved clinical outcomes appreciably and most gains in life expectancy with newer pharmacological therapy has been in those patients with chronic heart failure who maintain mild-moderate symptoms and have not transitioned to advanced stages.
      • Hashim T
      • Sanam K
      • Revilla-Martinez M
      • et al.
      Clinical characteristics and outcomes of intravenous inotropic therapy in advanced heart failure.
      ,
      • Nizamic T
      • Murad MH
      • Allen LA
      • et al.
      Ambulatory inotrope infusions in advanced heart failure: a systematic review and meta-analysis.
      For these reasons, recent cost-effectiveness analyses and reviews also used the REMATCH trial for developing the expected outcomes in the MT arm.
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Long EF
      • Swain GW
      • Mangi AA
      Comparative survival and cost-effectiveness of advanced therapies for end-stage heart failure.
      ,
      • Rogers JG
      • Bostic RR
      • Tong KB
      • Adamson R
      • Russo M
      • Slaughter MS
      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      Given the evidence available, the outcomes of inotropic therapy bound patients have not improved since the time of REMATCH, and it can be considered as best available evidence for inotropic therapy bound patients (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] 1-3 severity profile). The INTERMACS severity profile is a 7-stage classification developed in relation to population who can be considered for mechanical circulatory support, ranging from INTERMACS 1: critical cardiogenic shock, to INTERMACS 7: AHF with NYHA Class III symptoms.
      • Nizamic T
      • Murad MH
      • Allen LA
      • et al.
      Ambulatory inotrope infusions in advanced heart failure: a systematic review and meta-analysis.
      The INTERMACS 1-3 patients are those dependent on inotropic therapy, while INTERMACS 4-7 are considered less ill and referred to as ambulatory AHF patients. For ambulatory non-inotropic bound patients, the best estimates for outcome are sequestered in ROADMAP and MedaMACS studies, and data reported in the ROADMAP trial were used for these stages of disease.
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      • Starling RC
      • Estep JD
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: the ROADMAP study 2-year results.
      • Ambardekar AV
      • Kittleson MM
      • Palardy M
      • et al.
      Outcomes with ambulatory advanced heart failure from the medical arm of mechanically assisted circulatory support (MedaMACS) registry.
      In order to account for the uncertainty and potential variability, sensitivity analyses were performed to allow for conservative estimates of benefit.

      Health outcomes

      Patients receiving HM3 and MT were at risk for death, GI bleeding, stroke, infections (all infections, localized infections, driveline infections, and sepsis), and HF hospitalization. Age-specific mortality data were adjusted using English Life Tables to account for the proportion of people that would have been expected to die at a given age.

      Office for National Statistics. English life tables No. 17. 2019. Accessed December 10, 2021. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/lifeexpectancies/datasets/1englishlifetables

      Event rates and costs that populated the model were estimated for each quarter of a year, using 20 data points over the time horizon of 5 years each. Quarterly event probabilities for the HM3 group were estimated based on the Kaplan-Meier curves from the MOMENTUM-3 clinical trial data (Table 1).
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      We used the rate ratios from the REMATCH trial or the ROADMAP trial to estimate the corresponding event probabilities for the MT group (Table 1).
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      When explicit values were not available or reported, figures in the original manuscript were digitized for interpolation. Values beyond the 2-year follow-up period were linearly extrapolated using the last value (value at year 2) and by averaging the change over the past 6 months (e.g., Q6 to Q7, and Q7 to Q8). Recent economic evaluations of LVAD extrapolated survival mostly in a linear fashion by assuming constant mortality rate in the several years after the last observation.
      • Long EF
      • Swain GW
      • Mangi AA
      Comparative survival and cost-effectiveness of advanced therapies for end-stage heart failure.
      ,
      • Rogers JG
      • Bostic RR
      • Tong KB
      • Adamson R
      • Russo M
      • Slaughter MS
      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      ,
      • Baras Shreibati J
      • Goldhaber-Fiebert JD
      • Banerjee D
      • Owens DK
      • Hlatky MA
      Cost-effectiveness of left ventricular assist devices in ambulatory patients with advanced heart failure.
      Data from earlier generations of LVADs have also shown a linear trend of survival between year 2 and 5 as analyzed in the INTERMACS database series of studies.
      • Teuteberg JJ
      • Cleveland Jr., JC
      • Cowger J
      • et al.
      The society of thoracic surgeons intermacs 2019 annual report: the changing landscape of devices and indications.
      Reconstructed plots are shown in the Supplementary Materials.
      Table 1Treatment Effect of Study Endpoints
      YearQuarterAdjusted survival
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      Freedom from stroke
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      Freedom from GI bleeding
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      Freedom from LVAD replacement or removal
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      LVAD (Taken from study)LVAD (Age-adjusted)MT (Taken from study)MT (Age-adjusted)LVADMTLVADMTLVADMT
      001.0001.0001.0001.0001.0001.0001.0001.0001.000
      0.2510.9280.9300.6400.6430.9400.9860.8620.9980.998
      0.520.8880.8920.4550.4620.9320.9840.8210.9980.988
      0.7530.8640.8700.3500.3600.9200.9820.7900.9980.988
      140.8370.8500.2460.2600.9060.9780.7650.9970.988
      1.2550.8000.8110.1580.1750.9060.9780.7400.9970.988
      1.560.7830.7960.1100.1310.8900.9750.7200.9970.988
      1.7570.7800.7950.0770.1020.8810.9730.6900.9970.98
      280.7670.7850.0730.1020.8810.9730.6680.9960.972
      2.2590.7790.0000.0330.8770.9720.6350.9960.964
      2.5100.7710.0000.8740.9710.6070.9960.956
      2.75110.7650.8710.5790.948
      3120.7570.8680.5510.94
      3.25130.7510.8650.5230.932
      3.5140.7440.8620.4950.924
      3.75150.7370.8590.4670.916
      4160.7300.8560.4390.908
      4.25170.7230.8530.4110.9
      4.5180.7170.8500.6170.892
      4.75190.7100.8470.6450.884
      5200.7040.8440.6730.876
      YearQuarterFreedom from Sepsis
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      Freedom from Localized Infection
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      Freedom from Driveline Infection
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      Freedom from Device for RV Failure
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      ,
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      Freedom from Heart Failure Hospitalization
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      ,
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      LVADMTLVADMTLVADMTLVADMTLVADMT
      001.0001.0001.0001.0001.0001.0001.0001.0001.000
      0.2510.8930.9470.7990.8770.9770.9950.9960.9540.888
      0.520.8850.9430.7390.8400.9470.9900.9930.9270.775
      0.7530.8780.9400.7080.8210.9160.9850.9890.8930.663
      140.8710.9370.6810.8040.8860.9800.9860.8840.550
      1.2550.8650.9340.6490.7850.8550.9740.9820.8600.438
      1.560.8590.9310.6340.7750.8260.9690.9780.8510.325
      1.7570.8540.9280.6120.7620.7960.9640.9750.8410.213
      280.8490.9260.5920.7500.7670.9590.9710.8410.100
      2.2590.8440.9230.5710.7370.7380.9540.9670.8370.000
      2.5100.8390.9210.5510.7240.7080.9490.9640.835
      2.75110.8340.5300.6790.9440.831
      3120.8280.5090.6490.9390.828
      3.25130.8230.4890.6200.9330.825
      3.5140.8180.4680.5910.9280.822
      3.75150.8130.4470.5610.9230.819
      4160.8080.4270.5320.9180.816
      4.25170.8030.4060.5030.9130.813
      4.5180.7980.3860.4730.9080.810
      4.75190.7930.3650.4440.9030.807
      5200.7870.3440.4140.8980.804
      There have been about 100 LVADs implanted per year in England in recent years. A recent report indicates 105 implants for 2018/19 and 84 implants in 2019/20.
      • Baras Shreibati J
      • Goldhaber-Fiebert JD
      • Banerjee D
      • Owens DK
      • Hlatky MA
      Cost-effectiveness of left ventricular assist devices in ambulatory patients with advanced heart failure.
      ,
      • Cohen DJ
      • Osnabrugge RL
      • Magnuson EA
      • et al.
      Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents versus bypass surgery for patients with 3-vessel or left main coronary artery disease: final results from the synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) trial.
      With an assumption of 20% to 30% increased use attributable to the DT indication, expected annual costs for 20 to 30 patients were estimated, as this represents 4 to 6 patients per year per center in England.

      Utilities

      Utilities are a quality-of-life measure that can be converted into quality-adjusted life years frequently used in economic analyses.
      • Hawkins N
      • Sculpher M
      • Rothman M
      Modelling the cost-effectiveness of cardiac interventions: the case of sirolimus-eluting stents.
      The utility values to describe patients with and without LVAD were taken from Sutcliffe et al,
      • Sutcliffe P
      • Connock M
      • Pulikottil-Jacob R
      • et al.
      Clinical effectiveness and cost-effectiveness of second- and third-generation left ventricular assist devices as either bridge to transplant or alternative to transplant for adults eligible for heart transplantation: systematic review and cost-effectiveness model.
      who used a modelling of utilities for health states from patients in the Blood and Transplant Database, and are shown in Table 2. In the base case model, patients’ pre-LVAD and receiving medical therapy were assigned a utility of 0.55. Patients’ post-LVAD were assigned a utility of 0.74. A taper in quality of life was applied during the last 3 months of life from the 0.55 and 0.74 values above in the first month of the quarter, to 0.44 in the last month of the quarter. This was applied linearly, meaning that the second month values were 0.59 for LVAD and 0.50 for medical therapy. A taper value of 0.44 was chosen because this is the value reported for patients on medical therapy by Emin et al in a UK population.
      • Emin A
      • Rogers CA
      • Banner NR
      Steering Group, UK Cardiothoracic Transplant Audit
      Quality of life of advanced chronic heart failure: medical care, mechanical circulatory support and transplantation.
      A taper was applied because patients with heart failure are known to deteriorate over time.

      M Conolly, J Beattie, D Walker, M Dancy. End of life care in heart failure: a framework for implementation. 2019. Accessed December 10, 2021. https://www.england.nhs.uk/improvement-hub/wp-content/uploads/sites/44/2017/11/heart-failure.pdf.

      The QALYs lost due to the taper in quality of life in the last 3 months of life were subsequently deducted from the total QALYs in the LVAD and MT groups.
      Table 2Costs and Utilities Used in the Economic Model
      ItemMean valueLowerUpperSource
      Assessment£3,901£3,657£4,14595% CI, Calculated from tariff values.
      LVAD device£80,000Market price estimate. Fixed cost.
      LVAD implantation procedure£28,223£26,460£29,98595% CI, calculated from tariff values.
      LVAD implantation follow-up£917£859£97495% CI, calculated from tariff values.
      Mortality£8,827£8,357£9,296Hollingworth et al
      • Hollingworth W
      • Biswas M
      • Maishman RL
      • et al.
      The healthcare costs of heart failure during the last five years of life: a retrospective cohort study.
      . 95% CI given.
      Stroke year 1£13,452£9,416£17,488Xu et al
      • Xu XM
      • Vestesson E
      • Paley L
      • et al.
      The economic burden of stroke care in England, Wales and Northern Ireland: using a national stroke register to estimate and report patient-level health economic outcomes in stroke.
      .

      Lower value = cost – (cost x 0.3).

      Upper value = cost + (cost x 0.3).
      Stroke, each year, years 2-5£1,128£790£1,466Xu et al
      • Xu XM
      • Vestesson E
      • Paley L
      • et al.
      The economic burden of stroke care in England, Wales and Northern Ireland: using a national stroke register to estimate and report patient-level health economic outcomes in stroke.
      .

      Lower value = cost – (cost x 0.3).

      Upper value = cost + (cost x 0.3).
      GI bleeding£2,239£2,099£2,379HRG FD03. Activity-weighted average.

      95% CI, calculated from tariff values.
      LVAD replacement or removal procedure£29,682£27,829£31,53695% CI, calculated from tariff values.
      Sepsis£8,260£7,744£8,776HRG WJ06. Activity-weighted average.

      95% CI, calculated from tariff values.
      Localized infection£9.15£6.41£11.90NHS prescription cost

      Lower value = cost – (cost x 0.3).

      Upper value = cost + (cost x 0.3).
      Driveline infection£9.15£6.41£11.90NHS prescription cost

      Lower value = cost – (cost x 0.3).

      Upper value = cost + (cost x 0.3).
      Device for right ventricular failure implantation (procedure and follow-up).£58,700£55,034£62,36695% CI, calculated from tariff values.
      Device for right ventricular failure£5,000Market price estimate. Fixed cost
      Heart failure hospitalization£10,108£9,477£10,740HRG EB03. Activity-weighted average.

      Plus 3 days of critical care.
      Routine medical care per year£864£605£1,123Griffiths et al
      • Griffiths A
      • Paracha N
      • Davies A
      • Branscombe N
      • Cowie MR
      • Sculpher M
      The cost effectiveness of ivabradine in the treatment of chronic heart failure from the UK National Health Service perspective.
      .

      Lower value = cost – (cost x 0.3).

      Upper value = cost + (cost x 0.3).
      Medical therapy utility0.550.500.60Sutcliffe et al
      • Sutcliffe P
      • Connock M
      • Pulikottil-Jacob R
      • et al.
      Clinical effectiveness and cost-effectiveness of second- and third-generation left ventricular assist devices as either bridge to transplant or alternative to transplant for adults eligible for heart transplantation: systematic review and cost-effectiveness model.
      . Linear taper for the last 3 months before death: fixed at 0.44.
      Post-VAD utility0.740.590.89Sutcliffe et al
      • Sutcliffe P
      • Connock M
      • Pulikottil-Jacob R
      • et al.
      Clinical effectiveness and cost-effectiveness of second- and third-generation left ventricular assist devices as either bridge to transplant or alternative to transplant for adults eligible for heart transplantation: systematic review and cost-effectiveness model.
      . Linear taper for the last 3 months before death: fixed at 0.44.

      Costs

      The costs associated with LVAD and MT are summarized in Table 2. Tariff values were used where possible because these reflect the costs borne by NHS England.

      Improvement. National tariff payment system. 2019. Accessed December 10, 2021. https://improvement.nhs.uk/resources/national-tariff/

      Critical care costs have been taken from the National Cost Collection for the NHS as an average for cardiac surgical adult patients at £1,800 per day.

      NHS. 2018/19 National cost collection data. 2021. Accessed December 10, 2021. https://www.england.nhs.uk/national-cost-collection/.

      A cost for assessment for transplantation candidacy was also included, which requires procedures such as cardiac catheterization, echocardiography, lung and kidney function tests, comprehensive blood tests, and outpatient follow-up visits so that the full costs of therapy options could be projected. The cost of mortality was based on the expected healthcare cost of heart failure patients in the last 3 months of life.
      • Hollingworth W
      • Biswas M
      • Maishman RL
      • et al.
      The healthcare costs of heart failure during the last five years of life: a retrospective cohort study.
      The estimate includes the cost of medications, primary and hospital healthcare costs.
      Tariff values were multiplied by the Market Forces Factor (MFF) for each hospital trust in England that might undertake the procedure,

      Improvement. National tariff payment system. 2019. Accessed December 10, 2021. https://improvement.nhs.uk/resources/national-tariff/

      to provide an average cost. The hospital trusts were Newcastle upon Tyne Hospitals NHS Foundation Trust, University Hospitals Birmingham NHS Foundation Trust, Manchester University NHS Foundation Trust, Royal Papworth Hospital NHS Foundation Trust, and Royal Brompton & Harefield NHS Foundation Trust. The mean MFF was 1.1083. LVAD implantation was not described by tariff, but was costed as a complex, repair or replacement, of multiple heart valves, with complication and co-morbidity (CC) Score 8+, elective value plus 5 days of critical care. The cost of death included inpatient and outpatient costs incurred from hospital episode statistics (HES) database, healthcare resource group (HRG), and national reference costs.
      • Hollingworth W
      • Biswas M
      • Maishman RL
      • et al.
      The healthcare costs of heart failure during the last five years of life: a retrospective cohort study.
      While this reflects some resource use cost in the last 3 months of life, it does describe healthcare costs associated with advanced heart failure mortality. The costs of stroke were taken from Xu et al
      • Xu XM
      • Vestesson E
      • Paley L
      • et al.
      The economic burden of stroke care in England, Wales and Northern Ireland: using a national stroke register to estimate and report patient-level health economic outcomes in stroke.
      and were given for year 1 and subsequent years. An admission due to sepsis was costed as the activity-weighted tariff plus 2 critical care days. Driveline infections and localized infections were not described by tariff and were assumed to equal NHS prescription cost. The cost of routine medical care was taken from Griffiths et al
      • Griffiths A
      • Paracha N
      • Davies A
      • Branscombe N
      • Cowie MR
      • Sculpher M
      The cost effectiveness of ivabradine in the treatment of chronic heart failure from the UK National Health Service perspective.
      and was assumed to be twice the cost listed in this publication to allow for end-stage heart failure to consume more resource.

      Sensitivity and uncertainty analyses

      We conducted one-way deterministic sensitivity analyses to assess the relative impact of the event and cost parameters used in the model. Where upper and lower 95% confidence intervals were not given or not calculable, ± 0.30 of the base case was used to derive the upper and lower values.
      As recommended by NICE guidance for England, a probabilistic sensitivity analysis was also undertaken,

      NICE. The guidelines manual. 2021. Accessed December 10, 2021. https://www.nice.org.uk/process/pmg6/chapter/assessing-cost-effectiveness

      using a gamma distribution to reflect uncertainties in costs and a normal distribution to reflect uncertainties in QALYs.
      • Briggs A
      • Claxton K
      • Sculpher M
      Decision Modelling for Health Economic Evaluation.
      About 1,000 random draws were made from these distributions to estimate the proportion of ICERs that fell below a given willingness-to-pay threshold.

      NHS Blood and Transplant. 2020. Annual report on mechanical circulatory support related to heart transplantation report for 2019/2020 (1 april 2010 –31 march 2020)

      Results

      The patient demographics of the studies used in this research are presented in Table 3. The outcome measures were mainly sourced from the DT cohort of MOMENTUM-3 study
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      and REMATCH trial,
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Stevenson LW
      • Miller LW
      • Desvigne-Nickens P
      • et al.
      Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (randomized evaluation of mechanical assistance in treatment of chronic heart failure).
      and the ROADMAP trial
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      as appropriate respectively, for the LVAD arm and the MT arm. For those outcomes not available in the above studies, the next best options were used, namely the full cohort study of MOMENTUM-3 for LVAD replacement and infection. No interaction was observed between patient cohort groups of the MOMENTUM-3 trial regarding infection.
      • Patel CB
      • Blue L
      • Cagliostro B
      Left ventricular assist systems and infection-related outcomes: a comprehensive analysis of the MOMENTUM-3 trial.
      The ROADMAP study was used for device use in right ventricular (RV) failure and HF-related hospitalizations.
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      ,
      • Starling RC
      • Estep JD
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: the ROADMAP study 2-year results.
      Table 3Patient Demographics of Included Studies
      Demographic factorsMOM 3

      (LVAD)
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      MOM 3 - DT

      (LVAD)
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      REMATCH

      (MT)
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ROADMAP

      (MT)
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      Sample size (n)1,02862461103
      Age (years)59 ± 1263 ± 1268 ± 866
      Male (%)80828271
      Ischemic cause of heart failure (%)42476950
      History of atrial fibrillation (%)4247Not Stated35
      History of stroke (%)10Not StatedNot StatedNot Stated
      Duration of HF > 1 yr (%)Not StatedNot StatedNot Stated92
      Intravenous inotropes (%)Not Stated86720
      Previous cardiac surgical procedure (%)

      Coronary-artery bypass

      Valve replacement or repair


      20

      7


      26
      Not StatedNot Stated
      LVEF (%)17 ± 5Not Stated17 ± 4.5Not Stated
      Blood pressure (mm Hg)

      Systolic

      Diastolic


      109 ± 15

      67 ± 11
      Not Stated

      103 ± 17

      62 ± 11
      Not Stated
      Mean arterial pressure (mm Hg)80 ± 10Not StatedNot StatedNot Stated
      Heart rate (beats/min)Not StatedNot Stated84 ± 1.5Not Stated
      Cardiac index (L/min/m2)2.0 ± 0.5Not Stated2 ± 0.611.9
      Pulmonary-capillary wedge pressure (mm Hg)23.1 ± 9Not Stated25 ± 1022
      Pulmonary vascular resistance (Wood units)3.1 ± 2Not Stated3.2 ± 1.83.3
      Right atrial pressure (mm Hg)11 ± 7Not StatedNot Stated
      Aspartate aminotransferase (U/l)Not StatedNot StatedNot Stated26
      Sodium (mmol/L)135 ± 4Not Stated135 ± 5.8
      Creatinine (mg/dl)1.4 ± 0.41.4 ± 0.41.8 ± 0.71.3
      Albumin (g/dl)Not Stated3.6 ± 0.5Not Stated4
      BUN (mg/dl)Not Stated29.3 ± 13.6Not Stated28
      Estimated glomerular filtration rate (ml/min/1.73m2)61 ± 2457.6 ± 21.2Not Stated63
      Blood urea nitrogen (mg/dl)Not Stated14Not StatedNot Stated
      6 minute walk distance (m)Not StatedNot StatedNot Stated219
      VO2 max (ml/kg/min)Not StatedNot StatedNot Stated9.7
      INTERMACS profile (%)Not StatedNot Stated
      12
      230
      352
      41434
      5-7164
      Not provided12
      The outcomes used in the analyses are shown in Table 1, showing the proportion of patients expected to incur each outcome at 5 years in the base case. Since the outcome values were reported at limited time points, the input values to the model were reconstructed using interpolation and extrapolation. For every outcome measure, the figures sourced directly from the evidence is shown, along with those “reconstructed.” Those figures are blank, which are not relevant to the MT arm such as LVAD replacement, driveline infection, or survival after 2.5 years. None of the medical therapy patients are expected to survive to 5 years, as reported in REMATCH.
      • Rose EA
      • Gelijns AC
      • Moskowitz AJ
      • et al.
      Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study group. Long-term use of a left ventricular assist device for end-stage heart failure.
      ,
      • Stevenson LW
      • Miller LW
      • Desvigne-Nickens P
      • et al.
      Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH (randomized evaluation of mechanical assistance in treatment of chronic heart failure).
      Table 4 shows the expected cost-effectiveness over 5 years. The incremental cost-effectiveness ratio (ICER) for LVAD vs medical therapy was estimated to be £47,361/QALY gained.
      Table 4Cost-Effectiveness Results
      TreatmentCostQALYs
      LVAD£141,5982.8307
      Medical therapy£28,0470.4331
      Incremental cost LVAD£113,551
      Incremental QALYs LVAD2.3976
      ICER£47,361

      Sensitivity analyses

      An additional scenario compared the HM 3 LVAD arm vs a subgroup of patients in MT arm, namely those patients who are dependent on inotropic therapy. Using the survival data from the REMATCH subpopulation, the ICER was £45,616/QALY gained. Similarly, the ICER using the survival data from the ROADMAP study, which included ambulatory noninotropic therapy advanced heart failure patients was £64,051/QALY gained. In the ROADMAP study, no patients were involved who were INTERMACS 1-3, and only included less ill ambulatory patients in INTERMACS 4-7,
      • Estep JD
      • Starling RC
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study.
      ,
      • Starling RC
      • Estep JD
      • Horstmanshof DA
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: the ROADMAP study 2-year results.
      hence simulating a patient profile with less advanced stage of HF. We also looked at varying the survival of the REMATCH inotrope-dependent population by 30% to account for the upper end of the 95% CI, which yielded an ICER of £70,472 (which denotes the upper boundary of the 95% CI estimate).
      Figure 2 shows the Tornado plot that describes the results of one-way sensitivity analysis to account for uncertainty for all input parameters, and uncertainty related to the structure of the model and assumptions. That is, the result of changing each of the base case values to their lower and upper values. Results were arranged such that higher ICERs were placed at the top of the plot. It can be seen that the economic model is most sensitive to survival and to the rate of HF hospitalization. The lower value of utility (a quality-of-life measure) of patients receiving LVAD therapy was the only other scenario in which the ICER was greater than £50,000/QALY gained.
      Figure 2
      Figure 2Tornado plot showing expected ICERs at the lower and upper values of data inputs. ICER = incremental cost-effectiveness ratio; time horizon 5 years.
      Results of probabilistic sensitivity analysis are shown in Figure 3, Figure 4. Note that incremental cost is shown on the x-axis and incremental QALYs gained is shown on the y-axis. The mean probabilistic ICER was £41,514. The maximum incremental cost was £150,936 and the maximum incremental QALYs gained were 2.8688. The minimum ICER was £31,134 and the maximum ICER was £57,198. The probability of cost-effectiveness at £30,000/QALY gained (expressed as a percentage) was 0%, while the probabilities of cost-effectiveness at £40,000 and £50,000 were 36.3% and 97.1%, respectively.
      Figure 3
      Figure 3Cost-effectiveness plane for LVAD vs medical therapy; time horizon 5 years.
      Figure 4
      Figure 4Cost-effectiveness acceptability curve for LVAD vs medical therapy; time horizon 5 years.
      If 20 to 30 heart transplant ineligible patients were treated with LVAD in England, the expected cost would be £2,831,960 to £4,247,940 over 5 years from the point of treatment, compared with an expected cost of £560,940 to £841,410 if the same patients were treated with medical therapy, respectively. This gives an expected incremental cost of £2,271,020 to £3,406,530 associated with the provision of LVAD therapy, with a total population QALY gain of 48.0 to 71.9 over 5 years.

      Discussion

      This health economic analysis provides insight into the expected clinical effectiveness and cost-utility of LVAD therapy compared with medical therapy in patients with AHF who are ineligible for heart transplantation, cost-utility being assessed in the context of NHS England. The base-case scenario showed an ICER of £47,361/QALY gained for LVAD vs MT for patients who are ineligible for heart transplantation, which is below the end-of-life willingness-to-pay threshold of £50,000/QALY gained as generally accepted.
      • Paulden M
      Recent amendments to NICE’s value-based assessment of health technologies: implicitly inequitable?.
      , The high probability for cost-effectiveness according to the probabilistic sensitivity analysis indicates that HM3 LVAD in DT use is a reasonable use of the NHS budget in those patients with AHF who do not have other viable alternatives.
      In most European countries the intention of use (e.g., BTT or DT), and now even within the United States, is not a criterion for funding or reimbursement. In the United States, the Centers for Medicare and Medicaid Services (CMS) released the latest National Coverage Decisions in December 2020 that removed the therapeutic intent-to-treat criteria of BTT and DT on the basis of contemporary trials.

      CMS. National coverage determination for ventricular assist devices 20.9.1. Accessed December 10, 2021. https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=360&ncdver=&NC1AId=298&type=Open&bc=ABAAAAAAIAAA&

      In contrast, the UK is one of the few regions where the payer continues to make clear distinction. The current NHS England service specifications only allow BTT, while DT is excluded.

      NHS England. NHS standard contract for ventricular assist devices as a bridge to heart transplantation or myocardial recovery. Accessed December 10, 2021. https://www.england.nhs.uk/wp-content/uploads/2013/06/a18-vad-all.pdf

      Their policy proposition suggests that LVAD therapy should not be routinely commissioned because there is “not enough evidence of either clinical or cost-effectiveness to consider making this treatment available for a selected group of patients.”

      NHS England. Consultation on a policy proposition for long term left ventricular assist device therapy for advanced heart failure (all ages). 2019. Accessed December 10, 2021. https://www.engage.england.nhs.uk/consultation/long-term-left-ventricular-assist-device-therapy/

      NHS England is currently looking into the cost-effectiveness of LVAD compared to medical therapy for DT in patients with AHF who are ineligible for transplantation.

      NIHR. Funding and awards. Left ventricular assist devices as destination therapy for advanced heart failure. Accessed December 10, 2021. https://fundingawards.nihr.ac.uk/award/NIHR128996

      Here, the payer's willingness-to-pay may be higher than the usually reported threshold of £20,000 to £30,000/QALY gain given the end-of-life nature of the therapy in the target population, and be set at £50,000.
      • Paulden M
      Recent amendments to NICE’s value-based assessment of health technologies: implicitly inequitable?.
      , This study has discussed the economic analysis on this unmet need and brought clarity with the best evidence available to date. Of note, while the ICER is over £30,000/QALY gained, end-of-life therapies may be recommended if they breach this value.
      • Mehra MR
      • Goldstein DJ
      • Uriel N
      • et al.
      Two-year outcomes with a magnetically levitated cardiac pump in heart failure.
      ,
      • Goldstein DJ
      • Naka Y
      • Horstmanshof D
      • et al.
      Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: the multicenter study of MagLev technology in patients undergoing mechanical circulatory support therapy with HeartMate 3 (MOMENTUM-3) randomized clinical trial.
      The incremental cost of LVAD therapy over medical therapy in 30 patients is expected to be £3,406,530, assuming this annual rate of use.
      A number of economic evaluations have examined the cost-effectiveness of LVAD vs MT, and reported higher ICER at around US$ 200,000/QALY gained.
      • Rogers JG
      • Bostic RR
      • Tong KB
      • Adamson R
      • Russo M
      • Slaughter MS
      Cost-effectiveness analysis of continuous-flow left ventricular assist devices as destination therapy.
      ,
      • Baras Shreibati J
      • Goldhaber-Fiebert JD
      • Banerjee D
      • Owens DK
      • Hlatky MA
      Cost-effectiveness of left ventricular assist devices in ambulatory patients with advanced heart failure.
      ,
      • Chew DS
      • Manns B
      • Miller RJH
      • Sharma N
      • Exner DV
      Economic evaluation of left ventricular assist devices for patients with end stage heart failure who are ineligible for cardiac transplantation.
      However, the current analysis differs from those previous studies, which were done in a non-NHS context (in USA or Canada), the evidence for the LVAD arm was not contemporary to the current situation of the therapy and time horizons differed. Recent real-world evidence showed that the HM3 LVAD improved survival and reduced adverse events, leading to concomitant reduction in costs by 17.4% to 26.1% compared to other LVADs in the US context, which demonstrates evidence of the progress of therapy toward cost-effectiveness in this field.
      • Pagani FD
      • Mehra MR
      • Cowger JA
      • et al.
      Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study.
      Another analysis for cost-effectiveness using a different centrifugal LVAD developed a Markov multiple-state economic model using NHS cost data. In this analysis, deterministic ICER was £46,207/QALY over a lifetime horizon.
      • Schueler S
      • Silvestry SC
      • Cotts WG
      • et al.
      Cost-effectiveness of left ventricular assist devices as destination therapy in the United Kingdom.
      Additionally, the CLEAR LVAD real-world analysis demonstrated that the outcomes and healthcare costs in the US context were lower for the HM 3 LVAD compared to the other centrifugal pump.
      • Pagani FD
      • Mehra MR
      • Cowger JA
      • et al.
      Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study.
      The present evaluation brings up-to-date information in the clinical and cost-effectiveness of LVAD for DT in patients not eligible for heart transplantation, particularly with reference to the HM3 LVAD.
      This research had several limitations. First, the lack of direct comparison between LVAD for DT and MT in the context of recent clinical practice had to be addressed by developing an indirect comparison based on published literature pertaining to separate trials. Such indirect comparison of trials performed over 2 decades may be liable to biases that may not be accounted for however, for the specific population of patients who reach the point of inotropic therapy dependence; these estimates may still be relevant and accurate. Recent analyses have demonstrated the persistent dismal outcomes for patients, wherein it has been demonstrated that patients who preferred inotropic therapy over LVAD had median survival of 9.0 months and 2-year survival of only 38.4%.
      • Hashim T
      • Sanam K
      • Revilla-Martinez M
      • et al.
      Clinical characteristics and outcomes of intravenous inotropic therapy in advanced heart failure.
      It is possible that greater experience with LVAD therapy over time may contribute to better outcomes, which may result in a more favorable ICER. It is important to note that there is insufficient equipoise to replicate a direct comparison given the established survival benefit on LVAD therapy over medical therapy in AHF, even with less durable devices than the HM3 pump and especially in patients in INTERMACS 1-3 profile of severity (those requiring inotropic therapy). It should also be noted that despite advances in medical therapy, AHF by definition signifies a population that is poorly responsive to or deteriorating despite disease modifying pharmacological therapy. Most trials of pharmacological therapy therefore exclude these individuals. Hence there has not been a major improvement in survival simply by use of medical therapy in patients with advanced heart failure. The relevance of both arms was validated by choosing a common comparator (albeit LVADs of different generations) in between, and the relevance of the patient population as well as contemporality of the respective therapies were ensured by literature search and local practice. Second, the clinical outcomes were extrapolated beyond the time period originally reported in the literature. Linear extrapolation method was benchmarked with existing literature, and the outcome values using the quarter-year time steps were verified to match the survival data available from older generations of the LVAD therapy. This was reviewed from the INTERMACS analyses which looked at device related outcomes beyond 2 years and the linear slopes confirmed, although specific hazard ratios were not used due the analysis dominated by non-HM 3 LVADs.
      • Teuteberg JJ
      • Cleveland Jr., JC
      • Cowger J
      • et al.
      The society of thoracic surgeons intermacs 2019 annual report: the changing landscape of devices and indications.
      Moreover, the comparability of patient groups across the studies used were not performed in a statistical manner since some demographic data were not reported. Third, the cost-effectiveness analysis considered freedom from the events in the decision-analytics model. However, the model provides a likelihood of an event happening (once or multiple times) to individuals at risk, based on rates in the population. The likelihood is zero if there is freedom from an event in the same population. Also, the bias would apply to both arms for the main events such as HFH, and its accelerated impact during the terminal phase of the patient has been accounted for by tapering health utilities as well as the cost of mortality so as to best represent the patient and outcomes trajectory within the given limitations of the model.
      This analysis is based on costs under the single payer National Health System in the UK, and may not be directly translated into other healthcare systems. However, this analysis may be adapted for other healthcare systems using the current health outcomes and utilities and the costs relevant to the healthcare system. Fourthly, other costs inherent to the delivery of LVAD therapy such as VAD coordinators, therapy services, additional Cardiologists and Surgeons have not been included. Similarly, the costs of supportive care in the medical therapy group such as social care support (carers, therapy services and specialist community and palliative care nurses) were not accounted for. Lastly, there is uncertainty around relevant cost items. For instance, Schueler et al used the cost of driveline infections and localized infections that were estimated higher than in our study, whereas this study included sepsis as a separate endpoint.
      • Schueler S
      • Silvestry SC
      • Cotts WG
      • et al.
      Cost-effectiveness of left ventricular assist devices as destination therapy in the United Kingdom.
      To account for uncertainty, sensitivity analyses were performed both one-way and probabilistically. Cost-effectiveness exceeds £50,000/QALY gained as patients become less sick, such as those in the ROADMAP trial and where survival in the medical therapy arm increases or survival in the LVAD arm decreases. This confirms the highest added value in those sickest group of patients (patients on inotropes) for whom heart transplantation is not an option, whereby the ICER showed stable cost-effectiveness in the NHS context.
      In summary, we demonstrate that HM3 LVAD therapy in advanced HF patients ineligible for heart transplantation may be cost-effective compared to MT in the NHS UK-England context. The ICER is lowest for patients who are dependent on inotropic support; however, in ambulatory noninotropic therapy-dependent advanced HF patients, the ICER exceeds the willingness to pay threshold of £50,000, in the UK context.

      Disclosure statement

      Hoong Sern Lim reports honoraria from Abbott and Abiomed. Steven Shaw reports honoraria from Abbott. Mandeep R. Mehra reports payments made to his institution from Abbott for consulting; Consultant fees from Medtronic, Janssen, Mesoblast, Portola, Bayer, Triple Gene, and Baim Institute for Clinical Research. Scientific Advisory Board Member for NuPulseCV, Leviticus and FineHeart.

      Acknowledgments

      The authors would like to thank the following additional contributors: Dr. Steven Fearn, Abbott Medical UK Ltd, UK, for the contribution to the original health economic model; Dr. Zenichi Ihara, Abbott, Belgium, for the review for accuracy of the assumptions applied in the manuscript; and Abbott Laboratories, Chicago, USA, for the access to the original data of the MOMENTUM-3 Trial.

      Appendix. Supplementary materials

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