The clinical and cost-effectiveness of left ventricular assist devices for end-stage heartfailure: a systematic review andeconomic evaluation

AJ Clegg,1* DA Scott,2 E Loveman,1 J Colquitt,1

J Hutchinson,2 P Royle3 and J Bryant1

1 Southampton Health Technology Assessments Centre, Wessex Institute forHealth Research and Development, University of Southampton, UK

2 Fourth Hurdle Consulting Ltd, London, UK3 University of Aberdeen, UK

* Corresponding author

HTAHealth Technology Assessment NHS R&D HTA Programme

Health Technology Assessment 2005; Vol. 9: No. 45

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BackgroundHeart failure is an increasing health problem inEngland and Wales. Its incidence and prevalenceare increasing, leading to frequent admissions tohospital and long-term drug costs. Concerns aboutthe effects on the duration and quality of life ofpeople and costs upon the NHS have resulted inseveral government policy initiatives. End-stageheart failure (ESHF) is associated with majordisability and a poor prognosis. Hearttransplantation has become the accepted form oftreatment for people with ESHF, improvingsurvival and patient quality of life. With continueddecreases in organ donation in England andWales, it is an option available to few. Mechanicalcirculatory support through left ventricular assistdevices (LVADs) has attracted increased interest asan option for patients with ESHF whether as abridge to heart transplantation (BTT), as a bridgeto myocardial recovery (BTR) or as a long-termchronic support (LTCS). Continued developmentsof LVADs, declining costs and improvements inassociated care have made their wider use a reality.

ObjectivesThe objectives of this study were to carry out asystematic review and an economic evaluation toexamine the clinical and cost-effectiveness ofLVADS as a BTT, BTR and LTCS for people withESHF. The study focused on the effect of LVADson the duration and quality of life of people withESHF, the groups who may benefit from their useand assesses the implications for developing sucha service within the NHS in England and Wales.

MethodsA systematic review of the evidence and aneconomic evaluation were undertaken using apriori methods.

Data sourcesEighteen electronic databases were searched frominception to October 2003. Bibliographies ofrelated papers were assessed for relevant studiesand experts and manufacturers were contacted to

identify additional published and unpublishedreferences.

Study selectionStudies were included if they fulfilled the followingcriteria:

Interventions: studies that evaluated currentlyavailable LVADs used as a BTT, BTR and LTCSfor people with ESHF were considered forinclusion.

Participants: people aged 16 years or olderwith ESHF and considered suitable for receiptof an LVAD as BTT, BTR or LTCS.

Outcomes: survival, functional capacity [e.g. NewYork Heart Association (NYHA) functionalclassification, activities of daily living] and qualityof life were the primary outcome measuresconsidered within the systematic review.

Design: systematic reviews, randomisedcontrolled trials (RCTs), controlled clinical trials,cohort studies, case series, case studies, economicevaluations and cost studies were included.

Studies identified were assessed for inclusionthrough two stages with titles and abstracts andfull papers of retrieved studies assessed by tworeviewers, with differences in decisions resolvedthrough discussion or through recourse to a third,independent reviewer.

Data extraction and quality assessmentData were extracted by two reviewers using dataextraction forms developed a priori, with anydisagreements resolved through discussion orthrough recourse to independent assessment by athird reviewer. The methodological quality of thestudies included in the systematic review of clinicaland cost-effectiveness were assessed usingrecognised quality assessment tools using individualcomponents of methodological quality rather thanrelying upon summary scores. The quality criteriaused were applied by two reviewers, with anydisagreements resolved through discussion orthrough recourse to a third, independent reviewer.

Data synthesisStudies were synthesised using a narrativeapproach through subgroup analysis based on the indication for treatment, type of LVAD and quality of studies.

Executive summary: Left ventricular assist devices for end-stage heart failure

Executive summary

Economic evaluationThe economic evaluation developed two models toevaluate the use of LVADs, first as a BTT andsecond as LTCS for patients suffering from ESHF.Insufficient data prevented the assessment of theuse of LVADS as a BTR. The outcomes in theevaluation were assessed in terms of the benefits topatients (survival and quality of life) and costsincurred, with results presented in terms of acostutility analysis. Although medical therapy wasthe comparator treatment in the two models, thepatients differed. Patients in the BTT model werethose on the heart transplantation waiting list,whereas those in the LTCS model were excludedfrom the heart transplant waiting list owing to theseverity of their condition. The models focused onthose LVADs that were found in the systematicreview to be clinically effective for the differentindications and relevant to the UK setting.

ResultsClinical effectiveness of LVADs as a BTT for people with ESHFSixteen studies (one controlled clinical trial, fivecohort studies with comparators, five cohortstudies with no comparator, three case series andtwo case reports) assessed the clinical effectivenessof LVADs as a BTT, 11 studies of first-generationdevices and five of second-generation devices. Themethodological quality of the studies was generallyweak, reflecting the quasi-experimental andobservational study designs used and poorreporting of study characteristics. Despite the poorquality evidence, LVADs compared with othertreatment options appeared to be beneficial forpatients with ESHF when assessed using patientsurvival, functional status and quality of life. Whencompared with inotropic agents, LVADs appearedto provide a benefit in patient survival thatincreased with the length of support (difference inactuarial survival: 1 month 3%; 3 months 17%)and extended beyond heart transplantation(difference in actuarial survival: 1 year 24%;4 years 30%). Comparisons of the use of LVADswith usual care were less certain, with outcomesvarying from no difference in survival to, or after,heart transplantation, to improved survival forLVADs patients to heart transplantation (survivaldifference: range 1459%) and post-transplantation(difference in actuarial survival: 1 and 2 years100%). Studies of LVADs which did not include acomparator were often the only evidence available,particularly for the new devices. In these studies,implantation of an LVAD provided support for upto 390 days, with as many as 70% of patients

surviving to transplantation. Comparisons ofdifferent LVADs were limited. Only the HeartMateand Novacor LVADs were compared, with littledifference in survival to transplantation. There waslimited evidence assessing the effects of LVADs onthe functional status and quality of life of patientswith ESHF BTT. Patients supported by an LVADappeared to have an improved functional statuscompared with those on usual care. Also, patientswith an LVAD experienced an improvement intheir quality of life from before implantation ofthe device to the period during support. The useof LVADs is associated with risks of adverse events,with patients suffering mechanical device failures,bleeding, thromboembolic events, infections,reoperations and psychiatric conditions. Adverseevents rates varied between different LVADs andstudies and some caution should be exercised ininterpreting these results. With a scarcity ofevidence directly comparing the different LVADs itis difficult, and perhaps inappropriate, to identifyspecific devices as the most clinically effective.However, the HeartMate LVAD is the only devicethat has evidence comparing it with severaldifferent alternatives, appearing to be moreclinically effective than inotropic agents and usualcare and as clinically effective as the Novacordevice. Of the second-generation devices, theevidence suggests limited difference in the clinicaleffectiveness of the Jarvik 2000 and the MicroMedDeBakey LVADs. Although early in theirdevelopment, these second-generation devicesappear to show lower rates of adverse events, suchas infection, bleeding and thromboembolism,which have affected the development and use ofthe first-generation devices. However, longer termoutcomes are needed to ensure that theseapparent benefits are maintained in practice andthat the consequences associated with the non-pulsatile nature of the devices do not result inadditional adverse events.

Clinical effectiveness of LVADs as a BTRfor people with ESHFEvidence of the clinical effectiveness of LVADs as aBTR for people with ESHF was limited to sevennon-comparative observational studies (two caseseries and five case reports) of first-generationdevices, which were judged to be of poormethodological quality. The seven identifiedstudies appeared to show that the LVADs providedbenefit in providing support for the patients untilmyocardial recovery. As there were no directcomparisons of different interventions, it is notpossible to assess whether the LVADs are moreeffective than other alternatives or specific devices. No evidence was found to judge the

Health Technology Assessment 2005; Vol. 9: No. 45 (Executive summary)

effects of the devices on the quality of life orfunctional status of patients. Limited informationon adverse events was reported, althoughinfections and bleeding were the main concerns.

Clinical effectiveness of LVADs as an LTCS for people with ESHFSix studies (one RCT, one case series and four casereports) assessed the clinical effectiveness ofLVADs as an LTCS for people with ESHF.Although the nature and methodological qualityof the evidence varied between the differentdevices, it was evident that LVADs providedbenefits for patients in terms of improved survival,functional status and quality of life. TheREMATCH trial provided good-quality evidencethat the HeartMate LVAD provided a statisticallysignificant 48% reduction in the risk of death fromany cause when compared with optimal medicalmanagement. Actuarial survival was significantlyhigher for patients with the HeartMate LVADcompared with optimal medical management at1 year (52% versus 25%) and 2 years (23% versus8%) follow-up. Importantly, improvements in 1-year survival were evident for patients agedunder 60 years and those aged 6069 years. Lessrigorous evidence for the Novacor, Toyobo andJarvik 2000 devices showed relatively high survival(90%), with patients supported for up to 4 years.Limited information on changes in patientsquality of life and functional status suggested thatpatients experienced improvements on specificscales following implantation of the HeartMateand Jarvik LVADs. Inevitably there are adverseevents associated with the use of LVADs, withdevice malfunctions, infection and bleedingassociated with their use. The HeartMate LVADwas associated with twice as many serious adverseevents than optimal medical management, withsignificantly higher rates of non-neurologicalbleeding and neurological dysfunction. Otheradverse events affected the different treatmentoptions, whether devices or drug treatment.Despite these adverse events, the benefits of theseLVADs appear to outweigh limitations. Evidence ofthe clinical effectiveness of the different devicesindicates that the HeartMate LVAD appears to beeffective when compared with optimal medicalmanagement. For the second-generation devices,the early evidence suggests that the Jarvik 2000shows promise; however, further research isneeded to assess whether these benefits arereplicated in the longer term and whether therewill be any long-term consequences associated withthe change in the nature of the circulatorysupport.

Systematic review of the cost-effectiveness of LVADs for people with ESHFNineteen studies assessed the costs and cost-effectiveness of LVADS for people with ESHF, withthe majority being simple costing studies and veryfew studies of the cost-effectiveness of LVADs. Anumber of the costing studies had seriousmethodological flaws. Even those judged ofhigher quality had caveats limiting applicabilityand generalisability to a UK population.Significant limitations were the limited sample sizeand the lack of comparators against which tojudge the significance of the reported costs. Therewas only one UK-based costutility analysis, whichwas populated with costs based on treatmentprotocols, data from individual NHS Trust financedepartments and utilities derived from a US basestudy. The UK study reported cost per quality-adjusted life-year (QALY) values at the boundaryof acceptability given recent decision-making.Based on total treatment costs of both LVAD BTTsupport and heart transplantation, the discountedcost per QALY was approximately 39,790 (range28,51074,000). Threshold analysis found that anLVAD device and procedure cost of 19,300 wouldequate to a cost per QALY of 20,000 or less.

Economic evaluation to assess the cost-effectiveness of LVADs forpeople with ESHF within the UKThe economic evaluation has shown that neitherLVAD indication considered, that is, BTT andLTCS, is a cost-effective use. For the HeartMateLVAD used as a BTT the cost per QALY was65,242. Stochastic simulation calculated the 95%confidence interval at 34,194 to 364,564. Onlywhen the survival gain falls significantly does thecost-effectiveness rise to such upper bounds. Acost-effectiveness acceptability curve showed thelikelihood of acceptability at current cost-effectiveness thresholds. The BTT indicationapproaches cost-effectiveness only when the one-off costs associated with an LVAD fall considerably.At a combined LVAD device and operation cost of50,000 (compared with 87,877 in our model),the cost per QALY fell to approximately 40,000.Unfortunately, even assuming this eventuality, theBTT indication use parallels an ever-decreasingsupply of donor hearts capping the ability of thisinnovative technology to yield widespread benefit.In the less restrictive indication, LTCS, whereLVADs are not just given to patients awaitingtransplantation, the analysis has shown that LTCSis not cost-effective. The baseline cost per QALYof the first-generation HeartMate LVAD was170,616. One- and multi-way sensitivity analysis

Executive summary: Left ventricular assist devices for end-stage heart failure

had limited effect on the cost per QALY. Ahypothetical scenario based on the cost of asecond-generation MicroMed DeBakey deviceillustrated that a 60% improvement in survivalover first-generation devices was necessary beforethe incremental cost-effectiveness approached40,000 per QALY. Although the analysesrecognise the benefits in terms of survival andquality of life, these are outweighed by associatedincreases in cost. Uncertainties remain,particularly with the lack of trial data on LTCS,research on second-generation devices andongoing costs of medical management. The use ofexpert-based utilities in the LTCS data is alsoinnovative but the sensitivity testing has shown thisnot to be an influential factor on cost-effectivenessat the margin.

Discussion and conclusionsImplications for practiceAlthough the systematic review of clinicaleffectiveness showed that LVADs are clinicallyeffective as a BTT for people with ESHF, theeconomic evaluation indicated that they are notcost-effective. With the limited and decliningavailability of donor hearts for transplantation, itappears that the future of the technology is in itsuse as an LTCS. At present the evidence of clinicaland cost-effectiveness of LVADs as an LTCS is lesscertain, particularly for the second-generationdevices, and further study is needed. The limitedresearch available showed some clinical benefit forpatients receiving LVADs as an LTCS, but theeconomic evaluation suggested that they were nota cost-effective option. Limited numbers ofpatients with ESHF receive an LVAD withinEngland and Wales and uncertainty remains aboutthe potential need and demand that may exist. Asa consequence, it is likely that there will be limitedavailability of clinical teams who can undertakethese procedures and manage the patientssubsequently and there would need to be a rapidincrease in the training of staff and a step change

in the development of the necessary infrastructure.To provide the service to meet the needs of a conservative estimate of 3000 patients wouldresult in a discounted cost to the NHS annually of321 million. With less conservative estimatesputting the potential need at between 7000 and34,000 patients, the actual cost may be far higher.

Recommendations for future researchAlthough LVADs appear to be effective inimproving the survival of patients with ESHF,whether as a BTT, BTR or LTCS, themethodological quality and strength of theevidence are poor. Further research is needed toexamine the clinical effectiveness of LVADs forpeople with ESHF, assessing patient survival,functional ability, quality of life and adverseevents. Although difficult to undertake with suchfast-changing technologies, such evaluationsshould be RCTs and look at the head-to-headcomparisons of different devices or usual medicalcare. Importantly, these studies should encompassthe breadth of patient groups that may benefitfrom these devices. Evaluations of the clinicaleffectiveness of LVADs should include economicevaluations. It has become evident from this studythat data for undertaking such studies are verylimited. Data on quality of life, utilities, resourcesand costs are not readily available. Also, there islimited research on the epidemiology of ESHFand, as a consequence, it is difficult to establishthe possible need and demand for the service. Asystematic review of the epidemiology of ESHFshould be undertaken to assess its potentialimpact.

PublicationClegg AJ, Scott DA, Loveman E, Colquitt J,Hutchinson J, Royle P, et al. The clinical and cost-effectiveness of left ventricular assist devicesfor end-stage heart failure: a systematic review and economic evaluation. Health Technol Assess2005;9(45).

Health Technology Assessment 2005; Vol. 9: No. 45 (Executive summary)

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