Warwick Evidence, Warwick Medical School, University of Warwick, Coventry, UK.
Health Technol Assess. 2013 Nov;17(53):1-499, v-vi. doi: 10.3310/hta17530.
Advanced heart failure (HF) is a debilitating condition for which heart transplant (HT) offers the best treatment option. However, the supply of donor hearts is diminishing and demand greatly exceeds supply. Ventricular assist devices (VADs) are surgically implanted pumps used as an alternative to transplant (ATT) or as a bridge to transplant (BTT) while a patient awaits a donor heart. Surgery and VADs are costly. For the NHS to allocate and deliver such services in a cost-effective way the relative costs and benefits of these alternative treatments need to be estimated.
To investigate for patients aged ≥ 16 years with advanced HF eligible for HT: (1) the clinical effectiveness and cost-effectiveness of second- and third-generation VADs used as BTT compared with medical management (MM); and (2) the clinical effectiveness and cost-effectiveness of second- and third-generation VADs used as an ATT in comparison with their use as BTT therapy.
Searches for clinical effectiveness studies covered years from 2003 to March 2012 and included the following data bases: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), HTA databases [NHS Centre for Reviews and Dissemination (CRD)], Science Citation Index and Conference Proceedings (Web of Science), UK Clinical Research Network (UKCRN) Portfolio Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and National Library of Medicine (NLM) Gateway, Cochrane Central Register of Controlled Trials (CENTRAL), Current Controlled Trials and ClinicalTrials.gov. Reference lists of relevant articles were checked, and VAD manufacturers' websites interrogated. For economic analyses we made use of individual patient data (IPD) held in the UK Blood and Transplant Database (BTDB).
Systematic reviews of evidence on clinical effectiveness and cost-effectiveness of second- and third-generation US Food and Drug Administration (FDA) and/or Conformité Européenne (CE) approved VADs. Publications from the last 5 years with control groups, or case series with 50 or more patients were included. Outcomes included survival, functional capacity (e.g. change in New York Heart Association functional classification), quality of life (QoL) and adverse events. Data from the BTDB were obtained. A discrete-time, semi-Markov, multistate model was built. Deterministic and probabilistic methods with multiple sensitivity analyses varying survival, utilities and cost inputs to the model were used. Model outputs were incremental cost-effectiveness ratios (ICERs), cost/quality-adjusted life-years (QALYs) gained and cost/life-year gained (LYG). The discount rate was 3.5% and the time horizon varied over 3 years, 10 years and lifetime.
Forty publications reported clinical effectiveness of VADs and one study reported cost-effectiveness. We found no high-quality comparative empirical studies of VADs as BTT compared with MM or as ATT compared with BTT. Approximately 15-25% of the patients receiving a device had died by 12 months. Studies reported the following wide ranges for adverse events: 4-27% bleeding requiring transfusion; 1.5-40% stroke; 3.3-48% infection; 1-14% device failure; 3-30% HF; 11-32% reoperation; and 3-53% renal failure. QoL and functional status were reported as improved in studies of two devices [HeartMate II (HMII; Thoratec Inc., Pleasanton, CA, USA) and HeartWare (HW; HeartWare Inc., Framingham, MA, USA)]. At 3 years, 10 years and lifetime, the ICERs for VADs as BTT compared with MM were £122,730, £68,088 and £55,173 respectively. These values were stable to changes in survival of the MM group. Both QoL and costs were reduced by VADs as ATT compared with VADs as BTT giving ICERs in south-west quadrant of the cost effectiveness plain (cost saving/QALY sacrificed) of £353,467, £31,685 and £20,637 over the 3 years, 10 years and lifetime horizons respectively. Probabilistic analyses yielded similar results for both research questions.
Conclusions about the clinical effectiveness were limited by the lack of randomised controlled trials (RCTs) comparing the effectiveness of different VADs for BTT or comparing BTT with any alternative treatment and by the overlapping populations in published studies. Although IPD from the BTDB was used to estimate the cost-effectiveness of VADs compared with MM for BTT, the lack of randomisation of populations limited the interpretation of this analysis.
At 3 years, 10 years and lifetime the ICERs for VADs as BTT compared with MM are higher than generally applied willingness-to-pay thresholds in the UK, but at a lifetime time horizon they approximate threshold values used in end of life assessments. VADs as ATT have a reduced cost but cause reduced QALYs relative to BTT. Future research should direct attention towards two areas. First, how any future evaluations of second- or third-generation VADs might be conducted. For ethical reasons a RCT offering equal probability of HT for each group would not be feasible; future studies should fully assess costs, long-term patient survival, QoL, functional ability and adverse events, so that these may be incorporated into economic evaluation agreement on outcomes measures across future studies. Second, continuation of accurate data collection in the UK database to encompass QoL data and comparative assessment of performance with other international centres.
The National Institute for Health Research Health Technology Assessment programme.
晚期心力衰竭（HF）是一种使人虚弱的病症，心脏移植（HT）是其最佳治疗选择。然而，供体心脏的供应正在减少，而需求却大大超过了供应。心室辅助装置（VAD）是一种通过手术植入的泵，可用作移植（ATT）或桥接移植（BTT）的替代方法，供体心脏在等待患者的过程中使用。手术和 VAD 都很昂贵。为了使国民保健制度（NHS）以具有成本效益的方式分配和提供此类服务，需要估计这些替代疗法的相对成本和收益。
针对适合 HT 的年龄≥16 岁的晚期 HF 患者：（1）评估第二代和第三代 VAD 作为 BTT 与药物治疗（MM）相比的临床效果和成本效益；（2）评估第二代和第三代 VAD 作为 ATT 与作为 BTT 治疗的临床效果和成本效益。
临床有效性研究的检索涵盖了 2003 年至 2012 年 3 月的年份，包括以下数据库：MEDLINE、MEDLINE 正在处理和其他非索引引文、EMBASE、 Cochrane 系统评价数据库（CDSR）、疗效评价数据库（DARE）、NHS 经济评估数据库（NHS EED）、HTA 数据库[NHS 中心评价与传播（CRD）]、科学引文索引和会议论文集（Web of Science）、英国临床研究网络（UKCRN）投资组合数据库、 Cumulative Index to Nursing and Allied Health Literature（CINAHL）、PsycINFO 和美国国家医学图书馆（NLM）网关、Cochrane 中央对照试验注册库（CENTRAL）、当前对照试验和 ClinicalTrials.gov。检查了相关文章的参考文献，并查询了 VAD 制造商的网站。对于经济分析，我们使用了英国血液与移植数据库（BTDB）中持有的个体患者数据（IPD）。
对第二代和第三代美国食品和药物管理局（FDA）和/或欧洲共同体（CE）批准的 VAD 的临床有效性和成本效益进行系统评价。纳入了过去 5 年有对照组的出版物，或有 50 例或更多患者的病例系列。结果包括存活率、功能能力（例如纽约心脏协会功能分类的变化）、生活质量（QoL）和不良事件。从 BTDB 获得数据。构建了一个离散时间、半马尔可夫、多状态模型。使用生存、效用和成本输入到模型中的多种敏感性分析来确定确定性和概率方法。模型输出为增量成本效益比（ICER）、每获得一个质量调整生命年（QALY）的增量成本和每获得一个生命年（LYG）的增量成本。折扣率为 3.5%，时间范围为 3 年、10 年和终生。
40 篇出版物报告了 VAD 的临床效果，1 篇研究报告了成本效益。我们没有发现关于 VAD 作为 BTT 与 MM 相比或作为 ATT 与 BTT 相比的高质量比较性实证研究。大约 15-25%接受设备的患者在 12 个月时已经死亡。研究报告了以下广泛的不良事件发生率：4-27%需要输血的出血；1.5-40%中风；3.3-48%感染；1-14%设备故障；1-14%心力衰竭；3-30%再次手术；3-53%肾衰竭。两项设备[HeartMate II（HMII；Thoratec Inc.，Pleasanton，CA，USA）和 HeartWare（HW；HeartWare Inc.，Framingham，MA，USA）]的研究报告称 QoL 和功能状态得到改善。在 3 年、10 年和终生，VAD 作为 BTT 与 MM 相比的 ICER 分别为£122730、£68088 和£55173。这些值在 MM 组的生存率变化时是稳定的。与 VAD 作为 BTT 相比，VAD 作为 ATT 可以降低成本和 QoL，在 3 年、10 年和终生的时间范围内，ICER 值分别为£353467、£31685 和£20637，处于成本效益图的西南象限（成本节约/QALY 牺牲）。概率分析为这两个研究问题得出了类似的结果。
由于缺乏比较不同 VAD 用于 BTT 或比较 BTT 与任何替代治疗的有效性的随机对照试验（RCT），以及发表研究中的重叠人群，因此对临床效果的结论受到限制。尽管使用 BTDB 中的 IPD 来估计 VAD 与 MM 相比作为 BTT 的成本效益，但人群的随机化限制了对该分析的解释。
在 3 年、10 年和终生，VAD 作为 BTT 与 MM 相比的 ICER 高于英国通常应用的意愿支付阈值，但在终生时间范围内，它们接近用于生命末期评估的阈值值。VAD 作为 ATT 具有较低的成本，但与 BTT 相比会导致 QALYs 减少。未来的研究应关注两个方面。首先，如何对第二代或第三代 VAD 进行未来评估。由于从伦理角度出发，提供两组患者相等的 HT 概率的 RCT 是不可行的；未来的研究应充分评估成本、长期患者生存、QoL、功能能力和不良事件，以便将这些纳入未来研究的经济评估协议中。其次，继续在英国数据库中进行准确的数据收集，包括 QoL 数据，并与其他国际中心进行性能的比较评估。
英国国家卫生研究院卫生技术评估计划。
