In 1964, the National Institutes of Health established the Artificial Heart Program [2]. There was significant early enthusiasm for the development of a total artificial heart. However, in the 1970s, failures in this arena combined with challenges in transplantation secondary to the lack of modern immunosuppression, led to the development of the National Heart, Lung, and Blood Institute clinical ventricular assist device program in 1975. This program initially focused on mechanical circulatory support for patients who had recently undergone cardiac surgery [3], but ultimately expanded to focus on support for patients requiring mechanical assistance as a bridge to transplantation (BTT).

Throughout the 1970s and 1980s several VADs were developed, characterized by their large size and use of pulsatile flow and positive displacement. These devices, now commonly referred to as “first generation” VADs, underwent significant evolution, and three devices ultimately received Food and Drug Administration (FDA) approval for use in BTT support – the Thoratec paracorporeal VAD (PVAD)/implantable VAD (IVAD), the Heartmate IP/VE/XVE, and the Novacor LVAS, which is no longer marketed in the United States [4–8].

Much of the early focus on mechanical circulatory support involved use of VADs for temporary support after cardiac surgery or as BTT in critically ill patients on the wait list. Given the early success of VADs, attention turned to investigating an indication for use in destination therapy (DT) among end-stage heart failure patients who were not eligible for transplantation. The results of the landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) were published in 2001 [9]. The HeartMate XVE was introduced in 2001 with structural modifications, and received FDA approval for a BTT indication in 2001 and for destination therapy in 2003 based on the results of REMATCH.

Despite the significant impact on survival observed in early VAD trials, major opportunity remained for device improvement and innovation. In the REMATCH trial, patients in the device group were more than twice as likely to have a serious adverse event compared to the medical management group. In 1994, the NHLBI issued proposals for “Innovative Ventricular Assist Systems,” which sought to improve the durability of ventricular assist systems to at least 5 years and increase reliability to at least 90 %. As an outgrowth of this request for proposals, rotary axial flow devices were developed. These smaller, “second generation” devices differed from their pulsatile counterparts in that they employed rotary axial flow and thus provided continuous flow [10]. The HeartMate II, a continuous flow device first used clinically in 2001, was approved for BTT in 2008 and DT in January 2010 [11].

Since 2008, continued innovation has occurred through the development of third generation, or centrifugal, devices. Through the use of a bearing-less design, these devices may have improved durability. Moreover, the smaller size of these devices has important implications for improved quality of life after implantation. The potential for such a device may be reflected by the recent early conclusion of enrollment in the ADVANCE trial, which tests HeartWare’s (Framingham, Massachusetts) miniaturized, third-generation VAD in a BTT population. At the 2010 meeting of the American Heart Association, HeartWare reported that 92 % of enrolled patients had achieved the primary endpoint at 180 days [12].

This past year, the NIH issued a request for proposals for the Randomized Evaluation of VAD InterVEntion before Inotropic Therapy (REVIVE-IT) trial [13]. The goal of this study is to explore the potential benefit of mechanical circulatory support in less severe but functionally-impaired heart failure patients, not eligible for transplantation. Largely as a result of an improved durability and safety profile, the REVIVE-IT trial represents a potential paradigm shift in viewing VADs as salvage therapy for the most critically ill heart failure patients, to support for less critically ill patients with impaired functional capacity. The REVIVE-IT trial has yet to begin enrollment, however, the results of this trial have the potential to further expand the role of VADs. The evolution and innovation of VADs over the course of 40 years has not only led to improvements in safety profiles and durability but also expanded the potential clinical indications for mechanical circulatory support.

The early focus on mechanical circulatory support was on the safety and efficacy of such devices in the management of end-stage heart failure. As VAD trials completed enrollment and FDA approval was granted, attention gradually turned toward the challenging issues of insurance coverage and the cost of such devices. Not only were VADs resource intensive due to the cost of the device itself, but they were an added cost in the management of end-stage heart failure patients – an already resource intensive group. Economic evaluation of device therapy includes the costs of operative implantation, post-operative recovery and hospitalization, and management of complications which occur at relatively high rates when compared to most other surgical interventions. Clearly VADs prolonged survival of end-stage heart failure patients, but were these devices cost effective?

Despite the significant cost associated with LVAD therapy, it is essential when considering the cost effectiveness of LVADs, to understand the cost of alternative treatments – heart transplantation in the BTT population, and optimal medical management (OMM) in the DT population. DiGiorgi and colleagues examined the costs of patients bridged with the HeartMate XVE versus those receiving a heart transplant [16]. Their results demonstrated that overall, total actual hospital costs of LVADs exceed that of transplantation, with total hospital costs post-LVAD estimated at $197,957 and total hospital costs for transplanted patients estimated at $151,646. The overall net revenue for transplantation was $29,916 whereas for LVADs, net revenue was – $53,201. Importantly, there were a significantly greater number of readmissions among the LVAD group, with readmission costs in the device group estimated at $16,596 and only $6,356 in the transplantation group. In addition to the difference in number of readmissions, the authors also highlight the importance of length of stay which was 36.8 days in the sicker device group and 18.2 days in the healthier transplant group.

Russo and colleagues examined the costs of medical management in the final 2 years of life among the optimal medical management cohort in the REMATCH trial [17]. The mean total cost per patient in the final 2 years of life was $156,168, with more than half of the total cost incurred during the final 6 months of life. Approximately 75 % of the inpatient costs in the last 6 months were related to hospitalizations for heart failure exacerbations. Notably, during the final 6 months of life, patients spent approximately 1 out of every 4 days of life as hospital inpatients. The results of the analyses by DiGiorgi and Russo demonstrate that although the costs of VADs is great, the costs of alternative strategies for end-stage heart disease, such as transplantation and intensive medical management, are not without a significant cost burden. Thus, early data demonstrated that there existed an opportunity for mechanical circulatory support to compete with the currently available alternatives from a cost-effectiveness standpoint, but improvements would first be necessary in terms of device innovation, clinician experience, and patient selection.

Kenneth Arrow, who received the 1972 Nobel Prize in economics, described in his classic text, “The Economic Implications of Learning By Doing,” the process whereby workers improve productivity by repetition of a given action which results in increased productivity through practice and innovation [18]. Unlike pharmaceuticals, a “learning by doing” approach is particularly critical in the innovative process of medical devices and surgical procedures, whereby learning and ultimately innovation occur gradually through use and experience with a device or technique [19]. While innovation clearly occurs in the laboratory, there is a feedback pathway where research and development lead to clinical trials which in turn lead to clinic practice, and then ultimately to experience that informs and feeds back to the research and development process [20].

Such an innovative process can be seen in the development of LVADs. Experience with the first generation HeartMate device in the REMATCH trial led to several mechanical device innovations. For example, locking screw ring connectors were added to prevent detachment of the blood transport conduits, and outflow graft bend relief was added to prevent kinking and valve flow incompetence [21]. In addition to changes in the mechanical design of the device, experience in REMATCH gained from clinical practice or “learning by doing” led to refinements in patient selection and management.

As discussed previously in this chapter, early economic evaluation of LVADs highlighted the significant impact of device-related complications, such as sepsis, on total hospital costs. As such, institutions have developed specific guidelines on surgical infection prophylaxis for LVAD recipients. In addition, early economic analysis demonstrated the significant difference in cost of total hospitalization between LVAD recipients who survived the first year of implantation versus those who did not. Work by Leitz and colleagues demonstrated that use of a pre-operative risk score could be used to stratify LVAD recipients into low, medium, high, and very high risk which correlated with 1-year survival rates of 81 %, 62 %, 28 %, and 11 %, respectively [22]. As experience with VADs has grown, several subsequent risk models have been developed to more precisely predict peri-operative morbidity and mortality and aid in patient selection.

Early experience with LVADs clearly led to refinements in device technology and patient selection, which ultimately led to improvements in clinical outcomes. However, have refinements in devices themselves and the selection of device recipients ultimately led to improvements in the cost-effectiveness of VADs?

Initial economic evaluation of VADs focused largely on reporting of costs rather than cost-effective analysis. However, even a cursory examination of the reported hospital costs from the REMATCH trial, driven largely by the costs of the index hospitalization, hospital readmissions, and the need for device replacement, demonstrated that VADs would far exceed the generally accepted incremental cost effectiveness ratio (ICER) threshold of $50,000–$100,000 per quality adjusted life year (QALY). In fact, economic modeling by Clegg and colleagues demonstrated that LVADs offered an additional 0.6 QALYs per patient over the 5-year duration of their model at an additional cost of £102,000 or an ICER of £170,616, approximately $341,232 using a currency conversion adjusted for the time of publication [23]. One-way sensitivity analysis showed that the results were not sensitive to variations in cost, discount rate, or utility. Similarly, in 2002 the Technology Evaluation Center of Blue Cross and Blue Shield performed an independent cost-effectiveness analysis of LVADs using parameter estimates from published sources at the time. The results demonstrated that use of LVADs led to an increase in cost of $802,700 per one QALY gained, compared with optimal medical management. The calculated ICER was stable despite sensitivity analysis on the utility of New York Heart Association Category III/IV, cost of outpatient care, cost discount rate, cost of rehospitalization, and probability of rehospitalization for LVAD. Russo and colleagues calculated the ICER of patients enrolled in REMATCH to be $602,361/QALY [24].

Early American and European estimates of the cost-effectiveness of VADs were bleak. Not only were calculated ICERs far outside the range of medical therapies that would be considered cost-effective, sensitivity analyses demonstrated that acceptable ICER thresholds could be achieved only at the extremes of clinical variables that composed the economic models.

With growing constraints in healthcare funding, there is increasing demand for objective clinical and economic evidence to demonstrate that a particular intervention will be safe and effective while providing improved quality of life at an acceptable cost. However, given the rate of technological change, evidence to support the use of new technologies frequently lags behind their application. The need to evaluate device-based therapies has increased exponentially, particularly in cardiovascular disease.

Historically, tools to evaluate clinical therapies were developed for the evaluation of drug-based therapies. However, devices and drugs are inherently different – drugs are “discrete technologies.” That is, drugs are singular and driven by a fixed active agent. Research and development occurs at the benchtop, and they do not undergo significant evolution after introduction to the market. Application in clinical practice signals the end of the development process. Although doses and delivery mechanisms may change, the active chemical agent remains fixed. Therefore, the lifecycle of a drug is linear, and advances in therapy are discrete and discontinuous.