The role of mechanical circulatory support as destination therapy for ambulatory heart failure

Continuous flow technology has dramatically improved patient survival during ventricular assist device (VAD) therapy in recent years. Health-related quality of life is improved by at least two years. Despite remarkable progress in this field, major adverse events during VAD support limit the effectiveness of this therapy and present major barriers to its extension to ambulatory advanced heart failure patients. The pace of progress will depend on improvements in both the adverse event profile and development of semi-quantitative methodology to calculate and display a composite of survival and health-related quality of life.


INTRODUCTION
Since the earliest iterations of mechanical circulatory support (MCS) devices, engineers and visionary surgeons have contemplated truly long-term support of the failing circulation that could be applied before the terminal stages of heart failure. However, even after the REMATCH trial demonstrated a significant survival advantage for desperately ill advanced heart failure patients compared to medical therapy, 1 the adverse event profile was too unfavorable to justify application in less sick patients. A major paradigm shift emanated from the introduction of rotary pump technologies that gradually dominated the MCS landscape.

CURRENT OUTCOMES WITH MCS THERAPY
The survival advantage of isolated left ventricular support with a durable continuous flow device compared to prior pulsatile technology has been well documented in the United States NHLBI-sponsored Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). (Figure 1

DESTINATION THERAPY
Although the application of mechanical circulatory support as long-term destination therapy (DT) has increased in the recent era (Table 1) 2 , the majority of DT patients have progressive cardiac deterioration and/or inotrope dependence at the time of implant. Less than 25% of implants are in patients with truly ambulatory heart failure (INTERMACS Levels 4-7) 3 ( Table 2).
One of the most pressing groups of ambulatory advanced heart failure patients are those patients who have been accepted for cardiac transplantation, but whose status is not sufficiently urgent to justify the highest priority for donor allocation. Such patients often wait a year or more for a suitable donor.
According to data from the International Society for Heart and Lung Transplantation (ISHLT), the average survival rate following cardiac transplantation is approximately 80%      4 . Therefore, for chronic mechanical circulatory support to be a viable alternative for potential transplant recipients, 2-year survival with mechanical circulatory support would need to at least approach 80%.
A multi-variable analysis based on INTERMACS data for survival following implantation of durable continuous flow pumps indicates that patients with ambulatory heart failure have better expected survival than patients who are hemodynamically unstable (Table 3). 3 This survival benefit is most apparent in the first 3 months following device    Figure 4). 2 In a study of INTERMACS patients undergoing destination therapy, a lower risk group of patients in INTERMACS Levels 3-7 was identified who did not have important right ventricular failure, important renal dysfunction, or a history of prior cancer; were under age 75 years and had no prior major cardiac operations. ( Figure 5). 5 This lower risk group represented nearly 20% of Level 3-7 INTERMACS patients who underwent destination therapy. The 1-and 2-year survival in this patient subset was 89% and 80%, respectively. However, further analyses are needed since patients who currently receive DT are not comparable to standard heart transplant patients; DT patients currently must be considered ineligible for heart transplantation because of associated risk factors. Thus, the current population of DT patients has additional risk factors for mortality that may not be present in the transplant population. Any potential triage algorithm is further complicated by the reality that many risk factors (including renal dysfunction, right heart failure, previous cardiac surgery, and advanced age) that might identify a higher risk  group for heart transplantation also identify a higher risk group for mechanical circulatory support (Tables 4 and 3) 6,2 . Therefore, it is not evident that simply triaging higher risk transplant patients to VAD therapy will drive an effective treatment algorithm.
If ambulatory heart failure patients could be routinely well supported with LVAD therapy, one might also consider a pathway whereby these less sick LVAD patients received improved access to heart transplantation compared to patients who were sicker at the time of LVAD implant. However, data from INTERMACS fails to suggest any such advantage. A competing outcomes analysis indicates that patients in Levels 4 through 7 have only a very small increase in the likelihood of heart transplantation within one year of implant compared to patients implanted in Levels 1 through 3 ( Figure 6) 2 .

FAILURE OF THE REVIVEIT TRIAL
The REVIVEIT trial was a United States randomized clinical trial, supported by the National Heart, Lung, and Blood Institute (NHLBI), designed to examine the impact of mechanical circulatory support compared to optimal medical therapy for a group of patients with ambulatory advanced heart failure who were ineligible for cardiac transplantation. The HeartMate II device (Thoratec Inc.; Pleasanton, CA) was selected as the continuous flow pump, and the mechanical circulatory support community and the NHLBI felt that equipoise existed for designing a clinical trial with mechanical circulatory support devices in this less ill ambulatory advanced heart failure population.
However, despite a rigorous clinical trial design and multi-stage screening, in the end the trial was terminated because of the disruption of equipoise over concerns about adverse events and specifically pump thrombosis. Before the initial randomized patient could receive device therapy, an increasing rate of pump thrombosis was noted with this device. A detailed INTERMACS analysis identified a progressive increase in the hazard for pump thrombosis resulting in death or pump exchange from 2010 through 2012 (Figure 7) 7,8 . Notably, the mortality associated with pump exchange exceeded 25% at 6 months ( Figure 8

QUALITY OF LIFE
For many patients with advanced heart failure, their quality of life while supported by a durable pump is nearly or equally as important as the survival benefit. Grady and

ADVERSE EVENTS IN AMBULATORY HEART FAILURE PATIENTS WHO RECEIVE MCS THERAPY
Although ambulatory heart failure patients at implant are less likely than more seriously ill patients to suffer severe right heart failure ( Figure 11) 2 , they carry essentially the same risk for non-cardiac adverse events. Specifically, little or no difference between ambulatory and more seriously ill heart failure patients at VAD implant has been noted with respect to freedom from neurological events (Figure 12) 2 , pump-related infection Table 5 Factors associated with a change in VAS (6 months -Pre-implant), n = 2748. Negative coefficients indicate the decrement in change. The Intercept indicates the amount of change (improvement) for a patient with no 'risk factors'.  Figure 10. Change in visual analog score (VAS) from before to 6 months after VAD implant. The 3 lines depict patients with different post-implant adverse event burdens 9 (see Table 5).

QUANTIFYING THE DECISION-MAKING PROCESS
Time-related survival statistics are highly developed and readily quantifiable. However, such depictions, whether parametric or non-parametric, do not provide sufficient information for the patient with advanced heart failure to arrive at a truly informed decision about therapeutic choices, since quality of life and functionality are very important for most patients.   The impact of quality of life, adverse events, and survival on the composite decisionmaking algorithm are illustrated in the following fictitious depictions. In the first instance ( Figure 16) a stable ambulatory advanced heart failure patient is offered LVAD therapy vs. continued optimal medical treatment. With his/her risk profile, the expected timerelated survival curves are shown. In this instance, however, the considerable additional adverse event burden with device therapy is such that the combined adverse event burden/survival curve is inferior to that of medical therapy.
However, with the same patient profile and expected survival curves, a reduced expected adverse event burdened predicts a superior overall adverse event burden/ survival curve compared to medical therapy ( Figure 17). These hypothetical scenarios underscore the critical importance of reducing major adverse events if durable mechanical circulatory support is to become main stream therapy for advanced ambulatory heart failure.