Challenges of long-term mechanical circulatory support therapy

Worldwide, the prevalence of chronic heart failure (CHF) is increasing. In 2005, it was reported that 5.3 million adults in the USA were affected. The number of hospital discharges for CHF rose from 400,000 in 1979 to 1,084,000 in 2005, an estimated increase of over 150% (National Hospital Discharge Survey and National Heart, Lung, and Blood Institute [NHLBI]; American Heart Association computation) [1]. This increase occurred despite advances in medical therapies, including neuro–hormonal blockade (renin–angiotensin–aldosterone and adrenergic system inhibition), interventional therapies such as defibrillators and cardiac resynchronization therapy; as well as surgical therapies, such as revascularization, mitral valve repair, left ventricular geometry restoration and cardiac transplantation [2,3]. Powerful modalities, such as mechanical circulatory support devices (MCSD), initiated 40 years ago by the US-NIH, have evolved rapidly over the past 20 years as cardiac transplantation began to plateau at nearly 2200 per year in the USA [1,3].

The landmark study, Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH), enrolled 129 patients with New York Heart Association (NYHA) class IV symptoms who were not eligible for cardiac transplantation from 21 medical centers in the USA and randomized them to either optimal medical management (OMM) or left ventricular assist device (LVAD) implantation. The study revealed a statistically significant improvement in 1-year survival in the LVAD arm versus OMM, 52 versus 25%, respectively, as well as quality of life as determined by Minnesota Living with Heart Failure [4]. The first post-REMATCH experience confirmed (in unselected MCSD centers participating in the International Society for Heart and Lung Transplantation-MCSD database) the REMATCH survival results [5].

Despite these favorable outcomes in MCSD versus OMM, further analysis of the REMATCH trial revealed that survival in the first 12 months post device implantation was adversely affected by high postoperative mortality, particularly in the first 90 days [6]. This raised concerns regarding patient selection, implantation timing, choice of device and MCSD management, that is to say, MCSD center infrastructure and requirements [7]. The future development of the field in the context of MCSD-center performance criteria will require a focus on patient selection, patient management and device improvement.

In terms of patient selection, MCSD is unfortunately still often seen as the ‘last resort’ on the algorithm of disease management. This, is in large part, due to complications associated with MCSD. Despite technologic advances in the mechanical circulatory field, we are still plagued by similar complications as in the past 20 years. Consequently, we are caught in the midst of a ‘catch-22’ [8]. We avoid implantation in our less sick population because of potential complications but are forced to deal with these complications at a higher rate in our currently targeted sicker patient cohorts. Currently the eligibility for destination therapy (DT) as per Center for Medicare and Medicaid Services is based on REMATCH patient entry criteria: NYHA class IV symptoms despite maximal oral therapy for at least 60 of the last 90 days, left ventricular ejection fracture of less than 25%, peak oxygen consumption of less than 12 ml/kg/min or inability to wean inotropic support, contraindication to cardiac transplantation due to age or comorbidities and appropriate body size of over 1.5 m² for LVAD implantation [101]. Lietz et al. contributed to outlining the issue of patient selection by identifying preoperative predictors of in-hospital mortality in the first 90 days. Nine variables were outlined (platelet count < 148,000/µl, albumin < 3.3 g/dl, international normalized ratio > 1.1, vasodilator therapy anytime of implantation, mean pulmonary artery pressure < 25 mmHg, aspartate aminotransferase > 45 U/dl, hemotocrit < 34%, blood urea nitrogen > 51 U/dl and lack of intravenous inotropic support), which formulated a composite score to identify potential DT patients as low, moderate, high or very high risk for operative mortality in the first 90-day period [6]. This retrospective data analysis was the first step towards establishing stringent criteria to help identify DT patients who are low-to-moderate risk for early post-device implantation mortality. Future prospective studies need to be conducted for further detail the profile of which patients are best suited to DT.

In addition to continuously defining the patient criteria for DT, the limitations of current MCSD designs (device size, mode of action, durability, implantability, biocompatibility, manageability and cost) need to be addressed [2,9]. These confounders contribute to the morbidity and mortality associated with MCSD via infection, coagulopathies, right ventricular failure and device malfunction, thereby ultimately affecting outcomes and also cost. Due to innovative designs, such as the small rotary (axial) pumps, there has been a trend toward lower infection rates since the lack of turbulence associated with continuous flow pumps (axial) hinders bacterial colonization [2]. Yet infection, in particular driveline infections that plague most devices that are currently being tested in clinical trials, still remains a major cause of morbidity and mortality, accounting for approximately 30% of deaths [6]. Next to infection, the risk of coagulopathies leading to bleeding or embolic events limit survival and quality-of-life benefit. Technologic development in pump materials, pumping methodology, texture of surface and design have led to a reduction in the incidence of embolic events [2], but improvement in newer coagulation monitoring techniques or its implementation is still lagging. The challenge of pump design, specifically for partially unloading continuous flow LVADs, also extends to prediction models of right ventricular dysfunction in the setting of MCSD, which portends poor prognosis. Currently, in the presence of an elevated right atrial pressure, clinical variables such as preoperative low mean pulmonary artery pressure and impairment of hepatic function have been used. The identification of more comprehensive clinical predictors of right ventricular dysfunction is needed.

In summary, in order to improve the management of HF patients with destination MCSD and to overcome the hurdles inherent to MCSD, translational research focused on the prediction of end-organ dysfunction/recovery and complications of patient management – sepsis and multiorgan failure – is of paramount interest and need. Currently, the NHLBI-Specialized Center for Clinically Oriented Research program on biology of long term human MCSD is investigating mechanisms of infection, coagulopathy, and left ventricular recovery [102] and is planning to define molecular classifiers for future personalized decision-making algorithms.

Financial & competing interests disclosure

The authors were supported by the National Heart, Lung, and Blood Institute Specialized Center for Clinically Oriented Research grant HL 077096-01, named ‘The Biology of Human Long-Term Mechanical Circulatory Support,’ and by the Philip Geier Advanced Heart Failure Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.