- Email: [email protected]
Ventricular assist devices: The future is now
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Ventricular assist devices: The future is now Brian Lima, MDa, Michael Mack, MDb, and Gonzalo V. Gonzalez-Stawinski, MDa,n a
Department of Cardiac Surgery, Baylor University Medical Center, Dallas, TX Department of Cardiac Surgery, The Heart Hospital, Baylor Plano, Plano, TX
b
abstract Heart failure has become a global epidemic. For advanced heart failure, a broad assortment of device options have been introduced for both acute and prolonged intervals of hemodynamic assistance. Durable implantable ventricular assist devices (VADs) in particular play a key role in the management of advanced heart failure. This review focuses specifically on the current outcomes with VAD therapy, highlights the results from pivotal clinical trials, and summarizes the various device options on the market and those in preclinical development. & 2015 Elsevier Inc. All rights reserved.
Introduction The incidence of advanced heart failure is growing exponentially worldwide. In the U.S. alone, an estimated 10 million people will be affected by 2030 [1,2]. With limitations in donor availability, cardiac transplantation alone cannot address this global epidemic. Concerted efforts in mechanical circulatory support have yielded a broad array of device options tailored for short term or extended periods of hemodynamic support. These various options play central roles in the treatment of advanced heart failure. One of the most impactful developments in this rapidly evolving field has been the advent of durable, implantable left ventricular assist devices (LVADs). More widespread adoption of this technology has resulted in a steady increase in LVAD implants from approximately 100 per year in 2006 to over 2500 in 2014, a 2500% increase in only 8 years [3] (Fig. 1). Strategies for LVAD implantation are largely predicated on candidacy for cardiac transplantation, and thus primarily intended as either a bridge to transplant or destination therapy for those deemed transplant ineligible. The fraction of patients implanted for destination therapy indications continues to increase, comprising over 40% of all cases [3]. Patients presenting in hemodynamic extremis are often
temporized with other forms of mechanical circulatory support, such as extracorporeal membrane oxygen (ECMO) or percutaneous (non-implantable) VADs, including the Impella (Abiomed, Danvers, MA) [4] and TandemHeart System (CardiacAssist, Inc., Pittsburgh, PA) [5]. These are bridge-todecision patients who may subsequently undergo more definitive therapy with implantable LVAD or transplantation. Some patients require short-term right ventricular mechanical circulatory support following an LVAD placement and likewise can be supported with these various modalities. Discussion of these numerous options for short-term mechanical circulatory support, their relative efficacy, and associated outcomes, is beyond the scope of this review. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, published in 2001, established the efficacy of LVADs in the management of advanced heart failure [6]. The focus of this review will be to delineate the important developments in the field that have transpired since this initial trial. These include modern iterations in LVAD design available in current clinical practice and those undergoing preclinical evaluation. Additionally, a thorough summary of device-related outcomes, complications, and ongoing trials will be presented. Also included in the analysis is an overview of strategies for
The authors have indicated there are no conflicts of interest. n Corresponding author. Department of Cardiac Surgery, Baylor University Medical Center, 3900 Junius Street, Suite 605, Dallas, TX 75246. Tel.: þ1 214 820 7100; fax: þ1 214 820 6863. E-mail address: [email protected] (G.V. Gonzalez-Stawinski). http://dx.doi.org/10.1016/j.tcm.2014.11.008 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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Fig. 1 – Summary of durable, implantable VAD implants in the INTERMACS registry by year of implant [3]. LVAD, left ventricular assist device; TAH, total artificial heart. biventricular support, such as total artificial heart implantation. The review concludes with a look to the future as continued scientific and engineering advances may continue to reshape the mechanical circulatory support paradigm.
Patient selection Integral to the process of proper patient and device selection for mechanical circulatory support is risk stratification derived from the clinical profile at initial presentation [7]. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), an NHLBI-sponsored database that tracks all long-term VAD implants and outcomes, has defined seven distinct clinical profiles based on degree of hemodynamic compromise and inotrope dependency [3,8] (Table). Within this classification schema, higher INTERMACS level correlates favorably with improved survival following LVAD implant. Therefore, in patients at the low end of the INTERMACS spectrum, namely the level 1 patients in profound cardiogenic shock, the prognosis is grave. These findings were recapitulated in the most recent INTERMACS annual report, which cataloged outcomes in over 10,000 patients implanted with durable LVADs [3]. Specifically, INTERMACS levels 1 and 2 exhibited statistically significant early hazard ratios for mortality. Other important hazards identified included the following: advanced age, preoperative renal failure or indices of right ventricular dysfunction, perioperative RVAD placement, prior cardiac surgery, and concomitant cardiac procedures at the time of LVAD implantation [3]. Awareness of these reproducible risk factors has prompted a shift away from durable LVAD implantation in INTERMACS 1 profiles, or other critically ill patients, where optimization with a temporary MCS platform may be more clinically prudent [7]. On many occasions, ventricular unloading and medical optimization of these high-risk patients may
enable favorable outcomes with a subsequent LVAD procedure. Fastidious adherence to the guiding principles governing patient selection has resulted in improved survival following LVAD implantation [3,7]. Growing experience with the implantation procedure, prophylactic measures for right ventricular protection, and preoperative optimization of hemodynamics has also contributed to improved outcomes.
Durable implantable VADs HeartMates II LVAD To date, the HeartMate (HM) II LVAD has been implanted in over 15,000 patients worldwide (Fig. 2A). Following favorable outcomes of a nonrandomized trial of bridge-to-transplant patients [9], it became FDA-approved for bridge to transplant in 2008. It is the most commonly implanted secondgeneration LVAD, employing a continuous-flow rotary pump mechanism and capable of generating up to 10 L/min of flow. Its predecessor, the HM XVE, was among the first-generation LVADs that function via pulsatile volume displacement pumps. Despite their highly touted clinical success relative to conventional medical therapy in the REMATCH trial, these pulsatile devices were prone to infection, thromboembolism, and mechanical failures [6]. In order to overcome these limitations, the HM II was designed as a valveless axial flow pump, with a single moving part, the rotor (Fig. 2B). With fewer moving parts, and the elimination of a reservoir chamber, the device is significantly smaller, more durable, and easier to implant than the XVE. Specifically, with a weight of only 290 g, and dimensions of 7.0 cm (length) by 4.0 cm (width), the HM II is approximately 75% lighter and 85% smaller than its pulsatile predecessor [10]. In the REMATCH II trial of destination therapy patients, HM II decisively outperformed the XVE and firmly solidified its role
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Table – INTERMACS risk stratification [41]. Profile no.
Profile description
Time to MCS
1. Critical cardiogenic shock 2. Progressive decline
Persistent shock despite high-dose inotropes and IABP Stable hemodynamics on inotropic support but worsening end-organ (renal) function Stable but inotrope dependent
Within hours Within days
3. Stable but inotrope dependent 4. Recurrent advanced heart failure 5. Exertion intolerant 6. Exertion limited 7. Advanced NYHA III
Weaning inotropes but frequent relapses Comfortable at rest Comfortable with mild activity Comfortable with reasonable level of activity
Within weeks to months Within weeks to months Variable urgency Variable urgency Not indicated
INTERMACS, Interagency Registry for Mechanical Circulatory Support (MCS); IABP, intra-aortic balloon pump; NYHA, New York Heart Association.
in the management of advanced heart failure [11]. Shortly thereafter it became FDA-approved for destination therapy in 2010. The various device and power source components of the HM II system have been previously described in great detail [10]. Briefly, blood is continuously drained from the LV chamber via the apical inflow cannula and propelled through the pump housing where a magnetic field generated by the rotary pump transmits blood flow to the body via the outflow graft anastamosed to the ascending aorta (Fig. 2). A percutaneously tunneled driveline connects the external power source, or system controller, to the pump motor. The system controller has both manual and fixed settings that modulate pump speed, provide hazard alarms, and log any device malfunctions for future analysis. This device can deliver between 3 and 10 L/min of flow at pump speeds of 6000– 15,000 rpm. The batteries used to power the device may last up to 12 h before needing to be recharged.
HeartWares HVAD The HeartWares HVAD (Framingham, MA) is a centrifugal, continuous-flow, implantable rotary pump currently in clinical practice (Fig. 3). This “third-generation” VAD operates via a hydro-magnetically levitated rotor without mechanical bearings and can deliver up to 10 L/min of flow (Fig. 3C). Elimination of the contact bearings imparts a number of clinically relevant structural, and theoretical advantages relative to the HM II [12]. First, by affording further miniaturization, this 140-g pump can be implanted within the pericardial space, thus simplifying operative placement by eliminating the need for creating a pump pocket. This miniature size also makes the device more conducive to minimally invasive implantation techniques [13]. The absence of mechanical contact points within the pump eliminates friction and heat generation, which also portends improved device durability. Generally, the pump is set at a range of
Fig. 2 – (A) Components of the HeartMates II left ventricular assist device system, including the pump, driveline, system controller, and batteries. LVAD, left ventricular assist device; LVAS, left ventricular assist system. (B) HeartMates II axial flow pump design with internal rotor system. (Photo courtesy of Thoratec Corporation, Pleasanton, CA.)
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Fig. 3 – (A and B) HeartWares HVAD system and (C) internal view of centrifugal pump design. (Photo courtesy of HeartWare, Inc., Framingham, MA.)
2400–3200 rpm to deliver flow rates between 3 and 8 L/min. The batteries that power the device can deliver 4–6 h of support when fully charged. In a European multicenter prospective trial, the HVAD proved effective in bridge-to-transplant patients, improving both quality of life and neurocognitive function [14]. Subsequently, results from the ADVANCE trial were published, a U.S. nonrandomized multicenter noninferiority study of 140 bridge-to-transplant patients supported with HVAD. These patients were compared with 499 contemporaneous bridgeto-transplant patients (mostly HM II) in the INTERMACS registry [15]. With established noninferiority to other commercially available devices, the HVAD became FDA-approved for bridge to transplant in 2012. A more recent study examined 332 patients in the pivotal bridge-to-transplant and
continued access protocols trial. Survival at 6 months and 1 year was 91% and 84%, respectively, with a low adverse event rate and significant improvement in quality-of-life scores [16]. Currently underway is the prospective, randomized, multicenter noninferiority trial, the Evaluate the HeartWare Ventricular Assist system (VAS) for Destination Therapy for Advanced Heart failure (ENDURANCE), comparing the HVAD to HM II for destination therapy. The trial completed enrollment in May 2012 and was designed to include 450 patients at 50 U.S. centers. Results are forthcoming.
Total artificial heart For a subset of patients with heart failure, left ventricular support alone will not suffice, and some modality of
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Fig. 4 – (A) SynCardia total artificial heart and (B) biventricular support using two HeartWares HVADs [20]. biventricular assistance must be instituted [17]. From a device perspective, options for durable, implantable biventricular support remain limited. The most extensive clinical experience has been acquired using the SynCardia CardioWest total artificial heart (SynCardia Systems, Inc., Tucson, AZ). Approved by the FDA for bridge to transplantation in 2007, the SynCardia total artificial heart is a pneumatically driven, pulsatile pump, designed to orthotopically replace the native ventricles and all four valves (Fig. 4A). Surgically, this entails bilateral ventriculectomy and fashioning atrial cuffs that are anastamosed to rigid, spherical polyurethane chambers that serve as ventricles. Each chamber houses two Medtronic Hall (Medtronic, Minneapolis, MN) 27-mm inflow and 25-mm outflow mechanical valves. Two subcutaneously tunneled drivelines are connected to pneumatic drivers within the external console. Once implanted, total output from the total artificial heart is 7–8 L/min. Certain body size criteria must be met to accommodate the device, including a minimal body surface area of 1.7 m2 and a thoracic diameter of at least 10 cm [18]. In the seminal report by Copeland et al. [19] in 2004, the total artificial heart successfully bridged 79% patients to heart transplant compared to 46% in the control group. In this
prospective multicenter study of 130 patients between 1993 and 2002, survival following transplantation in the total artificial heart group was 86% and 65% at 1 and 5 years, respectively, on par with international registry benchmarks. However, this initial enthusiasm must be tempered with the reality that only about 30 total artificial heart devices are implanted yearly in the U.S., a very minor fraction of the total number of durable VADs implanted [3] (Fig. 1). Given this limited experience, the steep learning curve for this technically demanding operation, and the known inherent limitations to pulsatile pump designs, alternatives to biventricular support have been explored and implemented. A notable example is the off-label use of two HeartWares HVADs in a biventricular support configuration (Fig. 4B) [20]. While limited to published case reports and small series, proof of principle in these isolated patient experiences will likely spurn further efforts to optimize biventricular support modalities. At present, the authors favor using the total artificial heart in transplant eligible patients with established biventricular failure refractory to optimal medical management. This would include patients presenting at INTERMACS levels 2 through 4, with a low likelihood of right ventricular recovery
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following unloading of the left ventricle alone with an LVAD. Recently, the FDA has approved a Humanitarian Use Designation for the total artificial heart, and investigational trials for this indication are planned for the near future.
Outcomes Survival and quality of life Laudable strides in device-related outcomes have been accomplished since the REMATCH era of pulsatile pumps. Actuarial survival at 1 and 2 years following continuous-flow LVAD implantation (n ¼ 9112) has reached 80% and 70%, respectively (Fig. 5), which is roughly akin to that of cardiac transplantation [3]. Included in this cohort are destination therapy patients with 1-year survival exceeding 75%, a noteworthy feat given these are often older patients with multiple medical comorbidities. One-year survival for total artificial heart (n ¼ 239) approaches 60%, matched by mounting experience with continuous-flow biventricular assist device implants (n ¼ 260). Additionally, metrics for quality of life have been documented, consistent improvement after VAD implantation that is sustained out to 24 months [3]. These metrics include the EQ-5D Visual Analog Scale, as well as the “self-care” and “usual activities” dimensions. More specifically, this translates to a drastic reduction in patients reporting “severe problems” with self-care, from approximately 50% pre-implant to well below 5% at 3 months after implantation [21]. The improvement is more striking with “severe problems” in usual activities of daily living, decreasing from over 80% to approximately 5% following VAD. However, about 20– 40% of patients continue to report some problems in these aforementioned categories following implantation. Therefore, the majority of patients that survive to hospital discharge following VAD implantation do require some degree of intermittent assistance at home but can achieve a modicum of independent living.
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Hemorrhage All patients receiving implantable VADs are maintained on systemic anticoagulation with Coumadin. The targeted INR range is 2–2.5. The nonphysiologic flow dynamics of newergeneration continuous-flow pumps incites high shear stress that promotes von Willebrand factor (vWF) proteolytic degradation [22]. In addition to this acquired vWF deficiency, these patients exhibit a proclivity for arteriovenous malformations along the gastrointestinal tract, the mechanism of which remains poorly understood [23]. Not surprisingly, this coagulopathic milieu renders these patients quite susceptible to hemorrhagic complications [24–26]. Specifically, some studies have reported clinically significant bleeding from the gastrointestinal tract in approximately 30% patients with continuous-flow LVADs [23–26]. In a recent study of 956 discharged HeartMate II bridge-to-transplant patients, the observed bleeding rate was 0.67 events per patient-year, with 45% of these events attributable to gastrointestinal bleeding [24]. Another recent study identified a greater proclivity for gastrointestinal bleeding following implantation of the HVAD compared to the HeartMate II device, in appropriately matched patients [25]. These complications represent challenging clinical scenarios, often precipitating multiple hospital readmissions [27] and necessitating hazardous reversal of anticoagulation and blood product transfusions. Effective management of the culprit arteriovenous malformation lesions may require gastroenterology intervention and on some occasions, complete cessation of anticoagulation going forward.
Thrombosis In some VAD patients, the coagulation pendulum swings in the opposite direction, and problematic thromboembolic complications ensue. Pump thrombosis in particular, which can and does occur, is among the common manifestations of this grouping of adverse events [21,28,29]. Modern series have
Fig. 5 – Actuarial survival for primary implantation of durable implantable ventricular assist devices, stratified by device type [3]. CF, continuous-flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, total artificial heart.
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Fig. 6 – (A) Thoratec HeartMates III left ventricular assist device [37] that features fully magnetically levitated rotor that can generate an artificial pulse. (B) HeartMates X miniaturized pump that can be implanted in multiple configurations (C) to accommodate biventricular support. (Photo courtesy of Thoratec Corporation, Pleasanton, CA.) reported pump thrombosis rates as high as 8% for both the HM II [29] and the HVAD [28]. This dreaded complication is usually heralded by power spikes noted on the system controller, as well as marked elevation in serum levels of lactate dehydrogenase and plasma free hemoglobin [30]. An echocardiographic ramp study is performed for diagnostic confirmation, whereby stepwise increases to maximal pump speeds fail to elicit complementary augmentation in pump flow [31]. While variable success with thrombolytic therapy has been reported [32,33], definitive treatment usually entails operative pump exchange [30,34].
Infection VAD-related infections remain among the most frequently encountered adverse events. The ISHLT Infectious Diseases Working Group defined three categories of infections occurring in VAD patients [35]: (1) device-specific, which includes the pump, cannulae, pocket, or driveline; (2) device-related, such as infective endocarditis, bacteremia, and mediastinitis; and (3) non-device-related. The transition to continuous-flow second-generation pumps has substantially diminished the rate of VAD-specific infections by nearly 50% (0.90–0.48 events per patient-year) [11]. However, the continuing presence and/ or requirement for a percutaneous driveline poses constant
risk to bacterial colonization and infection. Meticulous care of the driveline site is essential, with care to avoid any trauma that could disrupt the biologic seal.
Future directions Until now, VAD therapy has been primarily reserved for patients at an advanced stage of heart failure, with some level of inotrope dependency. Success in the modern era of VAD technology has prompted many to wonder whether less critically ill patients may also derive clinical benefit from durable mechanical circulatory support. This lingering debate will hopefully be addressed by the ongoing Randomized Evaluation of VAD InterVention before Inotropic Therapy (REVIVE-IT) trial [36]. This prospective, randomized trial will compare 2-year outcomes between HeartMate II patients and an optimal medical management control group that consists of non-inotrope dependent, ambulatory, moderately advanced heart failure patients ineligible for heart transplantation. Primary endpoints will include the composite outcome of survival, freedom from stroke, and improvement in Six-Minute Walk Test. Also on the horizon is the market release of the highly anticipated HeartMates III device, set to begin clinical trials
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this year (Fig. 6A) [37]. This miniaturized, centrifugal pump incorporates a bearingless magnetically levitated rotor, 10 L/min flow capability, a modular driveline, and a pulse mode to generate more physiologic flow dynamics. This latter refinement may drastically mitigate the stresses and other aberrations associated with continuous-flow pump mechanisms. A multicenter trial evaluating performance and safety of this device began enrolling patients in June 2014. The primary outcome measure will be survival, with secondary endpoints including the following: quality-of-life measures, Six-Minute Walk Test, device malfunctions, reoperations, stroke, and other adverse events. Eligible patients must exhibit some degree of inotrope dependency. A number of promising devices remain in the preclinical pipeline. The ultra-compact, versatile HeartMates X (Fig. 6B) delivers partial or full MCS (8 L/min) and can be configured for both univentricular and biventricular support (Fig. 6C). Early feasibility testing was recently completed for the HeartWare MVAD (Fig. 7), with a specially designed outflow cannula positioned across the aortic valve [38]. This feature enables minimally invasive, transapical implantation without the need for cardiopulmonary bypass. Efforts to develop a continuous-flow total artificial heart are also in progress and have shown success in preclinical studies (Fig. 8) [39]. Looking farther into the future, the Holy Grail of durable mechanical circulatory support technology would be a completely implantable, wireless system. Untethering patients from a driveline would be a major achievement and vastly improve VAD outcomes. To that end, the concept of FreeRange Resonant Electrical Energy Delivery (FREE-D) has surfaced as a viable approach to wirelessly power a LVAD [40]. Using an implanted physiologic controller coupled with a FREE-D receiver coil (Fig. 9A), investigators from the Bonde Artificial Heart Laboratory at Yale were able to wirelessly power an LVAD for 2 weeks [40]. To sustain this continuous
Fig. 7 – HeartWares miniature ventricular assist device currently in preclinical animal investigational studies. (Photo courtesy of HeartWare International, Inc., Framingham, MA.)
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Fig. 8 – Continuous-flow total artificial heart in preclinical investigational studies [39].
energy transfer, one might envision a future where transmitting power coils are preinstalled throughout a patient's home (Fig. 9B). It remains to be seen how long before these and other key milestones will be reached in the field of
Fig. 9 – (A) System controller coupled with free-range resonant electrical energy delivery (FREE-D) to wirelessly power and run a left ventricular assist device. (B) Graphical user on smartphone to enable wireless display and modulation of the left ventricular assist device [40]. (C) FREED system may entail preinstalled energy panels to wirelessly charge and power LVADs in the future. (Photo courtesy of Dr. Pramod Bonde, Yale University Medical Center.)
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mechanical circulatory support. What is certain is that many significant strides have already been made, and boundless potential exists for the care of patients with advanced heart failure.
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Baldwin JT, Mann DL. NHLBI's program for VAD therapy for moderately advanced heart failure: the REVIVE-IT pilot trial. J Card Fail 2010;16:855–8. Farrar DJ, Bourque K, Dague CP, Cotter CJ, Poirier VL. Design features, developmental status, and experimental results with the HeartMate III centrifugal left ventricular assist system with a magnetically levitated rotor. ASAIO J 2007;53:310–5. Tamez D, LaRose JA, Shambaugh C, Chorpenning K, Soucy KG, Sobieski MA, et al. Early feasibility testing and engineering development of the transapical approach for the HeartWare MVAD ventricular assist system. ASAIO J 2014;60:170–7. Fumoto H, Horvath DJ, Rao S, Massiello AL, Horai T, Takaseya T, et al. In vivo acute performance of the Cleveland Clinic self-regulating, continuous-flow total artificial heart. J Heart Lung Transplant 2010;29:21–6. Asgari SS, Bonde P. Implantable physiologic controller for left ventricular assist devices with telemetry capability. J Thorac Cardiovasc Surg 2014;147:192–202. Stevenson LW, Pagani FD, Young JB, Jessup M, Miller L, Kormos RL, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009; 28:535–41.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Ventricular assist devices: The future is now Brian Lima, MDa, Michael Mack, MDb, and Gonzalo V. Gonzalez-Stawinski, MDa,n a
Department of Cardiac Surgery, Baylor University Medical Center, Dallas, TX Department of Cardiac Surgery, The Heart Hospital, Baylor Plano, Plano, TX
b
abstract Heart failure has become a global epidemic. For advanced heart failure, a broad assortment of device options have been introduced for both acute and prolonged intervals of hemodynamic assistance. Durable implantable ventricular assist devices (VADs) in particular play a key role in the management of advanced heart failure. This review focuses specifically on the current outcomes with VAD therapy, highlights the results from pivotal clinical trials, and summarizes the various device options on the market and those in preclinical development. & 2015 Elsevier Inc. All rights reserved.
Introduction The incidence of advanced heart failure is growing exponentially worldwide. In the U.S. alone, an estimated 10 million people will be affected by 2030 [1,2]. With limitations in donor availability, cardiac transplantation alone cannot address this global epidemic. Concerted efforts in mechanical circulatory support have yielded a broad array of device options tailored for short term or extended periods of hemodynamic support. These various options play central roles in the treatment of advanced heart failure. One of the most impactful developments in this rapidly evolving field has been the advent of durable, implantable left ventricular assist devices (LVADs). More widespread adoption of this technology has resulted in a steady increase in LVAD implants from approximately 100 per year in 2006 to over 2500 in 2014, a 2500% increase in only 8 years [3] (Fig. 1). Strategies for LVAD implantation are largely predicated on candidacy for cardiac transplantation, and thus primarily intended as either a bridge to transplant or destination therapy for those deemed transplant ineligible. The fraction of patients implanted for destination therapy indications continues to increase, comprising over 40% of all cases [3]. Patients presenting in hemodynamic extremis are often
temporized with other forms of mechanical circulatory support, such as extracorporeal membrane oxygen (ECMO) or percutaneous (non-implantable) VADs, including the Impella (Abiomed, Danvers, MA) [4] and TandemHeart System (CardiacAssist, Inc., Pittsburgh, PA) [5]. These are bridge-todecision patients who may subsequently undergo more definitive therapy with implantable LVAD or transplantation. Some patients require short-term right ventricular mechanical circulatory support following an LVAD placement and likewise can be supported with these various modalities. Discussion of these numerous options for short-term mechanical circulatory support, their relative efficacy, and associated outcomes, is beyond the scope of this review. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, published in 2001, established the efficacy of LVADs in the management of advanced heart failure [6]. The focus of this review will be to delineate the important developments in the field that have transpired since this initial trial. These include modern iterations in LVAD design available in current clinical practice and those undergoing preclinical evaluation. Additionally, a thorough summary of device-related outcomes, complications, and ongoing trials will be presented. Also included in the analysis is an overview of strategies for
The authors have indicated there are no conflicts of interest. n Corresponding author. Department of Cardiac Surgery, Baylor University Medical Center, 3900 Junius Street, Suite 605, Dallas, TX 75246. Tel.: þ1 214 820 7100; fax: þ1 214 820 6863. E-mail address: [email protected] (G.V. Gonzalez-Stawinski). http://dx.doi.org/10.1016/j.tcm.2014.11.008 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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Fig. 1 – Summary of durable, implantable VAD implants in the INTERMACS registry by year of implant [3]. LVAD, left ventricular assist device; TAH, total artificial heart. biventricular support, such as total artificial heart implantation. The review concludes with a look to the future as continued scientific and engineering advances may continue to reshape the mechanical circulatory support paradigm.
Patient selection Integral to the process of proper patient and device selection for mechanical circulatory support is risk stratification derived from the clinical profile at initial presentation [7]. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), an NHLBI-sponsored database that tracks all long-term VAD implants and outcomes, has defined seven distinct clinical profiles based on degree of hemodynamic compromise and inotrope dependency [3,8] (Table). Within this classification schema, higher INTERMACS level correlates favorably with improved survival following LVAD implant. Therefore, in patients at the low end of the INTERMACS spectrum, namely the level 1 patients in profound cardiogenic shock, the prognosis is grave. These findings were recapitulated in the most recent INTERMACS annual report, which cataloged outcomes in over 10,000 patients implanted with durable LVADs [3]. Specifically, INTERMACS levels 1 and 2 exhibited statistically significant early hazard ratios for mortality. Other important hazards identified included the following: advanced age, preoperative renal failure or indices of right ventricular dysfunction, perioperative RVAD placement, prior cardiac surgery, and concomitant cardiac procedures at the time of LVAD implantation [3]. Awareness of these reproducible risk factors has prompted a shift away from durable LVAD implantation in INTERMACS 1 profiles, or other critically ill patients, where optimization with a temporary MCS platform may be more clinically prudent [7]. On many occasions, ventricular unloading and medical optimization of these high-risk patients may
enable favorable outcomes with a subsequent LVAD procedure. Fastidious adherence to the guiding principles governing patient selection has resulted in improved survival following LVAD implantation [3,7]. Growing experience with the implantation procedure, prophylactic measures for right ventricular protection, and preoperative optimization of hemodynamics has also contributed to improved outcomes.
Durable implantable VADs HeartMates II LVAD To date, the HeartMate (HM) II LVAD has been implanted in over 15,000 patients worldwide (Fig. 2A). Following favorable outcomes of a nonrandomized trial of bridge-to-transplant patients [9], it became FDA-approved for bridge to transplant in 2008. It is the most commonly implanted secondgeneration LVAD, employing a continuous-flow rotary pump mechanism and capable of generating up to 10 L/min of flow. Its predecessor, the HM XVE, was among the first-generation LVADs that function via pulsatile volume displacement pumps. Despite their highly touted clinical success relative to conventional medical therapy in the REMATCH trial, these pulsatile devices were prone to infection, thromboembolism, and mechanical failures [6]. In order to overcome these limitations, the HM II was designed as a valveless axial flow pump, with a single moving part, the rotor (Fig. 2B). With fewer moving parts, and the elimination of a reservoir chamber, the device is significantly smaller, more durable, and easier to implant than the XVE. Specifically, with a weight of only 290 g, and dimensions of 7.0 cm (length) by 4.0 cm (width), the HM II is approximately 75% lighter and 85% smaller than its pulsatile predecessor [10]. In the REMATCH II trial of destination therapy patients, HM II decisively outperformed the XVE and firmly solidified its role
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Table – INTERMACS risk stratification [41]. Profile no.
Profile description
Time to MCS
1. Critical cardiogenic shock 2. Progressive decline
Persistent shock despite high-dose inotropes and IABP Stable hemodynamics on inotropic support but worsening end-organ (renal) function Stable but inotrope dependent
Within hours Within days
3. Stable but inotrope dependent 4. Recurrent advanced heart failure 5. Exertion intolerant 6. Exertion limited 7. Advanced NYHA III
Weaning inotropes but frequent relapses Comfortable at rest Comfortable with mild activity Comfortable with reasonable level of activity
Within weeks to months Within weeks to months Variable urgency Variable urgency Not indicated
INTERMACS, Interagency Registry for Mechanical Circulatory Support (MCS); IABP, intra-aortic balloon pump; NYHA, New York Heart Association.
in the management of advanced heart failure [11]. Shortly thereafter it became FDA-approved for destination therapy in 2010. The various device and power source components of the HM II system have been previously described in great detail [10]. Briefly, blood is continuously drained from the LV chamber via the apical inflow cannula and propelled through the pump housing where a magnetic field generated by the rotary pump transmits blood flow to the body via the outflow graft anastamosed to the ascending aorta (Fig. 2). A percutaneously tunneled driveline connects the external power source, or system controller, to the pump motor. The system controller has both manual and fixed settings that modulate pump speed, provide hazard alarms, and log any device malfunctions for future analysis. This device can deliver between 3 and 10 L/min of flow at pump speeds of 6000– 15,000 rpm. The batteries used to power the device may last up to 12 h before needing to be recharged.
HeartWares HVAD The HeartWares HVAD (Framingham, MA) is a centrifugal, continuous-flow, implantable rotary pump currently in clinical practice (Fig. 3). This “third-generation” VAD operates via a hydro-magnetically levitated rotor without mechanical bearings and can deliver up to 10 L/min of flow (Fig. 3C). Elimination of the contact bearings imparts a number of clinically relevant structural, and theoretical advantages relative to the HM II [12]. First, by affording further miniaturization, this 140-g pump can be implanted within the pericardial space, thus simplifying operative placement by eliminating the need for creating a pump pocket. This miniature size also makes the device more conducive to minimally invasive implantation techniques [13]. The absence of mechanical contact points within the pump eliminates friction and heat generation, which also portends improved device durability. Generally, the pump is set at a range of
Fig. 2 – (A) Components of the HeartMates II left ventricular assist device system, including the pump, driveline, system controller, and batteries. LVAD, left ventricular assist device; LVAS, left ventricular assist system. (B) HeartMates II axial flow pump design with internal rotor system. (Photo courtesy of Thoratec Corporation, Pleasanton, CA.)
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Fig. 3 – (A and B) HeartWares HVAD system and (C) internal view of centrifugal pump design. (Photo courtesy of HeartWare, Inc., Framingham, MA.)
2400–3200 rpm to deliver flow rates between 3 and 8 L/min. The batteries that power the device can deliver 4–6 h of support when fully charged. In a European multicenter prospective trial, the HVAD proved effective in bridge-to-transplant patients, improving both quality of life and neurocognitive function [14]. Subsequently, results from the ADVANCE trial were published, a U.S. nonrandomized multicenter noninferiority study of 140 bridge-to-transplant patients supported with HVAD. These patients were compared with 499 contemporaneous bridgeto-transplant patients (mostly HM II) in the INTERMACS registry [15]. With established noninferiority to other commercially available devices, the HVAD became FDA-approved for bridge to transplant in 2012. A more recent study examined 332 patients in the pivotal bridge-to-transplant and
continued access protocols trial. Survival at 6 months and 1 year was 91% and 84%, respectively, with a low adverse event rate and significant improvement in quality-of-life scores [16]. Currently underway is the prospective, randomized, multicenter noninferiority trial, the Evaluate the HeartWare Ventricular Assist system (VAS) for Destination Therapy for Advanced Heart failure (ENDURANCE), comparing the HVAD to HM II for destination therapy. The trial completed enrollment in May 2012 and was designed to include 450 patients at 50 U.S. centers. Results are forthcoming.
Total artificial heart For a subset of patients with heart failure, left ventricular support alone will not suffice, and some modality of
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Fig. 4 – (A) SynCardia total artificial heart and (B) biventricular support using two HeartWares HVADs [20]. biventricular assistance must be instituted [17]. From a device perspective, options for durable, implantable biventricular support remain limited. The most extensive clinical experience has been acquired using the SynCardia CardioWest total artificial heart (SynCardia Systems, Inc., Tucson, AZ). Approved by the FDA for bridge to transplantation in 2007, the SynCardia total artificial heart is a pneumatically driven, pulsatile pump, designed to orthotopically replace the native ventricles and all four valves (Fig. 4A). Surgically, this entails bilateral ventriculectomy and fashioning atrial cuffs that are anastamosed to rigid, spherical polyurethane chambers that serve as ventricles. Each chamber houses two Medtronic Hall (Medtronic, Minneapolis, MN) 27-mm inflow and 25-mm outflow mechanical valves. Two subcutaneously tunneled drivelines are connected to pneumatic drivers within the external console. Once implanted, total output from the total artificial heart is 7–8 L/min. Certain body size criteria must be met to accommodate the device, including a minimal body surface area of 1.7 m2 and a thoracic diameter of at least 10 cm [18]. In the seminal report by Copeland et al. [19] in 2004, the total artificial heart successfully bridged 79% patients to heart transplant compared to 46% in the control group. In this
prospective multicenter study of 130 patients between 1993 and 2002, survival following transplantation in the total artificial heart group was 86% and 65% at 1 and 5 years, respectively, on par with international registry benchmarks. However, this initial enthusiasm must be tempered with the reality that only about 30 total artificial heart devices are implanted yearly in the U.S., a very minor fraction of the total number of durable VADs implanted [3] (Fig. 1). Given this limited experience, the steep learning curve for this technically demanding operation, and the known inherent limitations to pulsatile pump designs, alternatives to biventricular support have been explored and implemented. A notable example is the off-label use of two HeartWares HVADs in a biventricular support configuration (Fig. 4B) [20]. While limited to published case reports and small series, proof of principle in these isolated patient experiences will likely spurn further efforts to optimize biventricular support modalities. At present, the authors favor using the total artificial heart in transplant eligible patients with established biventricular failure refractory to optimal medical management. This would include patients presenting at INTERMACS levels 2 through 4, with a low likelihood of right ventricular recovery
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following unloading of the left ventricle alone with an LVAD. Recently, the FDA has approved a Humanitarian Use Designation for the total artificial heart, and investigational trials for this indication are planned for the near future.
Outcomes Survival and quality of life Laudable strides in device-related outcomes have been accomplished since the REMATCH era of pulsatile pumps. Actuarial survival at 1 and 2 years following continuous-flow LVAD implantation (n ¼ 9112) has reached 80% and 70%, respectively (Fig. 5), which is roughly akin to that of cardiac transplantation [3]. Included in this cohort are destination therapy patients with 1-year survival exceeding 75%, a noteworthy feat given these are often older patients with multiple medical comorbidities. One-year survival for total artificial heart (n ¼ 239) approaches 60%, matched by mounting experience with continuous-flow biventricular assist device implants (n ¼ 260). Additionally, metrics for quality of life have been documented, consistent improvement after VAD implantation that is sustained out to 24 months [3]. These metrics include the EQ-5D Visual Analog Scale, as well as the “self-care” and “usual activities” dimensions. More specifically, this translates to a drastic reduction in patients reporting “severe problems” with self-care, from approximately 50% pre-implant to well below 5% at 3 months after implantation [21]. The improvement is more striking with “severe problems” in usual activities of daily living, decreasing from over 80% to approximately 5% following VAD. However, about 20– 40% of patients continue to report some problems in these aforementioned categories following implantation. Therefore, the majority of patients that survive to hospital discharge following VAD implantation do require some degree of intermittent assistance at home but can achieve a modicum of independent living.
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Hemorrhage All patients receiving implantable VADs are maintained on systemic anticoagulation with Coumadin. The targeted INR range is 2–2.5. The nonphysiologic flow dynamics of newergeneration continuous-flow pumps incites high shear stress that promotes von Willebrand factor (vWF) proteolytic degradation [22]. In addition to this acquired vWF deficiency, these patients exhibit a proclivity for arteriovenous malformations along the gastrointestinal tract, the mechanism of which remains poorly understood [23]. Not surprisingly, this coagulopathic milieu renders these patients quite susceptible to hemorrhagic complications [24–26]. Specifically, some studies have reported clinically significant bleeding from the gastrointestinal tract in approximately 30% patients with continuous-flow LVADs [23–26]. In a recent study of 956 discharged HeartMate II bridge-to-transplant patients, the observed bleeding rate was 0.67 events per patient-year, with 45% of these events attributable to gastrointestinal bleeding [24]. Another recent study identified a greater proclivity for gastrointestinal bleeding following implantation of the HVAD compared to the HeartMate II device, in appropriately matched patients [25]. These complications represent challenging clinical scenarios, often precipitating multiple hospital readmissions [27] and necessitating hazardous reversal of anticoagulation and blood product transfusions. Effective management of the culprit arteriovenous malformation lesions may require gastroenterology intervention and on some occasions, complete cessation of anticoagulation going forward.
Thrombosis In some VAD patients, the coagulation pendulum swings in the opposite direction, and problematic thromboembolic complications ensue. Pump thrombosis in particular, which can and does occur, is among the common manifestations of this grouping of adverse events [21,28,29]. Modern series have
Fig. 5 – Actuarial survival for primary implantation of durable implantable ventricular assist devices, stratified by device type [3]. CF, continuous-flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, total artificial heart.
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Fig. 6 – (A) Thoratec HeartMates III left ventricular assist device [37] that features fully magnetically levitated rotor that can generate an artificial pulse. (B) HeartMates X miniaturized pump that can be implanted in multiple configurations (C) to accommodate biventricular support. (Photo courtesy of Thoratec Corporation, Pleasanton, CA.) reported pump thrombosis rates as high as 8% for both the HM II [29] and the HVAD [28]. This dreaded complication is usually heralded by power spikes noted on the system controller, as well as marked elevation in serum levels of lactate dehydrogenase and plasma free hemoglobin [30]. An echocardiographic ramp study is performed for diagnostic confirmation, whereby stepwise increases to maximal pump speeds fail to elicit complementary augmentation in pump flow [31]. While variable success with thrombolytic therapy has been reported [32,33], definitive treatment usually entails operative pump exchange [30,34].
Infection VAD-related infections remain among the most frequently encountered adverse events. The ISHLT Infectious Diseases Working Group defined three categories of infections occurring in VAD patients [35]: (1) device-specific, which includes the pump, cannulae, pocket, or driveline; (2) device-related, such as infective endocarditis, bacteremia, and mediastinitis; and (3) non-device-related. The transition to continuous-flow second-generation pumps has substantially diminished the rate of VAD-specific infections by nearly 50% (0.90–0.48 events per patient-year) [11]. However, the continuing presence and/ or requirement for a percutaneous driveline poses constant
risk to bacterial colonization and infection. Meticulous care of the driveline site is essential, with care to avoid any trauma that could disrupt the biologic seal.
Future directions Until now, VAD therapy has been primarily reserved for patients at an advanced stage of heart failure, with some level of inotrope dependency. Success in the modern era of VAD technology has prompted many to wonder whether less critically ill patients may also derive clinical benefit from durable mechanical circulatory support. This lingering debate will hopefully be addressed by the ongoing Randomized Evaluation of VAD InterVention before Inotropic Therapy (REVIVE-IT) trial [36]. This prospective, randomized trial will compare 2-year outcomes between HeartMate II patients and an optimal medical management control group that consists of non-inotrope dependent, ambulatory, moderately advanced heart failure patients ineligible for heart transplantation. Primary endpoints will include the composite outcome of survival, freedom from stroke, and improvement in Six-Minute Walk Test. Also on the horizon is the market release of the highly anticipated HeartMates III device, set to begin clinical trials
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this year (Fig. 6A) [37]. This miniaturized, centrifugal pump incorporates a bearingless magnetically levitated rotor, 10 L/min flow capability, a modular driveline, and a pulse mode to generate more physiologic flow dynamics. This latter refinement may drastically mitigate the stresses and other aberrations associated with continuous-flow pump mechanisms. A multicenter trial evaluating performance and safety of this device began enrolling patients in June 2014. The primary outcome measure will be survival, with secondary endpoints including the following: quality-of-life measures, Six-Minute Walk Test, device malfunctions, reoperations, stroke, and other adverse events. Eligible patients must exhibit some degree of inotrope dependency. A number of promising devices remain in the preclinical pipeline. The ultra-compact, versatile HeartMates X (Fig. 6B) delivers partial or full MCS (8 L/min) and can be configured for both univentricular and biventricular support (Fig. 6C). Early feasibility testing was recently completed for the HeartWare MVAD (Fig. 7), with a specially designed outflow cannula positioned across the aortic valve [38]. This feature enables minimally invasive, transapical implantation without the need for cardiopulmonary bypass. Efforts to develop a continuous-flow total artificial heart are also in progress and have shown success in preclinical studies (Fig. 8) [39]. Looking farther into the future, the Holy Grail of durable mechanical circulatory support technology would be a completely implantable, wireless system. Untethering patients from a driveline would be a major achievement and vastly improve VAD outcomes. To that end, the concept of FreeRange Resonant Electrical Energy Delivery (FREE-D) has surfaced as a viable approach to wirelessly power a LVAD [40]. Using an implanted physiologic controller coupled with a FREE-D receiver coil (Fig. 9A), investigators from the Bonde Artificial Heart Laboratory at Yale were able to wirelessly power an LVAD for 2 weeks [40]. To sustain this continuous
Fig. 7 – HeartWares miniature ventricular assist device currently in preclinical animal investigational studies. (Photo courtesy of HeartWare International, Inc., Framingham, MA.)
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Fig. 8 – Continuous-flow total artificial heart in preclinical investigational studies [39].
energy transfer, one might envision a future where transmitting power coils are preinstalled throughout a patient's home (Fig. 9B). It remains to be seen how long before these and other key milestones will be reached in the field of
Fig. 9 – (A) System controller coupled with free-range resonant electrical energy delivery (FREE-D) to wirelessly power and run a left ventricular assist device. (B) Graphical user on smartphone to enable wireless display and modulation of the left ventricular assist device [40]. (C) FREED system may entail preinstalled energy panels to wirelessly charge and power LVADs in the future. (Photo courtesy of Dr. Pramod Bonde, Yale University Medical Center.)
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mechanical circulatory support. What is certain is that many significant strides have already been made, and boundless potential exists for the care of patients with advanced heart failure.
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