**2. History**

#### **2.1. Early LVAD devices**

A timeline of advances in LVAD technology and in heart transplantation is included in **Figure 1**. In the early 1950s, open-heart surgery was associated with high mortality as a result of the frequent complication of postcardiotomy shock, a problem for which there was little answer at the time. In order to combat this problem, cardiopulmonary bypass as a means of bridging to recovery became a major experimental target. Initial clinical use of a cardiopulmonary bypass system for temporary circulatory support may be attributed to the work of Gibbon in 1953. This work into circulatory support would pave the way for future innovation in development of intracorporeal left ventricular assist devices.

**Figure 1.** Timeline of advances in mechanical cardiac support and heart transplantation.

In 1964, the National Heart, Lung, and Blood Institute established the Artificial Heart Program with the express goal of developing therapies that would allow for the bridging of patients with postcardiotomy shock to recovery. Liotta and Crawford at the Texas Heart Institute are identified as performing the first LVAD implantation in 1963. The index patient was successfully weaned from the device from a cardiopulmonary standpoint; however, he ultimately succumbed to neurologic complications. Further modifications by Liotta and DeBakey led to first use of a paracorporeal LVAD for bridge to recovery after double valve replacement in a 37-year old female patient in 1966. After 10 days of support, the patient recovered and the LVAD was explanted without complication; the patient ultimately survived another 6 years prior to death due to a motor vehicle accident.

suitable candidates, heart transplantation is the gold standard therapy for this disease, providing the best opportunity for long-term survival and improved quality of life. However, organs that are suitable for transplantation are a scarce resource. This approach is limited for many years by availability of donor hearts as only approximately 2300 orthotopic heart transplants are performed each year; the pool of patients who are candidates for heart transplantation continues to increase, with no evidence that this trend will reverse any time soon. As a result, the management of end-stage heart failure with cardiac transplantation must increasingly rely on an armamentarium of medical and mechanical tools for bridging patients to transplant.

In particular, the introduction of the left ventricular assist devices (LVAD) has become instrumental in the management of the heart failure patient who is refractory to medical therapy; in their current iteration their use has been associated with a decrease in mortality and an improvement in the quality of life among suitable patients awaiting transplantation. In this review, we will discuss a brief history of the LVAD as it relates to heart transplantation, in particular the evolution of available devices, and the current indications for use. It bears highlighting that LVAD implantation is associated with significant device-related complications and these are described in detail. Lastly, we will discuss several topics of current controversy and areas of evolution within the field of mechanical device support of the heart transplant candidate.

A timeline of advances in LVAD technology and in heart transplantation is included in **Figure 1**. In the early 1950s, open-heart surgery was associated with high mortality as a result of the frequent complication of postcardiotomy shock, a problem for which there was little answer at the time. In order to combat this problem, cardiopulmonary bypass as a means of bridging to recovery became a major experimental target. Initial clinical use of a cardiopulmonary bypass system for temporary circulatory support may be attributed to the work of Gibbon in 1953. This work into circulatory support would pave the way for future innovation in development

**2. History**

46 Heart Transplantation

**2.1. Early LVAD devices**

of intracorporeal left ventricular assist devices.

**Figure 1.** Timeline of advances in mechanical cardiac support and heart transplantation.

Concurrent with these initial models for mechanical circulatory support for bridge to recovery, the innovative concept of orthotopic heart transplant was also undergoing experimentation. This therapy was first demonstrated in animal models by Lower and Shumway in 1966, and subsequently the first human-to-human heart transplant performed by Barnard in 1967. With the advent of this new therapy, an alternative use for the LVAD besides bridge to recovery was identified. In 1969, Cooley implanted the first temporary total artificial heart into a patient as a bridge to cardiac donor availability for heart transplantation; his patient survived with total artificial heart support for over two and a half days prior to transplantation but died in the early postoperative period due to pneumonia. Mechanical complications associated with the total artificial heart led to a greater focus on the LVAD as preferred mechanical support after open heart surgery; in 1975 the first clinical trials of LVADs as temporary support after open-heart surgery were initiated, and in 1978, the first LVAD as bridge to transplant was used by Dr. Frazier.

Advances in technology and better understanding of cardiac flow dynamics have contributed to the evolution of the rapid VAD as a mechanical device. Early VADs made use of implanted pneumatic pump-driven volume displacement technology to drive forward flow. These first generation LVADs, mimic the function of the heart. The first generation of volume displacement pumps had multiple complex moving parts, with one-way valves and a flexible pumping chamber. Because of this, the devices were susceptible to breakdown and failure, among other complications.

The Pierce-Donachy VAD was a displacement device that was developed at Penn State University in 1970; it would serve as the prototype for Thoratec pulsatile-low VADs utilizing a pusher-plate system which could be implanted either paracorporeally (Thoratec pVAD) or intracorporeally (iVAD). This membrane-displacement technology was also used in the development of the 1978 Model 7 LVAD, later modified to the Heartmate implantable pneumatic and first used in clinical trials in 1986 [2]. A further evolution would lead to a variation known as the HeartMate VE (vented electric), and subsequently the HeartMate XVE (extended vented electric). By 1990, the FDA had given approval of LVAD as a bridge to heart transplant therapy, and a 1999 single-institution retrospective review of the use of the HeartMate XVE in bridge to transplant identified 75% of candidates as undergoing successful transplantation after a mean LVAD use of 106 days [3].

The success of LVAD as a bridge to led to clinical trials exploring the use of the LVAD as durable therapy. Perhaps the most well-known of the major clinical trial assessing the functionality of a LVADs for long-term use was the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial of 2001 [4]. Here, patients with end-stage heart failure who were not candidates for heart transplantation underwent either LVAD implantation using the HeartMate VE or received maximal medical therapy; these two groups were compared for long-term complication and mortality outcomes. In this landmark study, survival among the VAD placement group was found to be 52% compared to 25% in the medical management group at 1 year, with a further 48% relative risk reduction in mortality over the 2-year study period. Additionally, the LVAD cohort was also highlighted as having improved quality of life.

endpoint of stroke, reoperation, or mortality-free VAD use of 46% in the continuous flow cohort compared to 11% in the pulsatile flow cohort [5]. Further multi-center reporting of adverse events between the two groups also demonstrated a statistically significant reduction in infection, neurologic dysfunction, renal and respiratory dysfunction, and need for device replacement resulting from mechanical failure among those patients with continuous-flow LVADs. The third generation of LVADs relies on centrifugal continuous flow. The key technological advancement in the third generation LVAD is the implementation of noncontact bearings, which utilize magnetic levitation and decrease the incidence of thrombosis due to the lack of contact. In recent years, much of the data regarding the comparative effectiveness of LVADS stems from the Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS) organization, which serves as a multi-center registry data registry. From this, we identify >20,000 patients that have been implanted with an LVAD nationwide [8]. A 2011 multicenter trial by Strueber et al. [9] identified survival rates during support in patients bridged to transplant at being 84 and 79% at 1 and 2 years post-transplant, respectively. The ADVANCE multicenter clinical trial identified greater than 86% survival at 1 year among those patients using a third generation VAD, with improved functional capacity, quality of life, and a decreased complication profile. Under a continued access protocol of the latter study, the use of third generation VADs as a bridge to transplant continues to demonstrate a high preoperative survival rate despite a low rate of transplant. Although frequent hospitalizations due to device-related issues and other complications are noted, rates of adverse event rates are similar to or improved from those observed in historical bridge-to-transplant trials,

Heart Transplantation in the Era of the Left Ventricular Assist Devices

http://dx.doi.org/10.5772/intechopen.76935

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despite longer exposure times due to longer survival and lower transplant rates.

complication freedom compared to 55% of HeartMate II users at 1 year [11].

**3. Indications for LVAD bridge-to-transplant**

**3.1. Current outcomes**

Recent advances include the approval of the HeartMate III as a bridge to transplantation. This is an intrapericardial centrifugal-flow pump making use of pump rotor that is levitated and completely suspended by magnetic forces. This is designed to minimize shear stress, stasis, and platelet activation compared to earlier LVAD models. Its unique design allows for functioning in the absence of any friction or heat generation; furthermore, it holds the capacity for device-initiated pulsatility of flow. The burgeoning evidence from clinical trials have been encouraging; results of the Conformité Européene Mark study evaluating the HeartMate IIII demonstrated a mortality rate of 18% with low rates of embolic events and no cases of pump thrombosis [10] the concurrent MOMENTUM 3 trial further supports a significantly reduced rate of bleeding or thrombotic complications among HeartMate III users, with 69% achieving

While left ventricular assist devices are increasingly used in the role of bridge to transplant, conflicting data exists regarding outcomes compared to the patients who proceed directly to transplant. Outcomes are improving both as a result of greater use of the continuous flow device, and as a result of more sophisticated algorithms for dealing with LVAD complications. Currently, current survival to transplant and post-transplant outcomes appear to be

However, we highlight the REMATCH study here primarily because it also identified a number of serious complications and limitations related to the use of LVAD support as durable therapy. The pulsatile flow HeartMate VE first-generation LVAD used in this study was found to have a rate of serious complications 2.35 times greater than in medical therapy group. Indeed, this group carried a relative risk of stroke 4.35 times that of the medical group. Intraperitoneal placement of the large LVAD device was associated with early satiety, and the extensive surgical dissection required for implantation was associated with a significant bleeding and infection risk. Over 21% of patients ultimately required device replacement. As a result, and primarily due to the long-term risk of infection and mechanical failure, the-year survival in the LVAD group was limited to 23% [4].

#### **2.2. The modern era of LVAD**

Continuous-flow devices making use of either an axial flow model (second-generation LVADs) or a centrifugal flow model (third-generation) were the next innovation in LVAD performance. The second generation has key mechanical advantages compared prior, including elimination of valves and chambers and the introduction of an internal rotor suspended by contact bearings. These alterations were theorized to lead to a decreased rate of complications, due in part to their fewer moving parts. However, analysis of outcomes has also shown that the direct contact between the bearings and blood in second generation LVADs serves as an area of thrombosis formation.

The second generation of LVADs were implemented into clinical practice in the late 1990's and demonstrated an acceptable safety profile for bridge to transplant when compared to existing pulsatile-flow devices despite the aforementioned higher-than-expected incidence of pump thrombosis. Approval of these later-generation LVAD's was primarily derived from three landmark clinical trials either directly comparing the pulsatile HeartMate XVE with the continuous flow HeartMate II [5], or with the use of historical controls to compare their outcomes [6, 7]. The earliest of these studies was a prospective multicenter trial of 133 patients with end-stage heart failure who underwent VAD therapy as a bridge to transplant [6]. Among these participants, a total of 100 (75%) survived to the principal aggregate outcome of either heart transplant, cardiac recovery, or survival to the end of the study; of note, of those patients on persistent mechanical support through the study, there was a 1-year survival of 67%. There was no control group in this study, but survival was compared favorably with a historical control of 53% 1-year survival among patients using the pulsatile-flow HeartMate XVE as a bridge to transplant. A followup study identified further improvements in survival among those using these devices, with that improvement being attributed to increased device experience [7]. Another major study evaluating the morbidity benefit of continuous over pulsatile-flow VADS identified an 1-year endpoint of stroke, reoperation, or mortality-free VAD use of 46% in the continuous flow cohort compared to 11% in the pulsatile flow cohort [5]. Further multi-center reporting of adverse events between the two groups also demonstrated a statistically significant reduction in infection, neurologic dysfunction, renal and respiratory dysfunction, and need for device replacement resulting from mechanical failure among those patients with continuous-flow LVADs.

The third generation of LVADs relies on centrifugal continuous flow. The key technological advancement in the third generation LVAD is the implementation of noncontact bearings, which utilize magnetic levitation and decrease the incidence of thrombosis due to the lack of contact. In recent years, much of the data regarding the comparative effectiveness of LVADS stems from the Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS) organization, which serves as a multi-center registry data registry. From this, we identify >20,000 patients that have been implanted with an LVAD nationwide [8]. A 2011 multicenter trial by Strueber et al. [9] identified survival rates during support in patients bridged to transplant at being 84 and 79% at 1 and 2 years post-transplant, respectively. The ADVANCE multicenter clinical trial identified greater than 86% survival at 1 year among those patients using a third generation VAD, with improved functional capacity, quality of life, and a decreased complication profile. Under a continued access protocol of the latter study, the use of third generation VADs as a bridge to transplant continues to demonstrate a high preoperative survival rate despite a low rate of transplant. Although frequent hospitalizations due to device-related issues and other complications are noted, rates of adverse event rates are similar to or improved from those observed in historical bridge-to-transplant trials, despite longer exposure times due to longer survival and lower transplant rates.

Recent advances include the approval of the HeartMate III as a bridge to transplantation. This is an intrapericardial centrifugal-flow pump making use of pump rotor that is levitated and completely suspended by magnetic forces. This is designed to minimize shear stress, stasis, and platelet activation compared to earlier LVAD models. Its unique design allows for functioning in the absence of any friction or heat generation; furthermore, it holds the capacity for device-initiated pulsatility of flow. The burgeoning evidence from clinical trials have been encouraging; results of the Conformité Européene Mark study evaluating the HeartMate IIII demonstrated a mortality rate of 18% with low rates of embolic events and no cases of pump thrombosis [10] the concurrent MOMENTUM 3 trial further supports a significantly reduced rate of bleeding or thrombotic complications among HeartMate III users, with 69% achieving complication freedom compared to 55% of HeartMate II users at 1 year [11].
