Clinical Trial Results in Mechanical Circulatory Support

Disclosure

Dr. Russell is a consultant for Medtronic and serves on the Data and Safety Monitoring Board for the HeartMate 3 trial sponsored by Abbott. Dr. Teuteberg has industry relationships with Medtronic (advisory board, speaking), Abiomed (advisory board), CareDx (advisory board, speaking), Abbott (HeartMate 3 Clinical Events Committee), and EcoR1 (consulting).

Overview of clinical trials of mechanical circulatory support devices

Clinical trials of mechanical circulatory support devices evolved from simple studies evaluating the efficacy of the device in a few patients to large-scale clinical trials with composite endpoints including quality of life, improvements in functional capacity, and freedom from major complications in addition to mortality. Mechanical circulatory support devices were first used clinically in 1963 when Dr. Michael DeBakey placed a device in the left thorax, connected to the left atrium and the descending thoracic aorta, and used for a patient who had a cardiac arrest 18 hours after an aortic valve replacement. The patient had clinical improvement in pulmonary edema and neurologic function, but unfortunately, he remained anuric and died 4 days later despite the continued function of the ventricular system device. In 1975, based on case reports of similar patients, two short-term trials were initiated for patients who could not be weaned from cardiopulmonary bypass. The trials were performed with a pneumatically powered single-chamber pump that could be placed either intraabdominally or extracorporeally. One of these case series included a 21-year-old man who successfully underwent heart transplantation after 6 days of support, which encouraged the field to move forward.

In 1976, the US Congress passed the Medical Device Amendments Act, which gave the US Food and Drug Administration (FDA) the authority to preapprove the use of medical devices in the United States. The FDA’s influence on clinical testing of these devices began to shape the early patient populations studied in clinical trials and the endpoints being evaluated. In 1977, the National Heart, Lung, and Blood Institute requested grant applications for the development of mechanical, electrically powered blood pumps. A second application request was issued in 1980 for long-term (2 years) left ventricular assist devices (LVADs). This support resulted in the development of the Novacor LVAD and the Thoratec LVAD, which eventually became the HeartMate XVE. Because of FDA concerns about the durability of these devices, initial clinical trials could enroll only patients who were eligible for cardiac transplantation. As devices demonstrated the ability to provide long-term support, the patient populations studied expanded to include non–transplant eligible patients. These early clinical trial populations were the source of the current indications for mechanical support: bridge to recovery, bridge to transplantation (BTT), and destination therapy (DT).

Since the mid-1980s, there have been changes in pump design from paracorporeal pumps to intracorporeal configurations and from pulsatile to continuous-flow designs. In this chapter, we review the major clinical trials that have been performed that have propelled the field forward for both BTT and DT.

Pulsatile flow

The first successful use of an LVAD as a BTT was reported by Hill in 1986 describing the use of the pneumatically actuated Thoratec Pierce-Donachy paracorporeal ventricular assist device (PVAD) ( Fig. 15.1 ) in a patient after a large myocardial infarction with cardiogenic shock. This was soon followed by a large series of patients successfully bridged to cardiac transplant in 1988. Twenty-nine patients underwent placement of either left or left and right (14 patients) ventricular assist devices in a paracorporeal position. Twenty-one of the patients survived to transplantation after a median of 3 days of support. For those who did not survive to transplantation, the two most common causes of death were multiorgan failure and bleeding. It should be emphasized that all 29 patients had severe cardiogenic shock preoperatively, requiring multiple vasopressors, an intraaortic balloon pump ( n = 25), and mechanical ventilation ( n = 21). Based on these early reports, LVADs were approved for BTT in 1995.

Fig. 15.1, (A) Thoratec paracorporeal ventricular assist device (PVAD) is a paracorporeal, pneumatically actuated ventricular assist device designed for right-sided, left-sided, or biventricular support. (B) Thoratec PVAD in left ventricular assist (left) and biventricular assist configuration (right) .

Some of the drawbacks of the PVAD were its large size, need for the patient to remain hospitalized while supported, two large percutaneous cannulas, external pumping chamber, and patient discomfort. Given these limitations, an implantable version of the device was developed (Thoratec Implantable Ventricular Assist Device; Fig. 15.2 ). Between 2001 and 2004, 39 patients underwent implantation of this device as either BTT or for postcardiotomy failure. Twenty-four of the patients had the device as left ventricular support and 15 as biventricular support, for a mean duration of 101 days. Eighteen patients were discharged from the hospital with ongoing support for a mean duration of 96 days. No survival difference was observed between the BTT and the postcardiotomy groups, and 69% of the patients were either transplanted or weaned from the device. The adverse effects of the device were quite similar to the PVAD and included infection in 22 patients, bleeding in 18 patients, and neurologic events in 14 patients. The incidence of ischemic or hemorrhagic stroke was 7.7%, which was somewhat lower than the 12.0% in the PVAD population.

Fig. 15.2, Thoratec intracorporeal ventricular assist device (IVAD) (lower right) beside a Thoratec paracorporeal ventricular assist device (PVAD). The Thoratec IVAD is an implantable version of the Thoratec PVAD.

With these early successes, pump design moved to the development of long-term, left ventricular only support with intracorporeal devices. The pumps that came to clinical trial included the HeartMate IP1000 (Thoratec Corporation), HeartMate VE/XVE (Thoratec Corporation), and Novacor LVAD (World Heart Corporation).

HeartMate IP1000

In 1992, Frazier reported on 34 patients who received the HeartMate IP1000 ( Fig. 15.3 ) as BTT and compared them to six control patients who met the enrollment criteria but did not receive the device. Sixty-five percent of the patients receiving the device went on to transplantation, with a posttransplantation survival of 80%. This compared to a 50% survival to transplantation in the control arm, with no patients surviving posttransplantation. Complications of the device included bleeding in 39%, infection in 25%, and right heart failure in 21%. No thromboembolic events were reported, with the maximum time of support being 324 days. A larger study of 75 patients compared to 33 control patients was reported in 1994. The survival rate to transplantation with the device was 71% compared to 36% in the controls. The adverse event profile was similar to the prior trial, with the exception of three patients having a thromboembolic complication: two with strokes and one with an embolus to the subclavian artery, which was successfully removed. This trial required a preimplantation pulmonary capillary wedge pressure > 20 mm Hg with either a cardiac index < 2.0 L/min/m ² or a systolic blood pressure < 80 mm Hg. In spite of these promising early results, this pump was short lived due to the development of the HeartMate VE and XVE, which had a similar pump housing but were driven by a mechanical rotor rather than pneumatically. This development allowed patients to be discharged from the hospital and have greater mobility because the pump could be powered by two smaller wearable external batteries rather than a large pneumatic console.

HeartMate VE/XVE

The HeartMate VE/XVE ( Fig. 15.4 ) was studied in a prospective, multicenter trial of 280 transplant candidates who had poor hemodynamics despite being inotrope dependent. Forty-nine percent of the patients also required a balloon pump and had a mean pulmonary capillary wedge pressure of 27 mm Hg with a systolic blood pressure of 76 mm Hg and a cardiac index of 1.67 L/min/m ² . The outcomes were compared to a control group of 48 patients who had higher blood pressure and cardiac index. The average pump support was 112 days, with 54 patients supported for over 180 days. Adverse events included bleeding in 11%, infection in 40%, neurologic dysfunction in 5%, and thromboembolic events in 6%. Only 29% of the device-supported patients died before transplantation, compared to 67% of the controls. The other highlight of this trial was that 115 of the patients were discharged from the hospital after a median of 82 days, and 86% of those patients received a transplant. This was the first major study that demonstrated that patients could be supported and successfully discharged home to await cardiac transplantation and introduced the possibility of long-term mechanical support for patients who were not eligible for cardiac transplantation, so-called destination therapy (DT).

Fig. 15.4, Thoratec HeartMate XVE is an implantable, pulsatile, electrically actuated left ventricular assist device.

The first trial of DT was the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study, which used the Thoratec VE pump. This study was supported by the National Institutes of Health and was performed at 20 experienced transplant centers. Enrollment criteria included the presence of New York Heart Association (NYHA) functional class IV symptoms for at least 90 days despite optimal medical therapy, an ejection fraction (EF) < 25%, and a peak oxygen consumption of < 12 mL/kg/min or the need for continuous intravenous inotropic therapy due to symptomatic hypotension, decreasing renal function, or worsening pulmonary congestion. Due to slow enrollment, the criteria were later eased to include patients with 60 days of NYHA class IV symptoms and a peak oxygen consumption < 14 mL/kg/min or patients who were class III/IV for 28 days plus either 14 days of either intraaortic balloon or inotropic support with at least 2 failed weaning attempts. A total of 129 patients were enrolled and randomized to either placement of an LVAD or continued medical therapy. A statistically significant improvement in survival was noted with LVAD therapy at both 1 year (52% (vs.) 25%) and 2 years (23% (vs.) 8%) ( Fig. 15.5 ), and median survival was longer in the LVAD group, 408 days (vs.) 150 days with medical therapy. The LVAD group also had significant improvements in NYHA class and scored better on the physical-function and emotional-role subscales of the 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36) and the Beck Depression Inventory. The Minnesota Living With Heart Failure score improved in the LVAD arm but not significantly ( P = 0.11). As expected, patients in the LVAD arm had more complications, including sepsis, LVAD failure, and neurologic complications. However, the tradeoff was less mortality due to heart failure and an increase in days spent out of the hospital. This trial resulted in FDA approval of the HeartMate XVE for DT.

Fig. 15.5, Kaplan-Meier analysis of survival in the group that received left ventricular (LV) assist devices and the group that received optimal medical therapy in the REMATCH trial. Crosses depict censored patients. Enrollment in the trial was terminated after 92 patients had died; 95 deaths had occurred by the time of the final analysis.

Improved surgical technique and enhancement of the pump design resulted in improved outcomes. Long et al. reported on 42 patients who were supported for a mean of 232 days, with a 1-year survival rate of 61% and with lower rates of adverse events and death due to sepsis. Despite this, there was not widespread clinical adoption of DT for a variety of reasons, including a lack of long-term durability, requiring device replacement in over 50% of the patients by 2 years ( Fig. 15.6 ).

Fig. 15.6, Freedom from left ventricular assist device replacement. A product-limit estimate curve plotting the probability of being free of device replacement (vs.) time (days) on the HeartMate VE device. Patients were censored (circles) when they died or if, at the last date of follow-up, they had not undergone a device replacement.

Novacor

The other durable pulsatile pump that was developed and studied was the Novacor left ventricular assist system ( Fig. 15.7 ). Similar to the Thoratec device, it was initially used as bridge to transplant (BTT) in 1984 and was optimized over the years for improved outcomes. In contrast to the Thoratec device, it did not have a textured blood-contacting surface and instead used a smooth-surfaced polyurethane sac that required anticoagulation with warfarin. Registry data were published describing the outcomes in over 100 patients in a variety of US and European studies. For BTT patients, 77% of the patients were transplanted, with a mean of 80 days of support compared to 37% of the control patients. However, the stroke rate with the Novacor was higher than seen in the HeartMate XVE experience, although the device was more durable. During the 76-year cumulative support period, there were no pump failures, which set the scene for a DT trial.

The Investigation of Nontransplant-Eligible Patients who are Inotrope Dependent (INTrEPID) trial enrolled 55 patients to either the Novacor LVAD or medical therapy. All patients had to meet similar eligibility criteria to the HeartMate for enrollment, and the control group consisted of patients who chose not to undergo LVAD implantation, had a mechanical aortic valve, or did not have the financial resources to cover the cost of the device or follow-up. Enrollment criteria included inotrope-dependent patients with an EF < 25% and NYHA functional class IV symptoms for at least the last 3 months who were not candidates for transplant. Additionally, all patients had to have two unsuccessful weaning attempts from inotropes. The LVAD patients had improved survival at both 6 (46% (vs.) 22%) and 12 (27% (vs.) 11%) months. Unfortunately, 62% of the LVAD patients experienced a stroke or transient ischemic attack (TIA) compared to 11% of the medically managed patients.

There has been one randomized trial of the Novacor LVAD (vs.) HeartMate XVE. Forty BTT patients were randomized, and there were no significant differences in survival to transplantation. The mean duration of support was 235 ± 210 days for Novacor and 175 ± 175 days for the XVE. More neurologic complications occurred with the Novacor pump, and more infections and pump durability issues with the XVE. Survival to transplantation was 65% for Novacor and 60% for the XVE. Based on the high stroke rate with the Novacor device, further development was halted in 2007.

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