Development of mechanical circulatory support systems
The methods for providing mechanical circulatory support (MCS) have varied greatly. The evolution of MCS technology has been gradual, as the biological barriers to progress have remained constant and difficult. Clinicians and engineers have collaborated for many years to develop an array of devices that range from very small catheter-mounted devices to fully implantable total cardiac replacement systems ( Table 10.1 ). This variety of device types is necessary to support the vast and complex needs of a heart failure population. Although considerable progress has been made in recent years with medical technology and medical care, the future of heart failure treatment remains complex and dynamic. MCS is increasingly a key component of heart failure management.
| Device Name | Manufacturer | Type of Pump | Type of Support | Pump Position |
|---|---|---|---|---|
| HeartMate II | Abbott, Chicago, IL | Axial flow, mechanical bearing | LVAD | Preperitoneal pocket |
| HeartMate 3 | Abbott, Chicago, IL | Centrifugal flow, magnetic bearing | LVAD | Intrapericardial |
| HVAD | HeartWare Inc., Framingham, MA | Centrifugal flow; magnetic and hydrodynamic bearings | LVAD | Intrapericardial |
| Jarvik 2000 | Jarvik Heart Inc., New York, NY | Axial flow with blood-immersed bearings | LVAD | Left Ventricle |
| InCor | Berlin Heart, Berlin, Germany | Axial flow with blood-immersed bearings | LVAD | Preperitoneal pocket |
| Evaheart | Evaheart Inc., Houston, TX | Centrifugal flow; hydrodynamic bearing | LVAD | Preperitoneal pocket |
| Excor | Berlin Heart, Woodlands, TX | Pneumatic, pulsatile, diaphragm | BiVAD | Paracorporeal |
| Syncardia TAH | Syncardia Inc., Tucson, AZ | Pneumatic, pulsatile, diaphragm | Biventricular replacement | Intrapercardial |
Various types of blood pumps have evolved as the development of smaller, biocompatible, and durable devices continue. Fig. 10.1 provides a concise timeline of MCS technology development. The modern era of MCS began in the early 1950s when cardiopulmonary bypass was first used to support patients during open heart operations for the repair of congenital heart defects. As the field of cardiac surgery proliferated through the 1960s, it became apparent that there was a need for MCS beyond the operating room. Patients with cardiogenic shock needed temporary circulatory support to avoid organ failure and to allow time for recovery of myocardial function. Counterpulsation with the intraaortic balloon pump (IABP) was introduced in 1968 as a means to augment cardiac function by improving cardiac output and decreasing myocardial work. Since that time, the IABP has supported large numbers of patients with heart failure. During this early era, it was also realized that some form of long-term circulatory support was necessary to treat the expanding heart failure population. Cardiac replacement with heart transplantation or a total artificial heart (TAH) and temporary support with a left ventricular assist device (LVAD) were attempted in a small number of cases during the 1960s, but the dismal results led to a suspension of these treatments, and researchers continued developing MCS technologies.
Throughout the 1970s, researchers continued to work on developing artificial heart technology with the goal of providing near total circulatory support with an implantable device for durations of many years. Because of immunologic barriers, a heart transplant was not an effective therapy; thus, developers believed that MCS systems must replace cardiac function and closely mimic the function of the natural heart. Therefore, early devices were large and bulky but could provide up to 10 L/min of cardiac output with a stroke volume and pump rate in the normal physiologic range. Early in the 1980s, heart transplantation was renewed with the development of effective immunosuppressive therapy, and MCS technology had undergone over a decade of research and development. Under the direction and funding support from the National Heart Lung and Blood Institute, pulsatile blood pumps for use as a TAH or ventricular assist device (VAD) were developed for clinical evaluation. Clinical trials for bridge to transplant (BTT) and bridge to recovery (BTR) with LVADs were initiated as a consequence of the limitations of heart transplantation. At the same time, the TAH was implanted in a small number of patients as destination therapy (DT) and for BTT, with mixed results.
Axial flow blood pumps were first introduced in the late 1980s, with a catheter-mounted device that was inserted either percutaneously via the femoral artery or directly through an open chest to the left ventricle and across the aortic valve. Clinical studies demonstrated that continuous blood flow generated by a miniature pump was feasible and that there may be a broader application of this type of pump. The early concerns of excessive hemolysis from these small devices were eventually dispelled as clinical results indicated that this type of pump caused clinically tolerable damage to blood components. In the 1990s, implantable axial flow devices were developed due to the need for smaller and more reliable devices for long-term support. Having a single moving component and durable bearings, these devices have proven to provide long-term support with a low incidence of mechanical pump failure. The smaller size of these devices and their improved durability have contributed to a reduction in life-threatening complications and enhanced survival. Recent LVAD designs have centrifugal flow pumps that utilize magnetic and/or hydrodynamic bearings to eliminate friction and wear of the rotating impeller. This type of pump design is used in both short- and long-term MCS systems. With the miniaturization of the centrifugal and axial flow blood pumps and improved catheter designs, LVADs that are inserted percutaneously are now being used for first-line support of patients with cardiogenic shock.
The best treatment option for patients with end-stage heart failure has been heart transplantation. However, the shortage of donor organs has encouraged the continued development of MCS systems for long-term use. Furthermore, the persistent high mortality rate of cardiogenic shock requires that MCS devices be inserted rapidly and with minimal invasiveness. Since their invention in the 1950s, MCS with VADs and artificial hearts has matured substantially, with outcomes approaching that of a heart transplant.
Durable left ventricular assist devices
During the 1980s and 1990s, the efficacy of implantable pulsatile VADs as BTT, BTR, and DT was established in patients with severe acute and chronic heart failure. Also, in this era, although to a smaller degree, the TAH was used in some centers for BTT in patients with obvious biventricular failure when other treatment options were not suitable. The HeartMate IP-1000, VE, and XVE left ventricular assist system (LVAS) (Abbott Laboratories, formerly Thoratec Corp., Abbott Park, IL) and the Novacor LVAS (Baxter Healthcare Corporation, formerly Worldheart, Deerfield, IL) underwent clinical trials for BTT indication and received market approval based on improved survival. The HeartMate XVE was then studied for DT in the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial, where it was demonstrated that device therapy was superior to medical therapy with regard to survival; however, adverse event rates were high, leading to low adoption of this therapy. The Thoratec paracorporeal VAD (pVAD) system offered versatility for univentricular or biventricular support to a wide range of patient sizes due to positioning of the blood pumps on the anterior abdomen. All of these devices saved many lives; however, bleeding, infection, pump thrombosis, and device failure were complications that limited the overall effectiveness of the therapy. As the need for smaller and more durable devices became more apparent, manufacturers responded by developing continuous-flow pumps—the primary type of device used today. Examples and descriptions of these devices follow.
HeartMate II LVAS
The HeartMate II (Abbott Laboratories) LVAD is an implantable, axial flow LVAD that is intended for long-term support for BTT and DT in patients with chronic heart failure. When implanted, the pump resides in a preperitoneal pocket below the left hemidiaphragm, with the inflow cannula in the left ventricle and the outflow graft anastomosed to the ascending aorta ( Fig. 10.2 ). A percutaneous driveline from the pump exits the right upper quadrant of the abdomen. The system includes a controller, a power base unit, a system monitor, rechargeable batteries, and a battery clip. A microprocessor-based controller, worn by the patient, monitors and controls the pump’s function. The device can provide up to 10 L/min of cardiac output support with a speed operating range of 6000 to 15,000 rpm. The usual operating speed range is 8000 to 10,000 rpm. Power is provided by both AC and DC power sources, with wearable batteries for ambulatory operation. A system monitor is used to make changes in pump speed, collect data on device function, and display pump parameters in the acute care setting.
This implantable LVAD device has been the most widely used in recent years. Clinical trials for BTT and DT have demonstrated that the use of this device is safe and effective when used for these indications. The BTT clinical trial for the HeartMate II included 489 patients, with published results of the initial 133 patients, and an 18-month follow-up analysis was completed on 281 patients. The 1-year survival rate was 68% in the initial 133 patient cohort, increasing to 73% in the follow-up analysis that included a larger number of subjects ( n = 281). The HeartMate II DT trial was a 2:1 randomized comparison against the HeartMate XVE LVAD in 200 patients (HeartMate II, n = 134, and HeartMate XVE LVAD, n = 66). In this trial, the primary study endpoint was 2-year survival free of disabling stroke and reoperation for pump replacement. A significantly higher percentage of patients supported by the HeartMate II reached the primary endpoint as compared to the patients randomized to the HeartMate XVE LVAD. The actuarial 1- and 2-year survival rates of the HeartMate II were 68% and 58%, respectively and significantly, than the 1- and 2-year survival rates for the HeartMate XVE LVAD.
Postmarket studies for the BTT indication showed that the overall 1-year survival rate increased from 76% during the clinical trial to 85% in the postmarket study. This increase in survival rate was attributed to better patient selection and the timing of LVAD implant. Earlier use of the LVAD resulted in fewer adverse events during support. Similarly, for DT patients supported by the HeartMate II, postmarket 2-year survival rates increased to 62% compared to 58% during the trial. Again, the posttrial patients had fewer adverse events, most likely due to the better timing of implantation and improved patient management.
The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) maintains a database of patients implanted with durable MCS systems that have received market approval. In 2012, the registry reported that a subset of patients, most of whom were implanted with the HeartMate II for DT, had early 1- to 2-year survival rates compared to that of heart transplantation. The INTERMACS registry has also demonstrated that survival rates for patients with continuous-flow devices have continued to improve over time with recent 1- and 2-year survival rates of over 80% and 70%, respectively.
In addition to better survival rates for both BTT and DT indication, a number of postmarket clinical studies have demonstrated improved functional status and quality of life during support with the HeartMate II. The Risk Assessment and Comparative Effectiveness of LVAD and Medical Management in Ambulatory Heart Failure Patients (ROADMAP) was a prospective, multicenter, nonrandomized, controlled observational trial of 200 patients with advanced New York Heart Association (NYHA) class III–IIIB or ambulatory NYHA class IV symptoms who received treatment with either optimal medical management or a HeartMate II. The results of the ROADMAP study demonstrated that patients receiving the LVAD experienced higher rates of adverse events but had better functional status and 2-year survival rates as compared to patients maintained on optimal medical management. However, overall survival was similar in both groups when patients in the medical arm of the study that subsequently received an LVAD were included in the follow-up analysis.
With improved outcomes, the rate of implants with the HeartMate II has increased considerably since market approval. However, in 2011, an increased rate of pump thrombosis was reported by Starling and colleagues. These finding were corroborated in a subsequent national analysis through INTERMACS. Pump thrombosis has an important effect on morbidity and cost due to the need for exchange of the device and subsequent recovery from the operation. The increase in pump thrombosis was believed to be multifactorial, including changes in anticoagulation therapy and lower pump speed. Some studies indicated that a lower anticoagulation regimen than recommended in the pivotal clinical trials levels was safe; however, a widespread change in practice may have been detrimental, leading to a higher incidence of pump thrombosis. In addition, gastrointestinal bleeding became a prominent complication that was often treated with lower anticoagulation therapy. A set of pump thrombosis prevention guidelines was developed and then studied prospectively at 24 medical centers. These prevention guidelines included surgical implant techniques to maintain unobstructed blood flow paths, an anticoagulation protocol that increased coagulation parameters, and pump speeds greater than 9000 rpm. With strict adherence to these prevention guidelines, the rate of pump thrombosis decreased.
HeartMate 3 LVAS
The HeartMate 3 LVAS (Abbott Laboratories) is the most recent generation of HeartMate devices that is intended to support patients as BTT or for lifetime DT ( Fig. 10.3 ). This system was designed for enhanced hemocompatibility to reduce thrombosis and hemolysis. The centrifugal blood pump incorporates a fully magnetically levitated rotor with wide blood-flow gaps, which minimize shear forces on blood components, thereby possibly reducing damage to red blood cells and von Willebrand factor. The rotor is the single moving component that contains no mechanical bearings, thereby eliminating wear, friction, and heat generation within the pump, important for reduction of thrombogenicity. Less hemolysis is thought to minimize thrombosis within the pump and preserve von Willebrand factor, which may help to lower the incidence or severity of gastrointestinal bleeding during support. The blood contacting surfaces within the pump are textured to allow adhesion of circulating cells and the development of a nonthrombogenic tissue lining. The device can provide 2.5–10 L/min of cardiac output support with a speed operating range of 3000 to 9000 rpm. Importantly, the device can operate in an artificial-pulse mode, which enables the rotor to change speed every two seconds in order to generate a pulse wave.
The HeartMate 3 LVAS was first introduced in 2014 for short- or long-term support of patients with advanced stage heart failure. The Conformité Européene (CE) mark clinical study included 50 patients implanted with the HeartMate 3 at 10 centers in Australia, Austria, Canada, Czech Republic, Germany, and Kazakhstan. Study inclusion criteria included adult heart failure patients with an ejection fraction ≤ 25%, cardiac index < 2.2 L/min/m 2 while not taking inotropes, or inotrope-dependent status while on optimal medical management. This study did not use BTT or DT indications as criteria for inclusion. At the 6-month study endpoint, 92% of patients were alive, exceeding the 88% performance goal. Physical status and quality of life were improved for most patients, with 43 patients being discharged from the hospital. There were no instances of hemolysis, pump thrombosis, or device failure. The 1-year follow-up analysis demonstrated satisfactory survival with no new adverse events. These study data resulted in the device receiving the European Union’s certification mark.
The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial conducted in the United States was a randomized, controlled, noninferiority investigation comparing outcomes of the HeartMate 3 and HeartMate II. Candidates for this study were NYHA class III–IV patients who were receiving optimal medical therapy with a left ventricular ejection fraction < 25%, were inotrope dependent or had a cardiac index < 2.2 L/min/m 2 without inotropes, and were failing to respond to optimal medical therapy for 45 of the past 60 days, or had advanced heart failure for the prior 14 days with at least 7 days of IABP support. The study design is unique in that the endpoints do not distinguish between the separate indications of BTT, DT, or recovery. The primary study endpoint was a composite of survival to transplant, recovery, or a specified duration of LVAS support, free of debilitating stroke or reoperation to replace the pump.
In the short-term follow-up study, 86.2% of patients supported by the HeartMate 3 ( n = 151) met the primary endpoint of survival free of disabling stroke (Modified Rankin Scale [MRS] > 3) or reoperation to replace or remove the device at 6 months after implantation. The HeartMate 3 showed noninferiority to HeartMate II LVAS ( n = 138), as 76.8% of the HeartMate II LVAS patients met the primary endpoint. Survival at 6 months with the HeartMate 3 was 89% and was consistent with the results of the CE mark study.
The long-term follow-up study included 190 patients implanted with the HeartMate 3 and 176 with the HeartMate II. The composite primary endpoint was 2-year survival free of disabling stroke or survival free of reoperation to replace or remove a malfunctioning device. The primary endpoint was reached by 151 patients (79.5%) in the HeartMate 3 group as compared with 106 (60.2%) in the HeartMate II group. Reoperation for device malfunction occurred in three (1.6%) patients with the HeartMate 3 and 30 (17%) patients with the HeartMate II ( P = 0.001). The rate for suspected or confirmed pump thrombosis remained very low for the HeartMate 3 (1.1%) compared to the HeartMate II (15.7%), whereas the rates for all strokes and ischemic strokes were statistically lower for the HeartMate 3 group ( P = 0.002 and P = 0.003, respectively). The long-term follow-up analysis of this trial revealed that the HeartMate 3 was superior to the HeartMate II with regard to a composite primary endpoint of survival free of disabling stroke or reoperation to replace or remove a malfunctioning device.
Studies have demonstrated that the HeartMate 3 offers improved hemocompatibility over other devices. One small study showed that the HeartMate 3 preserves von Willebrand multimeres better than the HeartMate II does, a factor attributed to the high incidence of gastrointestinal bleeding with continuous-flow LVADs. However, in the clinical studies, the incidence of gastrointestinal bleeding has not been different between the HeartMate 3 and HeartMate II. In a substudy of the MOMENTUM trial, fewer hemocompatibility-related adverse events (i.e., thrombosis and stroke) were reported with the HeartMate 3, likely contributing to better outcomes.
The Food and Drug Administration (FDA) approved the premarket approval application for HeartMate 3 in 2017 to be used as a short-term hemodynamic support system, and approval for long-term support is pending.
HeartWare HVAD
The HeartWare Ventricular Assist Device (HVAD) (Medtronic, HeartWare Inc.) is a centrifugal flow pump that is implanted in the pericardial space at the apex or diaphragmatic surface of the left ventricle ( Fig. 10.4 ). A short integral inflow cannula and the small size of the pump allow for pericardial positioning and avoidance of a pump pocket. The HVAD can generate up to 10 L/min of continuous blood flow with a pump speed operating range of 1800 to 4000 rpm. The pump contains a wide-blade impeller that is suspended by magnetic and hydrodynamic forces for frictionless rotation of the impeller. The frictionless movement of the impeller minimizes heat generation and component wear. An external microprocessor-based system controller connected to the pump by a percutaneous driveline controls and monitors the implanted device. Suction detection and alternating speed modes are automatically maintained by the controller, but their use is determined by the operator. An LED display on the controller provides information on pump operating parameters and alarm conditions. A system monitor can make changes in operating parameters and collect data regarding pump function. The device can operate with AC or DC power sources. Lithium-ion batteries are used during ambulatory operation and an automobile DC adaptor allows for extended travel time.
The HVAD system was initially evaluated for BTT in a multicenter, prospective study in patients with end-stage heart failure. Patients ( n = 332) were followed for ≥ 180 days following implantation or until cardiac transplantation, device removal for recovery, or death. The 180-day and 1-year survival rate was 94% and 86%, respectively. Despite excellent survival rates and an adverse event profile similar to other studies, pump thrombosis was seen in 14% of patients, and the incidence of stroke was 15.3%, indicating that complications with this device exist and its use must be closely monitored. Early in the trial, the device was modified to incorporate a textured inflow conduit to help reduce device thrombosis. In addition, during the trial, the recommended anticoagulation therapy was adjusted to include an increase in aspirin dosage from 81 mg/day to 325 mg/day. With the good overall survival, improved quality of life, and declining thrombotic adverse event rates, market approval for the BTT indication was gained in 2012. The Prospective, Randomized, Controlled, Unblinded, Multi-Center Clinical Trial to Evaluate the HeartWare Ventricular Assist Device System for Destination Therapy of Advanced Heart Failure (ENDURANCE DT) trial for the HVAD was conducted from 2010 to 2012 and included 446 patients who were randomized to either the HVAD or HeartMate II in a 2:1 ratio. The primary endpoint was 2-year survival free from disabling stroke (MRS ≥ 4). The outcome was not statistically or clinically different between HeartMate II and HVAD, 57.4% versus 55%, respectively. Importantly, more patients with the HeartMate II device required replacements due to malfunction or device failure (16.2% vs. 8.8%), while patients receiving the HVAD had a higher incidence of strokes (29.7% vs. 12.1%). It was determined that careful management of anticoagulation and antiplatelet therapy with good blood pressure control was necessary to minimize neurologic adverse events during support with the HVAD device. Results of a supplemental study that investigated the influence of blood pressure control on stroke incidence were recently published. The supplemental trial did not demonstrate noninferiority of HVAD versus control in regards to the primary endpoint of reduction of mean arterial blood pressure. However, HVAD subjects reached the composite endpoint (freedom from death, disabling stroke, and device replacement or urgent transplantation) at a higher rate than controls.
Due to the small size of the HVAD pump and its intrapericardial placement, a number of variations for implantation have been evaluated. Placement of the inflow conduit through the diaphragmatic surface of the left ventricle and minimally invasive techniques may offer some advantages in reducing adverse events. The HVAD has also been implanted for biventricular support or as part of a hybrid biventricular system.
Jarvik 2000
The Jarvik 2000 LVAD (Jarvik Heart Inc.) is a small axial flow device in which the blood pump is uniquely positioned within the left ventricular cavity ( Fig. 10.5 ). Outflow from the pump is through a graft that is anastomosed to either the ascending or the descending aorta. A percutaneous driveline that exits the skin in the right upper quadrant of the abdomen provides the means for power and control to the blood pump. An analog controller provides a display of alarm conditions and allows for adjustment of the pump speed from 8000 to 12,000 rpm in increments of 1000. Patients are allowed to make speed changes as their requirement for support changes. However, there is no method for monitoring the pump flow with this device. The Jarvik LVAD uses only DC battery power; AC power sources are needed to recharge batteries. There are portable lithium ion batteries for ambulatory operation and larger lead-acid batteries are for nonambulatory use.
The Jarvik 2000 has been in clinical trials for BTT approval for approximately a decade. Although the clinical trials have not been completed, numerous reports indicate that outcomes have been largely positive. A multicenter study in Japan had 1- and 2-year survival rates of 85% and 79%, respectively. Patients have been successfully supported by this device for durations greater than 7 years, with no device failures, and the mean survival time for patients supported for DT is 402 days. A unique skull-pedestal power cable connector appears to allow for long-term use with a low incidence of driveline infections. An early report described an observed high incidence of gastrointestinal bleeding in patients supported by this device, and this observation was later made in patients supported by the HeartMate II. Detailed analysis of patients supported by axial flow devices indicates that the gastrointestinal bleeding is related to acquired von Willebrand disease. This form of von Willebrand disease may be shear induced and may be a characteristic of continuous-flow devices. The Jarvik LVAD has also undergone a number of design enhancements and miniaturization for pediatric use. Currently, the Jarvik LVAD does not have market approval in the United States, but it is used for both BTT and DT in Europe and Asia.
Berlin Heart INCOR
The INCOR LVAD (Berlin Heart GmbH) is an implantable pump that is intended for long-term support for BTT or DT ( Fig. 10.6 ). The unique design feature of this axial flow pump is the contact-free impeller, which is unlike other axial flow pumps that utilize blood-immersed bearings. The pump has a displacement volume of 82 mL and weighs 200 g. Active and passive magnetic force is used to suspend and rotate the impeller along the axis of the cylindrical pump housing. The operational impeller speed range is 5000 to 10,000 rpm. The pump is positioned below the left hemidiaphragm in a pump pocket with the inflow in the left ventricle and the outflow is attached to the ascending aorta. The blood contacting surfaces are coated with Carmeda to reduce thrombogenicity. A percutaneous driveline connects to an external controller that monitors and controls the function of the implanted pump. The device is powered by AC or DC sources, with small batteries for portable operation. A laptop computer interfaced with the controller sets the operating parameters.
