Heart failure is an escalating global pandemic and one of the leading causes of death and disability in the developed world. At present, the incidence of heart failure in the Western world is staggering, affecting approximately 6.5 million people in Europe and 5.8 million people in the US.1–3 Even more alarming is the notion that approximately 10 % of this population suffers from advanced heart failure.1 Advanced heart failure patients have a very poor quality of life, often experiencing repeated hospitalisations and an annual mortality rate of around 50 %.1 Due to the ageing of the general population, the number of individuals with heart failure and advanced heart failure is expected to dramatically increase over the next 20 years.3,4
Due to the steady decline in coronary deaths, the number of patients with end-stage heart failure continues to increase. While cardiac transplantation is currently the gold standard for some patients, transplant numbers over the last decade have remained static worldwide due to the limited number of available donor organs and limitations on patient selection, especially in the older population. As a result, scientists and clinicians have been working on ventricular assist devices (VADs) as reliable alternatives to cardiac transplantation.
The idea of assisting the severely diseased heart with support from outside the heart came from Le Gallois, a French physiologist, and dates back to the early 1800s.5 The initial development, in the late 1960s, of devices for the treatment of heart failure began with both total heart replacement and ventricular assist support. Given that refractory heart failure usually involves dominant left ventricular failure, a left ventricular assist device (LVAD) was designed to take over most of the work of the left ventricle, leaving the right ventricle to function as normal. The theory guiding this approach was that by improving blood flow to the body and end organs, the symptoms and morbidity associated with left ventricular failure would be greatly improved.
The first clinical use of VADs was as short-term support for post-cardiotomy cardiogenic shock.6,7 Despite well-designed and efficient VADs, the survival rate for post-cardiotomy VAD support was poor, ranging from 15–35 %.8,9 By the mid-1980s, improvements in immunosuppression (development of cyclosporine) led to a resurgence of cardiac transplantation. However, there still remained a large discrepancy between the number of potential transplant recipients and the number of donor hearts available. Fortunately, mechanical support technology and its associated clinical outcomes continued to advance, leading to a broadened strategy that included the use of VADs as bridges to cardiac transplantation (BTTs). The outcomes in patients implanted with VADs as BTTs were immediately gratifying and significantly better than those of post-cardiotomy VAD support, with survival to transplant approaching 70 % and post-cardiac transplant survival averaging near 80 % at one year.10–13
Mechanical support, in particular VAD technology, continued to advance over the next 25 years. A major milestone was reached with the development of portable, wearable VAD systems, which allowed independent patient ambulation and discharge from the hospital to home. This developement was critical for VAD therapy to evolve into a more permanent solution, destination therapy (DT), for end-stage heart failure in patients who were either not eligible for, or chose not to undergo, cardiac transplantation. The Randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) trial (2001) was a historic, groundbreaking trial, not only because it was the first successful DT trial, but also because it documented in a prospective randomised fashion that LVADs were superior to optimal medical therapy in treating refractory heart failure.14 The REMATCH trial opened the door to permanent support, while at the same time highlighting the limitations of first-generation pulsatile VADs.
By the time the REMATCH trial was completed, a new generation of smaller, more efficient and reliable continuous-flow VADs were ready to be tested. The first continuous-flow VADs to enter clinical trials were axial flow systems.15,16 As anticipated, their use led to a reduction in adverse events and an improvement in device reliability, length of survival and quality of life. On the basis of these trials, LVADs were recently recommended for DT in guidelines from the European Society of Cardiology.17 As a result of this update, the number of implants and the duration of support increased. Shortly after axial flow pumps appeared, another type of continuous-flow pump – centrifugal-flow pumps – emerged, offering potential size, reliability and implantation advantages.18–22
The HeartWare® Ventricular Assist System
The HeartWare® Ventricular Assist System (HeartWare, Inc., Framingham, Massachusetts, US) is a continuous-flow centrifugal VAD that has supported more than 1,600 patients worldwide. At the core of the system is the HeartWare VAD® (HVAD®) pump (see Figure 1), an implantable centrifugal pump designed to be small, reliable and simple to insert and operate inside the chest.23 The HVAD pump has an integrated inflow cannula that is inserted into a sewing ring sewn to the left ventricle. This allows the pump to be situated within the pericardium, eliminating the need for the creation of a pump pocket (see Figure 2).
The HVAD pump delivers up to 10 litres/minute of flow using a special hydromagnetic levitation impeller system.23 The system’s operating parameters include: reliable flow estimation based on pump flow, speed and patient’s haematocrit; a suction detection alarm, which is activated if there is a sudden decrease in baseline flow; and pre-load and after-load sensitivity, which enhances auto-response during exercise and variations in natural circadian flow.24
External equipment for the HeartWare system includes both patient and hospital equipment. The patient peripheral equipment includes a pocketbook-sized controller, power sources and a battery charger. A thin driveline cable from the pump exits the body and is connected to the controller. The controller communicates with the pump to regulate its operation, manage the power sources, store data and provide troubleshooting assistance. A two-line message display on the controller shows pump parameters such as power (watts), flow(litres/minute) and speed (rotations/minute). These values are stored in the controller and can then be displayed as waveforms on the hospital’s HeartWare monitor. The controller stores the averaged VAD parameters every 15 minutes when not connected, and these data can be downloaded for waveform analysis on the monitor. Additionally, a history of alarms and event data are stored in the corresponding logs. During an alarm condition (e.g., low battery), the controller displays text describing the alarm and how to resolve it. Two power sources must be connected to the controller at all times. Power source options include batteries (rechargeable, lithium–ion batteries), AC power or 12 V DC power (for use in the automobile accessory port). The patient equipment is lightweight and portable, with the controller weighing 0.5 kg and each of the two batteries weighing 0.5 kg. A carrying case for the controller and batteries promotes an ambulatory lifestyle (see Figure 3). The batteries combined provide 12 hours of power.25
The clinical management of a patient using the HeartWare system includes education on how to operate the device, demonstration of driveline management and anticoagulation therapy. As with all VADs, patients require regular dressing changes of the driveline cable exit site in order to prevent infection. Additionally, an anticoagulant regimen consisting of warfarin with a target international normalised ratio (INR) of 2.0–3.0, and antiplatelet therapy consisting of aspirin or clopidogrel, are recommended with the HeartWare system.
HeartWare Clinical Results
The international Conformité Européenne (CE) mark trial for the HeartWare system included 50 patients who were enrolled between March 2006 and December 2008 at a total of five medical centres throughout Europe (three) and Australia (two).22 The primary study endpoint was survival to transplant, cardiac recovery with device explant or continuing device support at 180 days. Adverse events were defined using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions and were collected until all 50 patients reached endpoint. Patients who remained on support beyond the primary endpoint were followed up for status only. The patient baseline characteristics were similar to those in other BTT clinical studies. Haemodynamic variables significantly improved between 24 and 48 hours of implant when compared with baseline (see Table 1).
The most frequent adverse events were infection and bleeding, with almost half (49 %) of the adverse events occurring within the first 30 days of support. Haemorrhagic stroke occurred in four patients, all after 30 days. Other neurological events included three transient ischaemic attacks. The implantation of the HVAD pump caused minimal amount of tissue damage and cardiopulmonary bypass time. These factors might contribute to the low incidence of bleeding.
Forty-five of the 50 patients (90 %) successfully reached the primary study endpoint of survival to transplant, cardiac recovery with device explant or continuing device support at 180 days. As of 15 July 2011, 27 of the 50 patients had been transplanted, four had been weaned off following myocardial recovery and nine remained on support. The average time to transplant in the 27 transplanted patients was 430 days. There have been 26,588 days of cumulative support (72.84 years), with 28 patients supported for more than one year, 14 for more than two years and six for more than three years. All nine patients currently supported have been on the device for more than two years (and five of them for more than three years). The actuarial success (survival) rate was 90 % at six months, 85 % at one year, 78 % at three years and 69 % at four years (see Figure 4). At the time of study completion, these were the highest survival figures at these points in time seen with any VAD in clinical pre-commercial approval trials.
There was a steady improvement in quality of life and relief of symptom burden from pre-implant to six months post-implant, which are similar to that seen with patients who have received a heart transplant. Overall condition and physical limitations improved from pre-implant and stabilised at three months.
A vast majority of HeartWare system patients returned home within four weeks of the implant, with some even going back to work. There were dramatic improvements in functional status: 100 % of the patients were New York Heart Association (NYHA) class IV pre-implant and improved to NYHA class I or II within two months of the implant.
Ongoing HeartWare Clinical Studies
There are currently three clinical trials in the US for the HeartWare system. The ADVANCE trial is a Food and Drug Administration (FDA)-approved investigational device exemption (IDE) multicentre, non-randomised BTT clinical trial in which 140 patients were implanted in 30 US centres. The control group consists of a cohort of 499 contemporaneous patients taken from the INTERMACS registry. The primary endpoint of the trial is survival at 180 days, defined as alive on the originally implanted device, transplanted or explanted for recovery. Secondary endpoints include adverse events, such as bleeding and infection, as well as functional status, hospitalisation, assessment of neurocognitive function and patient quality of life.26 Enrolment and 180-day follow-up for the ADVANCE trial were completed in August 2010, and continued access programme (CAP) protocols are ongoing.
The ENDURANCE trial (A Clinical Trial to Evaluate the HeartWare® Ventricular Assist System) is a randomised controlled unblinded multicentre clinical trial designed to evaluate the use of the HeartWare system as DT in up to 450 patients at 50 US hospitals. This will be the largest controlled clinical VAD trial to date. Patients will be randomly selected to receive either the HeartWare system or an alternative LVAD approved by the FDA for DT in a 2:1 ratio. The primary endpoint of the trial is stroke-free survival at two years, defined as alive on the originally implanted device, electively transplanted or explanted due to patient recovery. All patients will be followed up to the primary endpoint at two years, with a subsequent period of follow-up extending to five years post-implant.
The REVIVE-IT trial (The Evaluation of VAD Intervention Before Inotropic Therapy) is a randomised controlled unblinded multicentre trial sponsored by the US National Heart, Lung, and Blood Institute and HeartWare, Inc. The trial will explore the potential benefits of LVADs in patients who will be given earlier access to these devices. Researchers will compare whether non-transplant eligible patients with heart failure less advanced than that of current LVAD recipients do better with implanted devices than with current medical therapy. The study device will be the HVAD pump. The enrolment target will be 100 patients in 10 centres. Enrolment is expected to commence in the second half of 2012.
Conclusions
The HeartWare system is a unique implantable long-term mechanical circulatory support system that extends the continuum of care for end-stage heart failure patients beyond medical management.The small size and ease of implantation of the HVAD pump allow the application of this system in patients who would not historically have been considered for LVAD implantation. Despite the small size of the device, it has been demonstrated that, while being supported by this system, patients experienced resolution of heart failure symptoms and an increase in functional capacity, while two-year survival rates rival those of orthotopic heart transplant. In fact, recent data presented about 240 patients from the ADVANCE trial at the European Association for Cardio-Thoracic Surgery meeting in Lisbon, Portugal, in October 2011, demonstrated 93 % survival at 180 days and 86 % at one year. These results suggest the HeartWare system is a viable option for patients with end-stage heart failure.