Devices as destination therapy

Destination devices 

Rotary pumps 

Considered the “next generation” LVADs, these pumps have emerged as a possible alternative to the large pulsatile devices. Continuous circulatory flow is a concept dating back as far as the invention of the heart-lung machine in the 1950s. Having the advantage of reduced size and noise, these devices were developed in the 1980s and early 1990s primarily by two manufacturers. The MicroMed-DeBakey VAD (Houston, TX) (Fig. 1) and the Jarvik 2000 pump (Jarvik Heart, Inc., New York, NY) (Fig. 2) are the two main devices in clinical use in the US bridge-to-transplant trials today. Both systems are small axial pumps based on an impeller rotating at high revolutions per minute (rpm). The DeBakey VAD is 3 inches long and capable of pumping 10 L/min [18]. The Jarvik unit is equally as small and produces a flow rate of 7 L/min [19]. Both pumps produce a low-pulsatile flow with the pulsatility diminishing with the rise in the rpm. A unique feature of the Jarvik pump is its intraventricular position and its skull-fixated percutaneous controller and energy connector. The outflow tract of the Jarvik VAD is also usually connected to the descending aorta as opposed to the ascending aorta as in the majority of VADs. Although neither of the systems is currently undergoing a formal trial for evaluation as destination therapy, both devices have shown promise in long-term reliability. The DeBakey VAD has shown a longest duration of greater than one year, and the Jarvik pump has been implanted as destination therapy in a number of patients in England [19], [20]. A third pump, the HeartMate II LVAD (Thoratec Corporation, Pleasanton, CA) like the two previously mentioned pumps, is an axial flow pump from the makers of the widely used HeartMate pulsatile VAD (Fig. 3). Like the DeBakey pump, this device is also small with an inflow cannula implanted in the left ventricular apex and the outflow graft connected to the ascending aorta. To improve reliability of continuous flow throughout the cardiac cycle and prevent ventricular collapse, the intraventricular portion of the inflow tract has been elongated and as a result tends to stent open the middle of the ventricle [21]. This device has also not undergone trials specifically with the focus of destination therapy, however, all of these pumps offer attractive features for patients looking for long-term support. Their small size coupled with the low noise and energy expenditure make these pumps very appealing in the long-term quality-of-life assessment.

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Fig. 1. MicroMed-DeBakey, VAD. (Courtesy of MicroMed Technology, Inc.)

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Fig. 2. Jarvik 2000. (Courtesy of Texas Heart Institute.)

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Fig. 3. The HeartMate® I and II ventricular assist systems. (Courtesy of World Heart Corp.)

Device and patient selection 

In choosing the type of device to use as part of destination therapy, the primary question to answer is whether the patient needs biventricular support or will an LVAD provide appropriate therapy. Currently no intracorporeal system is widely available for separate right and left ventricular support. In most instances, heart failure patients improve with the unloading and support of the left ventricle. In case of perioperative right heart failure, a temporary paracorporeal right ventricular assist device (RVAD) is used until the right side recovers or a donor heart becomes available for transplantation. However, a patient population exists that does require biventricular support, thus creating a need for a total artificial heart. A decreasing cardiac index in the setting of high pulmonary arterial (PA) and central venous pressures, low left atrial pressures, and low cardiac index all point to possible right heart dysfunction [24]. However, care must be taken not to assume normal right heart function in the setting of normal preoperative pulmonary pressures. With low cardiac output states, a patient may display normal PA pressures, which then increase dramatically after the cardiac output increases following VAD support. Kavarana et al reported no significant difference in preoperative hemodynamic parameters between patients who suffer from right ventricular failure after LVAD implantation and those who maintain adequate right heart function [25].

Another consideration in this matter is the size of the patient. The two currently tested TAHs described previously require a recipient to have considerable chest volume. Patients receiving the CardioWest heart require a 10-cm anteroposterior chest cavity diameter [22]. The currently available pulsatile LVADs also require a body surface area of greater than 1.5 m2. For smaller patients, axial rotary pumps may be the best option.

Appropriate patient selection is a challenge, especially as currently successful systems achieve FDA approval. The trials currently evaluating these devices as destination therapy include patients who otherwise do not fit the criteria to undergo heart transplantation. In many cases, particularly in the case of the TAH trials, these patients are very ill with significant comorbidities including end-organ dysfunction. In some cases, these patients are too old to undergo transplantation. In either situation, it is difficult to say whether these are the ideal patients to receive this therapy, which causes further insult to an already fragile system. Patients who receive device support as destination therapy should meet certain criteria that may predict initial survival after implantation. We have created a scoring system to predict which patients would survive device implantation. The initial scale, created in 1995, was recently revised to better reflect the current extensive LVAD experience (Table 1). The positive and negative predictive value of the current scoring system is 79% and 70%, respectively. Using the scale, a score of >5 corresponds to a 47% mortality compared with a 9% mortality for a score of <5 [26]. Renal failure, previously considered as a major comorbidity, has recently been shown to play less of a role in the prediction of overall survival. In many cases, increased cardiac output due to circulatory support improves renal function after VAD implantation. Liver failure, with subsequent coagulopathy, may lead to increased perioperative bleeding with subsequent correlation to increased right heart failure. These selection criteria were developed after evaluating patients who received the device as a bridge to transplantation. As a result, the selection process may need further revision when considering patients who will be treated with destination therapy.

Table 1. Risk factors for poor survival after left ventricular assist device placement

	Risk factor	Score
	Mechanical ventilation	4
	Reoperation	2
	Previous LVAD	2
	Central venous pressure >16 mmHg	1
	Prothrombin time >16 seconds	1

Adapted from Rao V, Oz MC, Flannery MA, et al. Revised screening scale to predict survival following left ventricular assist device insertion. J Thorac Cardiovasc Surg, in press.

Many questions still remain as to the ideal population that would survive and benefit from this technology. Further evaluation of the clinical trial results combined with cautious and judicious use of this treatment option is warranted to answer the question of which patient population would benefit the most from the use of circulatory assist devices as destination therapy.

Clinical trials 

The most significant trial to test circulatory assist devices as an alternative to transplantation was the REMATCH trial mentioned previously. The study was undertaken in 1998 with 129 patients in 20 centers. The patients enrolled included adults with end-stage (NYHA class IV) heart failure who did not qualify for heart transplantation. The patients were randomly assigned to either LVAD implantation or optimal medical therapy. The Thoratec HeartMate LVAD was the device used in the trial. Death was the primary end-point of the study; however, multiple secondary end-points were evaluated including quality of life, complications, and hospitalizations [27]. The study was concluded in July 2001 with data presented at the annual American Heart Association Scientific Assembly Meeting in November 2001. The results showed that the two groups were matched in pre-study characteristics. The LVAD-treated group showed a 48% reduction in risk of death compared with the medically treated group. The disturbing finding was the 1-year and 2-year survival of this patient population. The medically treated patients showed a 25% 1-year survival and 8% 2-year survival with the LVAD patients surviving 52% and 23% of the time, respectively [10]. These results not only demonstrated the potential of the circulatory assist devices as an alternative to medical therapy in this patient population but also highlighted the morbid outcome of the natural course of this disease. Further analysis of the REMATCH data is ongoing, and new data examining this issue should be available shortly.

Another trial currently near its conclusion is the INTrEPID trial using the Novacor device. Similar to the REMATCH trial, this trial is looking at the use of the Novacor device as destination therapy and as an alternative to medical therapy in an inotrope-dependent patient group not eligible for heart transplantation. The results of this study may further point to the potential and benefits of circulatory assistance therapy.

The AbioCor TAH trial is another trial currently underway to evaluate the efficacy of device support as destination therapy. The initial trial is conducted by a limited number of centers with more centers to be included in the second larger trial. Currently, patients included in the study must have an estimated life expectancy of 30 days or less and not be eligible for heart transplantation. One of the patients has been supported on the device for more than 200 days and has been discharged home on the device. Further experience with this device is necessary before we can clearly define the patient population that would benefit from this therapy.

All of the currently proposed devices will need to undergo challenging clinical trials before obtaining FDA approval. We believe that a modified regulatory process will be required for device companies, because the financial constraints of the large randomized evaluations are overwhelming to the small companies involved in this field. Innovative approaches could include creation of a generally agreed-upon control population such as the REMATCH trial optimal medical management group or a group of patients gathered from subgroups of each company's randomized trial.

Summary 

The use of circulatory support as destination therapy has been a goal for the treatment of end-stage heart failure for several decades. Current investigations are evaluating several circulatory pumps with that particular objective. With continued modification of design, the current and future pumps will become more reliable and provide improved quality of life to patients in need of mechanical circulatory assistance. The new pumps on the horizon specifically address reliability, size, and cost, and are based on the centrifugal system. These devices use the Maglev (Magnetic Levitation) concept that allows for frictionless pumping, low thrombogenicity, minimal noise, and increased durability. Further research with this goal in mind and support from the federal government will be the key to the future use of circulatory assistance as destination therapy for heart failure patients. In addition, the cost-effectiveness of these devices will need to be maintained as the technology improves, as in any new technology that confronts a more intuitive option like the native heart.