A Changing Trend Toward Destination Therapy: Are We Treating the Same Patients Differently?

The left ventricular assist device (LVAD) has been approved as a bridge to heart transplantation (BTT). However, as outcomes improve, and particularly since U.S. Food and Drug Administration (FDA) approval of the HeartMate II® Left Ventricular Assist System (Thoratec Corporation; Pleasanton, Calif), patients are increasingly undergoing LVAD implantation as destination therapy (DT). Only 3,500 heart transplants are performed worldwide each year. Performing LVAD implantation in patients under the transplantation umbrella will always severely limit the number of patients with advanced heart failure who can be treated; therefore, it may be time to change the approach to the patient. The U.S. data for the number of LVADs that have been implanted are now available, through the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS),1 and the number of heart transplants has been recorded.2 Due to the improved outcomes and lower complication rates of the newer devices, LVAD implantations are increasing while heart transplantations remain static; therefore, the ratio of implants to transplants is increasing steadily (Fig. 1). Fig. 1 The number of left ventricular assist devices (LVADs) implanted and transplantations performed from 2006 through 2010 with the total set at 100%, to show the proportional increase in LVAD implantations. The number of transplantations has ... Before consideration for LVAD implantation, patients are evaluated to determine whether they are actually or potentially eligible for transplantation after a period of LVAD support. Destination therapy is considered for those patients who are ineligible for transplantation. However, instead of looking at the LVAD implant as a BTT, it is becoming more logical to consider a patient for LVAD implantation first and then consider who should receive the limited number of donor hearts. There is also a large gray area. Some conditions are relative contraindications but are likely to improve after a period of LVAD support (for example, renal dysfunction or pulmonary hypertension that should reverse, or reduction in body mass index), so that the patient can become a transplant candidate. Generally, these patients undergo LVAD implantation as BTT, but it might be more appropriate as DT with evaluation for transplantation later, if the reversible contraindications have improved. The data from recent BTT trials with the newer continuous-flow pumps show not only improvements in survival, but a decreasing trend in the number of patients who receive heart transplants within a certain period of time, despite the initial intent in such trials to perform transplants. In the recent BTT trials, the primary endpoint was 180 days (6 months). In the HeartMate II BTT trial, published by Miller and colleagues,3 133 patients were recruited by 26 centers from March 2005 through May 2006; 42% of those patients received transplants at 6 months, and the median time to transplantation was 97 days. In the next report, by Pagani and associates,4 281 patients (including 133 patients followed from the previous study) were recruited by 33 centers from March 2005 through April 2008; after 6 months, only 36% of those patients underwent transplantation, and the median time to transplantation was longer (118 days). After the FDA's approval of the HeartMate II for use as BTT, Starling and colleagues5 studied the first consecutive 169 patients who received the device from April through August 2008 at 52 U.S. centers. These patients were enrolled into INTERMACS either as BTT and listed for transplantation or as BTT and likely to become eligible for transplantation. In this cohort, only 20% of patients underwent transplantation at 6 months (Table I and Fig. 2). The reduction in the percentage of transplants that were performed 1 year after implantation was the same over time. In the HeartWare BTT clinical trial,6 performed at 5 centers in Europe and Australia that recruited 50 patients from March 2006 through December 2008, only 14% of patients received transplants at 6 months and 26% at 1 year; the median time to transplantation was 267 days. Therefore, the trend has been to wait longer until transplantation and to perform such operations in fewer patients at each stage over time. Fig. 2 The percentage of patients in the bridge-to-transplantation trials who underwent transplantation after 6 months of left ventricular assist device support. TABLE I. Recent Bridge-to-Transplantation Clinical Trial Results Initially, LVAD implantation was always performed as BTT, if possible, because of the device's limited durability and the high complication rates. However, the continuous-flow pumps have become more durable and the complication rates have decreased.3–6 Patients who might have an LVAD implanted as DT rather than BTT can be placed in 3 categories. The 1st category includes unchangeable conditions, such as age, hepatitis, severe end-organ diabetic small-vessel disease (for example, retinopathy or neuropathy), peripheral vascular disease, or other absolute contraindications to transplantation. In these patients, DT status does not change. The 2nd category includes one or more contraindications that may improve during the period of LVAD support: renal dysfunction that may reverse itself with restored blood flow; pulmonary hypertension that may resolve with ventricular unloading; excessive weight, which the patient may lose after prolonged LVAD support; or other social circumstances or compliance problems (such as tobacco or drug use or alcohol abuse, inconsistent outpatient appointment attendance or medication consumption, or driveline neglect). Upon improvement, these may no longer be impediments to transplantation. Patients in the 1st group have always undergone LVAD implantation as DT. However, patients in the 2nd group have previously generally undergone implantation as BTT; subsequently, they have been listed for transplantation only after reversible contraindications have improved. Currently, there is an increasing trend in practice to perform LVAD implantation as DT in the 2nd group of patients, and then for the team to reevaluate whether these patients can become eligible for transplantation (in other words, reclassify a patient's LVAD therapy as BTT if the relative contraindications have resolved). A 3rd group consists of surgically complex patients, such as those who have undergone 4 or 5 previous sternotomies, previous aortic aneurysm surgery, or previous breast cancer and radiotherapy with considerable scarring. Before deciding whether transplantation surgery is feasible, one should determine how difficult LVAD implantation might be, given the patient's surgical adhesions and other considerations. It is probably best that these patients undergo LVAD implantation as DT, and then the team can consider whether to reclassify their therapy as BTT, depending on the patients' improvement. Also in this group are the increasing number of patients who have heparin-induced thrombocytopenia. It is usually possible to implant the LVAD with use of a heparin alternative, or even off bypass (especially with the HeartWare device), so that 1 infusion of heparin can be saved for a transplantation at a later date. However, depending on the course of the surgery, it may be necessary to administer heparin during the LVAD implantation if the dissection is difficult or the patient bleeds with the heparin alternative. Then, transplantation at a later date might not be wise. The patient may also have severe clinical heparin-induced thrombocytopenia complications so that any dose of heparin is considered high risk and transplantation too risky. The 2nd and 3rd groups typically undergo LVAD implantation as DT, rather than as BTT, and then patients are reconsidered for transplantation later; therefore, the limited organ supply can be reserved for the patients who are most in need and for those who will do best. In the past, patients in these categories would have received implants as BTT. At our own institution over recent years, we have performed more DT than BTT implantations. We have begun approaching these patients differently now that we have 2 options. We tend to treat the borderline transplant candidates as DT and later consider them for BTT. Most centers appear to be following the same trend. Some countries (for example, Germany) do not allocate the funding according to a BTT or DT indication but instead implant the pump when the patient clinically needs it. They keep most patients on LVAD support and perform transplantation in transplant candidates. In the future, this is likely to go a step further: the patient will be given an LVAD when it is clinically needed (and that threshold will become lower as outcomes from the devices improve further), most patients will stay on the device, and those who experience device complications will undergo transplantation along with patients who are not suitable for device implantation in the first place. In this way, good candidates can be listed for transplantation after a full evaluation, and our limited organ supply can be allocated most appropriately.