Heart Transplantation Versus Left Ventricular Assist Device in Advanced HFrEF
Stage D HFrEF patients are typically referred to cardiac transplant centers, where they undergo an extensive evaluation to determine their candidacy. Optimization of the medical regimen and consideration for revascularization or other standard therapies are assessed. Significant comorbidities that could be life-threatening at the time of transplant surgery or post-transplant are carefully excluded before patients are accepted as transplant candidates. The short- and long-term outcomes following cardiac transplantation have been exceptional, with a median survival of 10.7 years and survival conditional on surviving to 1 year after transplant of 13.6 years. Quality of life has greatly improved as immunosuppressive agents have become more targeted for the rejection process. This therapeutic success has resulted in a glut of patients awaiting this life-saving therapy.
The Chronic Limitation of Organ Availability
In the United States, 3,990 patients are currently listed for heart transplant. The medical urgency of patients listed has steadily increased, with the majority of those now registered for cardiac transplant requiring inotropic or mechanical support. The major limitation to the growth of cardiac transplant has been the limited donor supply. Despite many campaigns to increase donor volume by local or federal agencies, the donor supply has remained flat and is limited to approximately 2,500 hearts annually in the United States. Currently, warm preservation devices, such as the Organ Care System (Transmedics, Amherst, Massachusetts), which provides a clinical platform for ex vivo human heart perfusion, offer hope for increased numbers of potential donor organs. This device may provide donors beyond the current geographic limit imposed with cold preservation techniques and/or identify viable donors with clinical characteristics that ordinarily would preclude transplant in the absence of a metabolic assessment. The recently completed PROCEED II (Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation) trial demonstrated noninferiority of ex vivo preservation to cold ischemia in 130 transplant recipients undergoing transplant with standard donors. Three cases of heart transplant using organs from after cardiac death were reported in Australia using this organ preservation system. Nevertheless, despite the hope for more usable organs, the donor supply remains flat; clearly transplant is not the solution for the estimated 250,000 patients with advanced HFrEF who could benefit from cardiac replacement therapy. Fortunately, concomitant with the improvement in therapy for heart transplantation, mechanical assist devices to support patients with end-stage HFrEF have continued to evolve. More and more transplant candidates are requiring mechanical support as they wait for an acceptable organ. In 2000, the International Society for Heart Transplantation reported that 19.1% of transplant recipients were mechanically supported; this number increased to 41.0% in 2012. Left ventricular assist device (LVAD) support is typically offered to transplant candidates who are developing end-organ damage despite maximal medical therapy, including inotropic support, or to those candidates who are inotrope-dependent with an anticipated long waitlist time (i.e., large size and/or blood type O recipients). These categories correspond to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels 1 to 3. The INTERMACS is a North American registry established in 2005 that collects clinical data for patients receiving mechanical circulatory support device therapy to treat advanced HF. The INTERMACS scale assigns patients with advanced HF into 7 levels according to hemodynamic profile and functional capacity (Figure 1). Ventricular support devices offer improved survival to transplant with excellent quality of life. However, implantation of the LVAD is another surgical procedure with associated risks, such as stroke, infection, bleeding, and sensitization, that may prolong the time to finding a suitable organ and, in some cases, may preclude transplant.
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Figure 1.
INTERMACS Scale for Classifying Patients With Advanced HF
Percent of implants by INTERMACS profile. Current U.S. Food and Drug Administration (FDA) approval status and acceptance in the medical community. Modified with permission from Estep et al (48,76). HF = heart failure; INTERMACS = Interagency Registry for Mechanically Assisted Circulatory Support; NYHA = New York Heart Association.
Patient Selection for Heart Transplant Versus LVAD
In patients with cardiogenic shock or post-cardiotomy syndrome, many short-term mechanical devices provide biventricular support. For chronic patients with Stage D HFrEF who are not transplant candidates, the only mechanical device option is LVAD support. We will focus on the use of long-term LVADs in this patient population.
The criteria for implantation of an LVAD as DT as outlined by the Centers for Medicare and Medicaid Services, are as follows and are derived from the HeartMate I (REMATCH [Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure]) and HeartMate II DT trials:
Patients with NYHA functional class IV symptoms who have failed to respond to optimal medical management, including angiotensin-converting enzyme inhibitors or beta-blockers, for at least 45 of the past 60 days, or have been intra-aortic balloon pump-dependent for 7 days or IV inotrope-dependent for 14 days;
Left ventricular ejection fraction <25%; and
Functional limitation with a peak oxygen consumption <14 ml/kg/min, unless on an intra-aortic balloon pump, IV inotropes, or physically unable to perform the exercise test.
Separation of LVAD patients into bridge to transplant (BTT) and DT populations has been problematic. During their acute illness, many patients may fall into a gray zone with comorbidities that reverse over time. These patients are frequently categorized as "bridge to decision." In an attempt to normalize end-organ function that currently precludes long-term cardiac replacement therapies, these patients are often supported using extracorporeal membrane oxygenation or short-term single or biventricular assist devices. Selection criteria for DT are less rigid, in some respects, than for transplant candidacy. Table 1 contrasts the key exclusion criteria used in our center for heart transplant and DT candidates.
The presence of certain comorbidities, such as a recent malignancy and elevated pulmonary vascular resistance, may initially disqualify patients from transplant listing, as cancer is more likely to recur during immunosuppression and right HF may occur when the allograft is exposed acutely to severe pulmonary hypertension post-transplant. Patients with significant end-organ dysfunction, such as renal and liver insufficiency, may eventually be reconsidered for transplant if the end-organ function subsequently improves.
Although an elevated pulmonary vascular resistance may not exclude a patient from LVAD implantation, screening for potential right HF is much more rigorous, as no approved chronic right ventricular support is currently available. Patients with severe right ventricular failure may not qualify for LVAD support and, in any case, are likely to require prolonged temporary mechanical right ventricular support and/or inotropes post-operatively. Prediction models, hemodynamic parameters, and echocardiographic measurements are used to assess right ventricular function before LVAD implantation. A prediction score for post-operative right ventricular failure developed by the University of Michigan group incorporates the following variables: use of vasopressors, aspartate aminotransferase, bilirubin, and creatinine levels. Other investigators have focused on hemodynamic parameters, such as right ventricular stroke work index ≤0.25 mm Hg × l/m, the ratio of right atrial pressure to pulmonary capillary wedge pressure >0.63, and right atrial pressure >15 mm Hg. Other clinicians have emphasized echocardiographic indexes, such as severity of tricuspid regurgitation, right to left end-diastolic dimension >0.72, and right ventricular free-wall strain. However, there are no absolute prediction criteria for the development of intractable right HF while on LVAD support in the short or the long term.
In contrast, LVAD support is an excellent option for those HFrEF patients with high pulmonary vascular resistance rejected for heart transplant in the setting of adequate right ventricular function. Frequently, implantation of the device will allow the vascular resistance to decline and allow these patients to become transplant-eligible.
Unlike heart transplantation, those HFrEF patients with intractable angina or intractable ventricular tachycardia are not device candidates, except in the setting of chronic severe HF symptoms. Due to their small ventricular cavities and frequently normal ejection fractions, patients with restrictive cardiomyopathies are also not LVAD candidates.
The need for adequate social support is required for both transplant and mechanical assist device patients, but it is more imperative for device candidates, who may need immediate assistance at home in the event of a serious device alarm.
Age is a key criterion for acceptance for heart transplant that has generated much debate. Some centers will accept candidates in the seventh decade of life, whereas other centers are more conservative. Results of outcomes of heart transplant in elderly patients have been mixed, whereas outcomes of destination LVADs in this patient population have improved. However, no study has prospectively compared heart transplant with LVAD-DT in elderly patients. Realistically, whether a scarce resource, such as a cardiac allograft, should be used in elderly patients is unclear. With the excellent long-term survival of allografts, the organ can very well outlast the recipient; thus, we may be using a scarce resource for a patient group that may not reap all of its benefits. In reports of alternate list heart transplant candidates, many over 65 years of age who received extended donors, these recipients frequently died, not from cardiac problems, but from comorbidities or the development of new, unforeseen medical problems. The intense immunosuppression needed at the time of transplant can unmask or trigger malignancies. At our center, we performed a retrospective analysis on the use of continuous-flow (CF)-LVADs comparing 23 patients from 65 to 72 years of age with 47 heart transplant recipients in the same age group. Those patients selected for LVAD as DT were slightly older and had greater hemodynamic impairment than those who were transplanted. Despite these differences, the 2-year survival rates post-LVAD or -transplant were comparable. Whether the long-term outcomes would be similar is unknown. The choice of the ideal therapy for these patients needs to be studied in a prospective trial.
Statistical survival models that include both BTT and DT LVAD have also been developed. The Model for End Stage Liver Disease (MELD) has been used to prognosticate the risk of patients with cirrhosis undergoing shunt placement and is currently used to risk stratify patients for liver transplant. This formula includes the log transformation of serum creatinine, bilirubin, and prothrombin time international normalized ratio (INR). MELD scores >17 were associated with increased risk for perioperative bleeding and mortality in DT and BTT LVAD patients. In an analysis of the HeartMate II registry, maintained by Thoratec, Inc. (Pleasanton, California), age, serum albumin, creatinine, INR, and center volume of LVAD surgeries were the strongest parameters in determining 90-day mortality. A HeartMate II Risk Score was derived. Patients were risk stratified by the scores, with a low risk score <1.58 and a high risk score >2.48, using the following equation (0.0274 × [age in years]) − (0.723 × albumin g/dl) + (0.74 × creatinine mg/dl) + (1.136 × INR) + (0.807 × 1 if LVAD volume <15 and 0 if LVAD volume >15). However, subsequent analysis questioned the reproducibility of such scores in discriminating outcomes in high-volume centers.
Analysis of the INTERMACS data has provided insights as to characteristics of DT patients who have survival comparable to transplant outcomes. Of the 1,287 DT candidates analyzed from June 2006 to December 2011, of whom 1,160 received CF-LVADs and 128 received pulsatile pumps, 112 patients who were not INTERMACs Level 1, had no prior history of cancer, no previous cardiovascular surgery, and blood urea nitrogen <50 mg/dl comprised the low-risk patients with 1- and 2-year survival of 88% and 80%, respectively. Risk factors for increased mortality included: older age (>75 years), elevated body mass index (>32 kg/m), history of malignancy, history of cardiac surgery, cardiogenic shock (INTERMACS level 1), dialysis, renal insufficiency (blood urea nitrogen >50 mg/dl), and use of a pulsatile device or a right ventricular assist device. Further risk stratification could conceivably be performed to identify subsets of patients who would have survival comparable to transplant, thus helping to decompress the ever-lengthening cardiac transplant recipient waitlist.
With the continued expansion of LVAD therapy as a BTT and DT, cardiac transplantation may eventually become the future bailout strategy for device patients who develop complications. Analysis of United Network of Organ Sharing data already shows a shift in the allocation of organs to more Status 1A patients with device complications. The greater numbers of BTT listed as United Network of Organ Sharing 1A due to device malfunction, thrombosis, and infection may negatively affect the current excellent long-term transplant outcomes. In this study, however, infected ventricular assist device patients had significantly lower 1-year post-transplant survival.