Heart failure (HF) is a leading cause of morbidity and mortality with a current prevalence of more than 5.8 million in the United States and more than 23 million worldwide.1,2 More than 2.4 million patients who are hospitalized have HF as a primary or secondary diagnosis, and approximately 300,000 deaths annually are directly attributable to HF.1 Left ventricular assist devices (LVADs) are most often used as bridge to transplantation (BTT) or destination therapy. Bridge to transplantation provides short-term support for patients awaiting cardiac transplantation. Destination therapy provides long-term cardiac support and is indicated in patients ineligible for transplantation. These pumps have improved the quality of life and overall survival of patients when all other therapeutic options have been exhausted.3–5 However, there are risks associated with LVAD therapy such as infection, stroke, and device malfunction. Heart transplantation also has substantial risks because of prolonged immunosuppression and is limited by the lifespan of the donor heart.
Over the past decade, there has been a shift in LVAD technology, where pulsatile LVADs have been superseded by the continuous-flow LVADs that are smaller, quieter, and more durable. Continuous-flow LVADs utilize a rotary pump to provide blood flow with reduced pulsatility and have been shown to improve the hemodynamics, end-organ function, quality of life, and functional capacity of patients awaiting transplantation.4,6 These improvements have allowed continuous-flow LVADs to increase the duration of ventricular support from months to years. A recent randomized trial demonstrated that treatment with a continuous-flow LVAD in patients with advance HF significantly improved the probability of survival free from stroke and device failure at 2 years compared with the pulsatile device (only 2 patients of 59 were alive, both of whom had replacement devices).5
Recently, studies have reported that a proportion of patients who have exhibited cardiac recovery during LVAD support can have their device explanted with reasonable long-term survival. This use of LVAD is otherwise termed as bridge to recovery (BTR).3,7–9 These select patients have exhibited improvement in a number of physiologic, histologic, and subcellular markers of native heart function after a variable period of mechanical circulatory support and subsequent weaning.7,8,10,11 However, it remains uncertain whether patients suited for LVAD explantation continue to recover their cardiac function or redevelop HF. There has also been limited evidence on long-term survival after LVAD explant. The aim of this systematic review is to assess survival and cardiac function in patients with explanted LVADs from the current literature.
Literature Search Strategy
Electronic searches were performed using Ovid Medline, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club, and Database of Abstracts of Review of Effectiveness from their dates of inception to July 2015. To achieve maximum sensitivity of the search strategy and identify all studies, we combined the terms “LVAD,” “left ventricular assist device,” “explants,” “explantation,” “removal,” “recovery,” “weaning,” and “bridge” as either keywords or MeSH terms. The reference lists of all retrieved articles were reviewed for further identification of potentially relevant studies. All identified articles were systematically assessed using the inclusion and exclusion criteria.
All studies published in English assessing LVAD explantation were included. Case reports or studies containing fewer than four explanted patients were excluded. When institutions published duplicate studies with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included for quantitative assessment. All publications were limited to those involving human subjects and in the English language. Abstracts, case reports, conference presentations, editorials, reviews, and expert opinions were excluded.
Data Extraction and Critical Appraisal
All data were extracted from article texts, tables, and figures. Two investigators independently reviewed each retrieved article (D.F.Z. and K.P.). Discrepancies between the two reviewers were resolved by discussion and consensus with senior reviewers (V.T. and T.D.Y.). Assessment of risk of bias for each selected study was performed according to the most updated Cochrane statement. Discrepancies between the two reviewers were resolved by discussion and consensus. Long-term survival was assessed by pooled actuarial freedom from mortality extracted from Kaplan–Meier curves or data presented in text or tables. Perioperative mortality was defined as death within 30 days after explantation. Late mortality was defined based on the survival at least 1 year after explantation.
Data are presented as mean ± standard deviation. For weighted pooled means, a meta-analysis of proportions was conducted. First, to establish variance of raw proportions, a Freeman–Tukey transformation was applied. To incorporate heterogeneity (anticipated among the included studies), transformed proportions were combined using DerSimonian–Laird random effects models. Finally, the pooled estimates were back transformed to proportions. Heterogeneity was evaluated using Cochran Q and I2 test. Weighted means were calculated by determining the total number of events divided by total sample size. All analyses were performed using R Software, version 3.02 (R Foundation for Statistical Computing, Vienna, Austria). The systematic review analysis was performed using the metafor package for R Software. p values <0.05 were considered statistically significant.
A total of 234 studies were identified through 6 electronic database searches and from other sources including reference lists (Figure 1). After exclusion of duplicate or irrelevant references, 22 potentially relevant articles were retrieved. Manual search of reference lists did not yield further studies. After detailed evaluation of these articles, a total of 11 relevant retrospective studies were identified and included in the present systematic review and meta-analysis.3,7–9,12–19 A total of 213 patients were included for analysis (Table 1). Baseline patient characteristics are summarized in Table 2.
All included studies were observational, retrospective studies without comparison groups. There were 2 studies with more than 40 patients,7,8 4 studies with more than 20 patients,3,9,12,13 and 4 studies with less than 10 patients.14–17,19 Eight studies reported mean follow-up of 12 months or longer. Nine studies reported HF recurrence rates. The rate of LVAD reimplantation, transplantation after LVAD explantation, and perioperative mortality were reported in all but three included studies. Late mortality was reported in all but two included. Early postexplant left ventricular ejection fraction (LVEF) was reported in three studies, whereas late postexplant LVEF was reported in six studies. Survival analysis at 1, 5, and 10 years was reported by six, five, and two studies, respectively. Assessment of postoperative outcomes and cardiac function after LVAD explant are summarized in Tables 3 to 6.
Continuous-Flow and Pulsatile LVADs
Continuous-flow LVADs were used in 94 (44.1%) of all patients included in this study. Pulsatile-flow LVADs were used in 119 patients (55.9%; Table 1). Four studies used only continuous-flow LVADs, five studies used only pulsatile LVADs, and two studies used a combination of both types (continuous flow used in 55 and 29.2% of the cohort of two studies).
Baseline patient characteristics are summarized in Table 1. The mean age of patients ranged from 28.4 to 50 years, with the male sex predominating in most studies [odds ratio 2.28, p=0.25] (Table 2). Most patients had nonischemic cardiomyopathy, with pooled weighted average proportion of 92.6%, compared with 7.0% of patients having ischemic cardiomyopathy (Figure 2). The mean duration of HF ranged from less than 1 month to 58.3 months, whereas the mean duration of LVAD support ranged from 57 to 606 days. Preimplant mean LVEF ranged from 12.3% to 22%, whereas mean left ventricular end-diastolic diameter (LVEDD) ranged from 53 to 74.3 mm. Mean Fick cardiac index ranged from 1.6 to 2.24 L/min/m2.
Risk of Bias Assessment
Supplemental Table 1 (see Supplemental Digital Content 1, http://links.lww.com/ASAIO/A89) provides detailed information on study appraisal. Because quality scoring is controversial in meta-analyses of observational studies, two reviewers (D.F.Z. and K.P.) independently appraised each article included in our analysis according to a critical review checklist of the Dutch Cochrane Centre proposed by MOOSE. The key points of this checklist include 1) clear definition of study population; 2) clear definition of outcomes and outcome assessment; 3) independent assessment of outcome parameters; 4) sufficient duration of follow-up; 5) no selective loss during follow-up; and 6) important confounders and prognostic factors identified.
Assessment of Mortality
From all included studies, the perioperative mortality rate ranged from 0% to 22.7%, with weighted pooled mean of 9.2% (95% CI, 5.0–14.5%; I2 = 0). Subgroup analysis revealed that the pooled perioperative mortality was comparable in studies that used continuous-flow LVADs compared with pulsatile LVADs (5.1 vs. 10.9%, p = 0.285; Figure 3 and Table 5). The overall rate of late mortality ranged from 0% to 40%, with weighted pooled mean of 15% (95% CI, 9.0–22.1%; I2 = 31%). Subgroup analysis revealed that the pooled late mortality was not significantly different in continuous-flow LVADs compared with pulsatile LVADs (9.1 vs. 16.5%, p = 0.267; Figure 3 and Table 5).
The overall rate of cardiovascular deaths was 10.8% (95% CI, 4.6–19.2%; I2 = 40.4%), with a range of 0–22.2%. The stroke rate ranged from 0% to 20%, with weighted pooled mean of 4.9% (95% CI, 1.4–10.5; I2 = 23.7%). The rate of postexplant infection ranged from 2.2% to 20%, with weighted pooled mean of 4.3% (95% CI, 1.6–8%; I2 = 0; Figure 3). When analyzed based on type of LVAD, the overall rate of cardiovascular deaths, stroke rate, and postexplant infection had a trend of being lower in the studies that used continuous-flow LVADs compared with pulsatile LVADs (4.5 vs. 7.1%; 11.2 vs. 20%, and 3.7 vs. 6.8%, respectively; Figure 3 and Table 5); however, this did not reach statistical significance.
Recurrence of HF
The recurrence of HF occurred in 0–59.1% of patients, with weighted pooled mean of 18.7% (95% CI, 8.6–31.7%). There was significant heterogeneity between the studies (I2 = 76.8, p < 0.001). However, subgroup analysis revealed that the pooled recurrence of HF was lower in the studies that used continuous-flow LVADs compared with pulsatile LVADs (6.6 vs. 28.3%, p = 0.03). There was no significant heterogeneity for the studies with continuous-flow LVADs (I2 = 0%, p = 0.41); however, significant heterogeneity was present for the studies that used pulsatile LVADs (I2 = 75.3%, p < 0.007; Table 3 and Figure 4). The total number of explants was 205, given an explant rate of 4.98% (range 1.8%–23.5%). When this was analyzed in subgroups, the continuous device group had an explant rate of 2.9% compared to 6.0% in the pulsatile device group.
LVAD Reimplantation and Heart Transplantation
Patients requiring LVAD reimplantation ranged from 0% to 40%, with weighted pooled mean of 8.9% (95% CI, 1.4–20.1%; I2 = 67.2%). The overall risk of patients requiring transplantation after LVAD explantation was 11.2% (95% CI, 4.4–20.1%; I2 = 51.1%), with a range of 0–33% (Table 3 and Figure 4). When analyzed based on the type of LVAD, the rate of patients requiring LVAD reimplantation was substantially lower in the studies that used continuous-flow compared with pulsatile (7.5 vs. 37%, p = 0.001; Figure 3 and Table 5). There was also a trend for higher heart transplantation rates in the pulsatile versus continuous-flow LVAD subgroup (13.9 vs. 4.8%, p = 0.126); however, this difference did not reach statistical significance.
Assessment of Cardiac Function and Long-Term Survival
In terms of LVEF, the pooled preexplantation, early postexplantation, and late postexplantation values were 49% (95% CI, 45.7–52.3%; I2 = 59%; range, 46.9–56.3%), 47.3% (95% CI, 45.4–49.3%; I2 = 0; range, 45.6–58.5%), and 41.2% (95% CI, 34.7–47.7; I2 = 94.8%; range, 24–57.4%), respectively. Subgroup analysis revealed that the pooled preexplantation, early postexplantation, and late postexplantation LVEDD for the studies that used only continuous-flow LVADs were 51.8, 45.6, and 41.5 mm, respectively. Late postexplantation LVEF was found to be significantly higher in the continuous-flow LVAD versus pulsative LVAD (41.5 vs. 24%, p = 0.001).
In terms of LVEDD, the overall preexplantation value was 45.2 mm (95% CI, 36.3–54.1 mm; I2 = 85.1%), with a range of 40.3–49.4 mm. The postexplantation weighted pooled mean LVEDD was 54 mm (95% CI, 50.4–57.6 mm; I2 = 85.0; p < 0.001), with a range of 50–59.4 mm (Figure 5). Subgroup analysis revealed that the pooled preexplantation and postexplantation LVEDD for continuous-flow LVADs were 45.2 and 52.4 mm, respectively. Only one study reported the postexplant LVEDD with a pulsatile LVAD (52 mm).20 The pooled 1, 5, and 10 year survival was 91 (89.9–100%), 76 (71.4–85%), and 65.7%, respectively (Table 3).
The results of this systematic review show encouraging safety and long-term survival outcomes for the use of LVAD as a BTR treatment in carefully selected patients. Pooled meta-regression of the current literature demonstrated that LVAD explantation had a perioperative mortality of 9.2% and late mortality of 15%, with the main cause of death because of HF or other cardiac causes (10.8%). Pooled postweaning 5 year freedom from HF recurrence reached 81.3%. Pooled 1, 5, and 10 year survival rates after the removal of a LVAD were 91, 76, and 65.7%, respectively.
Mechanisms of Left Ventricular Recovery
Several reasons have been hypothesized to explain the mechanism behind how LVAD allows cardiac recovery enabling explantation without heart transplantation. Because of the different proportion of patients who recover, and the speed of recovery between the different etiologies of myocardial disease, the recovery mechanisms are likely to vary. A proportion of patients with dilated cardiomyopathy can achieve recovery of ventricular function after several months of LVAD support.11,21 It is suggested that this is because of reverse remodeling during chronic left ventricular unloading with a LVAD, where cardiac structure is normalized and chamber enlargement is reversed.22,23 Studies have also identified evidence of improvements in myocyte structure and function, as well as favorable reductions in the levels of neurohormones and cytokines in response from LVAD support.10,22,24–26 Conversely, reports have shown that severe acute myocarditis and noncoronary shock can completely reverse after weeks to months of LVAD support.27–30 This has been suggested to be because of the utility of the LVAD to provide the circulatory requirements of the body and improve coronary flow for the time necessary for natural resolution of the disease process or burn out of the inflammatory process.31
Incidence and Predictors of Recurrent Heart Failure After LVAD Explantation
In this review, pooled postexplant freedom from HF recurrence reached 81.3%. Because HF is the most frequent complication after LVAD removal and cause of mortality, several studies have attempted to identify predictors of postweaning cardiac stability and HF recurrence. Dandel et al.8 identified the highest predictive values for >5 year cardiac stability, reporting a LVEF ≥45% with a LVEDD ≤55 mm at a LVAD-off test. This was the largest study included in this review, which evaluated 47 patients with chronic cardiomyopathy who had a 5 and 10 year survival postexplantation of 71.4 and 65.7%, respectively. Postweaning 5 year freedom from HF recurrence was 66%. However, very few patients could fulfill these full-recovery criteria (e.g., only 5.1% [7 of 137] in the study by Saito et al.9). Saito et al. aggressively explanted the LVAD devices in patients with partial cardiac recovery. Saito et al.9 achieved a success rate of LVAD weaning in the partially recovered patients of 50%, and 3 of the 6 patients suffered from recurrence of HF. This was an appropriate success rate considering the overall 5 year freedom from HF recurrence of 66% for the Berlin group.8 Furthermore, Saito et al.9 succeeded in delaying the timing of heart transplantation in two patients for 22 and 42 months.
These findings and the pooled results from this review also highlight that LVAD explantation is feasible in patients without complete recovery of cardiac function.8,12,32 In this review, pooled postweaning 5 year freedom from HF recurrence reached 81.3%, despite the mean pooled preexplantation LVEF being only 49%. Frazier et al. demonstrated that patients who had progressed to a state of compensated HF could undergo explantation safely. One postexplant patient consistently had an ejection fraction of 30–40% and continued to be maintained on conventional medical therapy 6 years after device removal.12
Survival After LVAD Explant Compared with Transplantation
The outcome postexplantation for myocardial recovery is comparable, if not better, survival and lower failure rates and a lower rate of long-term complications than after BTT. Farrar et al.3 demonstrated identical 1 and 5 year survival between the explanted group and the transplanted group (86 vs. 86% and 77 vs. 77%, respectively). In the long term, the transplanted patients encountered typical complications related to their immunosuppression such as hypertension, dyslipidemia, coronary disease, and malignancy. Furthermore, Dandel et al.8 demonstrated that with the option of heart transplantation, 72.7% of patients who were weaned from LVADs were alive at the end of 5th postweaning year (79.2% with their native hearts). This survival is better than that expected after a heart transplant.33 In addition, studies have demonstrated that a significant number of explanted patients achieve a good quality of life without requiring a device or heart transplant.7,34 These findings suggest that the recovery of the native heart, which can take weeks to months of LVAD support, is the most desirable clinical outcome and should be actively sought, with transplantation used only after recovery of ventricular function has been ruled out. This is particularly important in young patients who are unlikely to live a normal lifespan even after a successful heart transplant.
Selection Criteria for Explantation and Assessments for Myocardial Recovery
It is important to highlight that these outcomes after explantation were a result of a regular assessments for myocardial recovery and various selection criteria to determine those patients suitable for LVAD explantation. Birk et al. performed echocardiography with the LVAD turned off for 5, 10, and 15 minutes. If this was well tolerated, the echocardiogram would be repeated after a “6 minute walk” with the device turned off. If a 6 minute walk distance of 300 m was achieved with no deterioration in echo parameters, exercise capacity would be determined with the device off after an appropriate period of rest (>6 hours). MUGA scans were used to assess the LVEF and right ventricular ejection fraction and response to exercise with the LVAD turned off.
After the investigations for myocardial recovery, the decision to explant remains difficult because of the lack of standardized criteria. For example, Birks et al.35 considered LVAD explantation if, with the device off, ventricular dimensions were normalized, LVEF was ≥45%, left ventricular end-diastolic pressure was ≤8 mmHg, cardiac index >2.8, VO2 max ≥20, and VE/VCO2 <34. In comparison, Dandel et al.36 considered weaning if the LVEF was ≥45%, LVEDD ≤ 55mm, cardiac index >2.6, pulmonary artery wedge pressure <13 mmHg, brachial artery pressure ≥65 mmHg, and heart rate <90 beats per minute when the patient was at rest. These variations in criteria likely account for the heterogeneity across studies. Future long-term studies with larger cohorts will be necessary to determine the relevant criteria to optimize patient outcomes.
Combination Program to Maximize Myocardial Recovery
Another potential confounder may be the differences in adjuvant pharmacologic therapy used to promote myocardial recovery before explantation.36,37 Birks and coworkers proposed a combination therapy that aggressively promoted myocardial recovery in patients with advanced dilated cardiomyopathy on LVAD support using a combination of additional specific drug therapies,38–41 combined with close monitoring42,43 of underlying myocardial function with the LVAD turned off or at very low speeds, which resulted in device explantation in several patients.35,44 The rationale of combination therapy is to achieve maximum loading of the myocardium combined with pharmacologic therapy, aimed at reversal of remodeling. It has been suggested that combining LVADs with β-blockers, angiotensin-converting-enzyme inhibitors and angiotensin-1 receptor antagonists, and spironolactone may maximize reverse remodeling through the effects on the renin-angiotensin system, endothelial function, and sarcoplasmic reticulum.45–47 In addition, Yacoub and coworkers40 suggested using an active exercise program and the β2 agonist clenbuterol to induce skeletal muscle hypertrophy, improve performance, and stimulate physiologic myocardial hypertrophy.41,48
Do Outcomes Differ Between Continuous-Flow Versus Pulsatile LVADs?
It is believed that pulsatile LVADs achieve higher coronary flow compared with continuous-flow LVADs, which may result in higher rates of myocardial recovery.49,50 Kato et al.51 studied the changes in markers of myocardial recovery: left ventricular ejection fraction, mitral E:EЈ ratio, and serum levels of molecular markers (BNP, MMP-9, and TIMP-4) in 61 patients supported with LVADs as bridge to transplant. Thirty-one of these patients were supported with pulsatile LVADs (29 with HeartMate XVE [Thoratec Corp., Pleasanton, CA] and 2 with Thoratec PVAD, [Thoratec Corp., Pleasanton, CA]) and 30 patients with continuous-flow LVADs (27 with HeartMate II [Thoratec Corp., Pleasanton, CA], 2 with Durahart [TerumoHeart, Ann Arbor, MI], and 1 with DeBakey VAD [Houston, TX]). On the basis of improved marker levels, authors concluded that pulsatile-flow LVADs are more effective in inducing myocardial recovery; however, none of the patients were actually explanted to allow analysis of the actual recovery or freedom from recurrence of HF. Krabatsch et al.52 studied 387 patients with dilated cardiomyopathy who underwent LVAD placement at their institution and were able to explant 34 (8.8%) patients in this patient category and found 3 times higher likelihood of explant in patients supported with pulsatile LVADs. The authors suggested that either pulsatility itself or the difference in left ventricular unloading may play a role in this difference.
Although in the study by Kato et al. no patient was actually explanted to study whether the patients have really recovered, in the study by Krabatsch et al.,52 all patients had dilated cardiomyopathy, which may not be representative of the entire patient population who requires LVAD support. Other studies on possible advantage of improved coronary flow in LVAD patients are either based on small number of animal models50 or in vitro.49 Overall, the published results in the literature are hypothesis generating but not sufficient to show the advantage of pulsatile LVADs in increasing the likelihood of explant.
Our analysis also suggested that pulsatile pumps got explanted more often than continuous-flow pumps, but the difference was not statistically significant (6.0% vs 2.9%, p=0.12). Shorter life and higher complication profiles of these pumps may factor indirectly in the decision to explant. Conversely, our pooled analysis of all published data identified that explantation from continuous-flow LVADs had low rates of HF recurrence (6.6 vs. 28.3%), LVAD reimplantations (7.5 vs. 37%), and heart transplants (4.8 vs. 13.9%) compared with pulsatile LVADs. Late post-explantation LVEF was significantly higher in the continuous-flow LVAD versus pulsatile LVAD subgroup (41.5 vs. 24%, p = 0.001). Given these findings, it could be possible that patients with pulsatile LVADs are more likely to get explanted; however, they are also more likely to get recurrence of HF and require LVAD reimplantation compared with continuous-flow LVADs. There was also a trend for higher heart transplantation rates in the pulsatile versus continuous-flow LVAD subgroup (13.9 vs. 4.8%, p = 0.126), which could have contributing to higher explant rates in pulsatile LVAD patients. Given too much heterogeneity in the pulsatile LVAD group, however, these differences should be interpreted with caution.
In further attempt to enhance the myocardial recovery, currently, flow modulation control strategies are being examined to generate pulsatility in centrifugal continuous-flow LVADs. For example, the new HeartMate III LVAD (Thoratec Corp.) includes a pulse mode that can produce near-physiologic pulse pressure,53 whereas the HeartWare HVAD (HeartWare Inc., Framinham, MA) speed modulating function, intended to avoid thrombus formation, is currently being further developed to induce greater pulsatility.54 Although strengths of the present systematic review include a pooled meta-analysis of the data from all currently available literature, as well as subgroup analysis according to LVAD device type, future large randomized controlled trials involving newer LVADs are warranted to shed more light at the outcomes after LVAD explantation.
The clinical implications of LVAD explantation are significant considering the risks associated with LVAD therapy (i.e., infection, device failure), in addition to the increasing number of patients with HF paired with the limited number of donor hearts available for transplantation. Moreover, although the proportion of patients suitable for explantation is widely believed to be low, the true number of patients who are suitable to undergo explantation is not actually known as LVAD centers do not to actively pursue a reconditioning strategy. Birks et al.7 have demonstrated that aggressively attempting recovery in patients in a bridge-to-transplant program can avoid transplantation in a significant proportion. Therefore, to achieve larger, more reliable studies, as well as ease the demand for donor hearts, LVAD centers need to vigorously assess whether patients in the bridge-to-transplant program are viable to undergo explantation.8
Future Research and Improvement for LVAD Explantation
For LVADs to be used routinely as a BTR and as viable alternative to cardiac transplantation, further clarification as to which patients have the best possibility of recovering ventricular function with LVADs is warranted. Also, optimal modalities of support, appropriate adjuvant medical therapies, and other appropriate weaning strategies need to be developed. Some authors have suggested that full left ventricular pressure unloading for periods of time should be implemented to encourage stretch-mediated reverse remodeling.3 Others have suggested a strategy of combined mechanical and pharmacologic therapy to stimulate physiologic hypertrophy during LVAD support.55 Moreover, there has been increasing interest in the use of stem cell therapy to synergistically enhance LVAD-mediated cardiac recovery (ongoing trials by Cardiothoracic Surgical Trials Network http://www.ctsurgerynet.org)
Interpretation of the results from this review needs to take into consideration several limitations. First, there were only a small number of patients in the included studies. This restricted additional statistical evaluation based on the etiology of disease and also reduced statistical power of analysis. Second, there was a paucity of data regarding the change of LVEF and LVEDD over time and essential absence of other parameter such as stroke volume. This makes it difficult to assess the change of cardiac function after LVAD explant.
The results of this systematic review of LVAD patients show encouraging safety and long-term survival outcomes using a bridge-to-recovery treatment option as a competitive strategy since outcomes exceed that documents for heart transplant. Recovery of ventricular function should be actively sought in LVAD centers, using aggressive recondition methods, leaving transplantation for patients which sufficient recovery does not occur.
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