Effect of ABO-Incompatible Listing on Infant Heart Transplant Waitlist Outcomes: Analysis of the United Network for Organ Sharing (UNOS) Database

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1 FEATURED ARTICLES Effect of ABO-Incompatible Listing on Infant Heart Transplant Waitlist Outcomes: Analysis of the United Network for Organ Sharing (UNOS) Database Melanie D. Everitt, MD, a,b,c Amy E. Donaldson, MS, c T. Charles Casper, PhD, c Josef Stehlik, MD, a,c,e John A. Hawkins, MD, a,b,c Lloyd Y. Tani, MD, a,b,c Dale G. Renlund, MD, a,d Peter C. Kouretas, MD, PhD, a,b,c Aditya K. Kaza, MD, a,b,c Emily A. Bullock, RN, a,b Michelle Cardon, PNP, a,b and Abdallah G. Kfoury, MD a,d Background: Methods: Results: Conclusions: Midterm heart transplant outcomes of ABO-incompatible (ABO-I) organ use in infants are favorable. ABO-I transplantation has resulted in reduced waitlist mortality in some countries. This study assessed the effect of an ABO-I listing strategy on pre-transplant outcomes in the United States. The Organ Procurement and Transplantation Network (OPTN)/United Network of Organ Sharing (UNOS) database was used to identify infants aged younger than 1 year listed as status 1 for heart transplantation between January 1, 2001, and May 20, The cohort was divided into 2 groups: eligible for ABO-compatible (ABO-C) transplant and eligible for ABO-I transplant. Baseline characteristics, waitlist times, and outcomes were compared in univariate analysis. Competing risks analysis evaluated differences in time to transplant in the presence of other outcomes. Of 1,029 infants listed for transplant, 277 (27%) were listed for an ABO-I transplant. Overall, 92% of transplant recipients received an ABO-C organ regardless of listing type. Among recipients eligible for ABO-I, only 27% received an ABO-I organ. The percentage that underwent transplant in each group did not differ. Although infants listed for an ABO-I organ had a shorter wait time for transplant, waitlist mortality was similar. Despite the intended merits of ABO-I heart transplantation, ABO-I listing and organ acceptance have not yielded lower waitlist mortality in the United States under the current UNOS allocation algorithm. Consideration should be given to altering the allocation system to one that gives less preference toward blood group compatibility in hopes of improving organ use and reducing waitlist mortality. J Heart Lung Transplant 2009;28: Copyright 2009 by the International Society for Heart and Lung Transplantation. With the introduction of cyclosporine in 1980, heart transplantation has been a promising treatment option for children with cardiomyopathies refractory to medical therapy and congenital heart defects (CHD) not amenable to surgical treatment. 1 The success of heart transplantation, however, depends on the timely availability of suitable donor organs. The shortage of donor organs is most apparent among infants aged younger than 12 months old. Although 218 infants were added From a Utah Transplant Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, b Primary Children s Medical Center, c University of Utah, School of Medicine, d Intermountain Medical Center, and e Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah. Submitted May 8, 2008; revised June 22, 2009; accepted June 26, Reprint requests: Melanie D. Everitt, MD, Department of Pediatrics, Division of Cardiology, Primary Children s Medical Center, 100 N. Mario Capecchi Dr, Ste 1500, Salt Lake City, UT Telephone: Fax: melanie.everitt@imail.org Copyright 2009 by the International Society for Heart and Lung Transplantation /09/$ see front matter. doi: / j.healun to the heart transplantation waitlist in the United States in 2008, only 114 organ donors of the same age were available, and from these, only 87 hearts were transplanted, 84 to recipients in the United States and 3 to recipients in Canada. 2 Larger infants can accept an organ from an older donor, but the availability of donor organs remains limited. Moreover, with few options for prolonged mechanical circulatory support while awaiting a suitable organ, the mortality rate among infants listed at age younger than 1 year remains 10-times greater than that of older children and approaches 20 times the death rate per patient-years of adults awaiting heart transplantation in the United States. 3 Since the publication by West et al 4 establishing the feasibility of ABO-incompatible (ABO-I) heart transplantation in infants, many centers in the United States have used this strategy in hopes of decreasing waitlist mortality and optimizing organ use. A recent analysis of the United Network for Organ Sharing (UNOS) Database reported the experience in 25 infants undergoing ABO-I heart transplantation between January 1999 and January The outcomes in this cohort of infants have 1254

2 The Journal of Heart and Lung Transplantation Everitt et al Volume 28, Number 12 been favorable, with 3-year survival being similar to the 556 infants who underwent ABO-C transplants during the same time period. 5 However, the goal of accepting ABO-I donor hearts is not only to achieve comparable post-transplant survival rates but also to improve waitlist outcomes by reducing pre-transplant death through increased organ use. After the adoption of a strategy to accept ABO-I donor hearts for infants in Canada, ABO-I transplants rose to 40% of all transplants in this age group, and the waitlist mortality rate in infants aged younger than 6 months decreased from 58% to 7%. 6 Under the Canadian system of organ allocation, failure to accept an ABO-I organ was shown to be an independent risk factor for death after listing in infants aged up to 18 months old. Moreover, the only factor associated with a greater likelihood of undergoing heart transplantation was being listed as eligible for an ABO-I organ. 6 Although the acceptance of ABO-I organs has dramatically improved waitlist outcomes and increased the likelihood of transplantation in Canada, the allocation system differs significantly in the United States. Heart allocation algorithms elsewhere focus on listing status and geographic location, such that the first suitable organ is allocated to the patient with the longest waiting time at the highest medical urgency, without preferential allocation to compatible donor and recipient blood groups. 6,7 Under the current UNOS allocation system in the United States, ABO blood type is factored into the allocation algorithm such that donor hearts are distributed with priority to potential recipients of identical blood groups, followed by compatible and lastly, incompatible blood groups. This study sought to assess the effect of ABO-I listing on waitlist time and death in the United States, where organ allocation policy favors identical ABO blood group recipients. METHODS Patient Population After administrative review and approval by our institutional research ethics board, we retrospectively reviewed de-identified patient data extracted from the Organ Procurement and Transplantation Network (OPTN)/UNOS research database. We identified all infants aged younger than 12 months listed for primary heart transplantation between January 1, 2001, and May 20, Medical urgency as defined by UNOS includes status 1A (highest clinical acuity), 1B, and 2. Only patients designated at status 1A or 1B at the time of initial listing were included for analysis. When the initial listing occurred in utero, only the postnatal listing was used for analysis. The cohort was then divided into 2 groups: candidates listed as eligible for ABO-C only heart transplant and candidates listed as eligible for ABO-I heart transplant. Infants of blood type AB who were listed to accept multiple or incompatible blood types were included in the ABO-C only group. According to UNOS policy 3.7.8, an infant aged younger than 1 year may be listed as eligible to accept a heart from any blood type donor if the infant is listed at status 1A or 1B and has a current isohemagglutinin titer of 1:4 or less. Excluded were patients with a history of prior heart transplantation or listed for combined heart-lung transplantation. Data collected with respect to listing included the year of listing for heart transplant, geographic region in which the patient was listed, and the eligibility of the patient for an ABO-I organ. Clinical status (1A or 1B) at the time of initial listing, weight at the time of listing, blood type, the presence of congenital heart disease, and a history of cardiac surgery were also collected. Information pertaining to invasive support at the time of initial listing was noted and included the use of mechanical ventilation, intravenous inotropes, intravenous prostaglandin, and extracorporeal membrane oxygenation (ECMO) or ventricular assist device. The total number of days on the waitlist as well as days listed as status 1A and/or status 1B were extracted for each infant. Data regarding the end points of transplantation, death, waitlist removal for deterioration, and waitlist removal for improvement were obtained. For patients who received a heart transplant, blood group of the donor was collected. Statistical Analysis We compared patient and clinical characteristics at the time of listing for ABO-C and ABO-I infants and evaluated differences using the chi-square test for categoric variables and a Wilcoxon rank sum test for continuous variables. Descriptive statistics are presented as counts and percentages for categoric data. Continuous variables are described using the mean and standard deviation, or the median and interquartile range (IQR, 25th 75th percentile), as appropriate. A basic comparison of waitlist time, defined as time from initial listing to outcome or end of study, was done using a Wilcoxon rank sum test. The primary outcome of interest was time to one of several competing events: transplantation, death or waitlist removal for deterioration, waitlist removal for improvement, and other. Data of patients who were still awaiting a transplant at study end were censored. The cumulative incidence function for each competing outcome was estimated and compared between ABO-C and ABO-I using methods described by Gray. 8 We used competing risks regression with weighted estimating equations to model the sub-distribution of time to transplant in the presence of other outcomes. 9 This model controlled for baseline characteristics that differed significantly between ABO-C and ABO-I infants

3 1256 Everitt et al. The Journal of Heart and Lung Transplantation December 2009 at the time of listing. The hazard ratios (HR) of the subdistribution are presented with corresponding 95% confidence intervals (CI). We examined residual plots and considered inclusion of interactions between the predictor variables and time to assess the proportional hazards assumptions for these models. Because studies of infants awaiting heart transplant have found blood group O to be associated with higher waitlist mortality and longer interval to transplant, we prospectively identified patients with blood type O as a sub-group of interest, and analyses were repeated for this group. 10,11 The need for ECMO support has also been shown to predict waitlist mortality, 12 so patients supported by ECMO were identified prospectively and analyses were repeated. A significance level of 0.05 was used for all analyses. Analyses were performed using SAS 9.1 software (SAS Institute Inc, Cary, NC) and the statistical package R (cmprsk analysis package used for competing risks). RESULTS Patient Demographics As of May 20, 2008, 1,029 infants aged younger than 12 months were listed to undergo heart transplantation, and 277 (27%) were listed as eligible to receive an ABO-I organ. The percentage of infants during the study period listed as eligible to accept an ABO-I organ increased over time from 5.8% (9 of 154) in 2001 to 43.9% (65 of 148) in Baseline patient characteristics at the time of listing differed between groups. Infants listed as eligible for an ABO-I transplant were smaller by weight at the time of initial listing, were more likely to be supported with ECMO, were more likely to be listed initially as status 1A, and were less likely to be receiving intravenous prostaglandin or inotropic support (Table 1). With respect to transplant center listing practices, there was significant variability across 11 geographic regions within UNOS, ranging from 1.9% (2 of 104) of total registrants listed as eligible for an ABO-I transplant to as high as 63% (15 of 24) of total infants listed as eligible for an ABO-I transplant. Outcome and Survival of Patients Listed for Transplant During the study period, 543 of the 1,029 infants (53%) underwent transplantation, with a median time to transplant of 29 days (IQR, days). Irrespective of listing strategy, 92% of all transplant recipients received an organ from an ABO compatible donor. Among 147 transplant recipients eligible for ABO-I, 107 (73%) received an ABO-C organ and 40 (27%) received an ABO-I organ. The overall percentage of infants who underwent transplantation in each group did not differ: 53% (396 of 752) of those eligible for ABO-C only and 53% (147 of 277) of those eligible for ABO-I (p 0.91). With Table 1. Patient Characteristics at the Time of Initial Listing According to ABO Listing Strategy Eligible for ABO-C Eligible for ABO-I Characteristics at initial listing N 752 N 277 p-value Weight, mean (SD), kg 4.5 (1.7) 4.1 (1.5) 0.01 Blood group, No. (%) a 0.68 O 382 (53.4) 147 (53.1) A 252 (35.2) 93 (33.6) B 82 (11.5) 37 (13.4) Primary diagnosis, No. (%) b 0.1 Cardiomyopathy 242 (32.4) 68 (25.4) Congenital heart disease 478 (63.9) 190 (70.9) Other 28 (3.7) 10 (3.7) Prior cardiac surgery, No. (%) c 127 (39.7) 88 (45.1) 0.22 Prostaglandin support, No. (%) 121 (16.1) 27 (9.7) 0.01 IV inotropic support, No. (%) 446 (59.3) 144 (52.0) 0.04 Mechanical support, No. (%) Ventilatory 372 (49.5) 134 (48.4) 0.76 Circulatory (ECMO) 128 (17) 94 (33.9) 0.01 Medical urgency status 0.02 IA, No. (%) 672 (89.4) 261 (94.2) 1B, No. (%) 80 (10.6) 16 (5.8) ABO-C, ABO compatible; ABO-I, ABO incompatible; ECMO, extracorporeal membrane oxygenation; IV, intravenous; SD, standard deviation. a This comparison excluded 36 registrants of blood type AB due to the universal compatibility of this blood group with all donor blood types. b Registrants with missing data for this category were excluded, 4 in the ABO-C group and 9 in the ABO-I group. c Registrants with missing data for this category were excluded, 432 in the ABO-C group and 82 in the ABO-I group. regard to waitlist mortality, there was no difference in death or removal from the waitlist due to clinical deterioration. Specifically, of the 752 infants listed for ABO-C transplant only, 152 (20.2%) died and 63 (8.4%) were delisted as too sick. Of the 277 infants eligible for an ABO-I transplant, 55 (19.9%) died and 28 (10.1%) were delisted as too sick. Waitlist times are detailed in Table 2. Total waitlist time and waitlist time by status did differ statistically between the groups. Overall, infants eligible for an ABO-I organ had a 2-week shorter median waitlist time than infants listed as eligible for an ABO-C organ only (21 vs 35 days, p 0.001). Among 481 infants listed at the highest clinical acuity status (1A) who received an allograft, 136 (28%) were listed as eligible for an ABO-I organ and 345 (72%) were listed as eligible for an ABO-C organ only. Those transplant recipients eligible for an ABO-I organ had a shorter median time to transplantation than those listed for an ABO-C organ only (21 vs 32 days, p 0.001). At study end, 56 patients (5.4%) were still awaiting transplantation. Among those eligible for an ABO-I organ who underwent transplantation, 14.3% of blood group A recipients, 22.2% of blood group B recipients, and 36.3% of blood group O recipients received an organ from an

4 The Journal of Heart and Lung Transplantation Everitt et al Volume 28, Number 12 Table 2. Waitlist Times by Listing Strategy: Eligible for ABO-Compatible Transplant Only vs Eligible for ABO-Incompatible Transplant Eligible for ABO-C only Eligible for ABO-I Variable Waitlist time, days No. Median (IQR) No. Median (IQR) p-value Total (1A 1B) (12 81) (7 53) Time (status 1A) (11 71) (7 48) Time (status 1B) (24 289) (36 108) 0.95 Percentage transplanted Status 1A 1B (N 543) Status 1A (N 481) Waitlist time to transplant, status 1A at listing (12 65) (5 44) ABO-C, ABO compatible; ABO-I, ABO incompatible; IQR, interquartile range. ABO-I donor (p 0.02 for association between blood group and receipt of an ABO-I organ). The probability of competing outcomes for the entire group of 1,029 patients is shown in Figure 1. Figure 2 shows the probability of competing outcomes stratified by ABO-I and ABO-C listing mode. In the unadjusted competing risks analysis of ABO-C and ABO-I eligible infants, no significant differences were noted in any of the outcomes. Table 3 summarizes the estimated cumulative incidence for each of the competing outcomes at 7, 14, 30, 60, 90, and 180 days after listing for each sub-group, ABO-C and ABO-I eligible infants. The multivariable competing risks regression analysis of time to transplant and of time to death or waitlist removal for deterioration in the presence of other outcomes is detailed in Table 4. After controlling for key clinical covariates, infants listed as eligible for ABO-I organs had a shorter expected wait time for transplant than infants listed to receive ABO-C organs only (HR, 1.26; 95% CI, ). Greater weight at the time of listing was a key predictor of shorter expected time to transplant. As in the univariate analysis, the risk of death or waitlist removal for deterioration over time was not Figure 1. Cumulative plot for probability of competing outcomes is shown for the 1,029 patients in the study. significantly different between infants listed as ABO-I and ABO-C. Smaller weight, the need for mechanical ventilation, the need for ECMO support, and listing at the highest clinical acuity were independent risk factors for a shorter expected time to death or waitlist removal for deterioration (Table 4). Findings were similar when the outcomes of death and waitlist removal for deterioration were analyzed as separate outcomes. When the competing risks regression models included terms for interactions between the predictor variables and waitlist time, the observed effect of ABO listing type was not found to vary with time and the results for this variable remained as reported in Table 4. Although some of the predictor variables changed with waitlist time, their inclusion in the competing risks regression models did not change the HR estimates or values of p corresponding to the other predictor variables. Sub-group Analysis of Blood Type O Infants The blood type O sub-group in our study comprised 382 infants listed to receive ABO-C organs and 147 infants listed as eligible to receive ABO-I organs. The percentage of patients with blood type O who underwent transplantation was 54.4% for infants listed to receive ABO-I organs and 44.5% for those listed for ABO-C organs (p 0.04). In competing risks analysis, infants listed as eligible to receive ABO-I organs had a shorter expected wait time for transplant than infants listed to receive ABO-C organs only, even before adjustment for key baseline characteristics, (p 0.001). This result still held after adjustment for baseline covariates (HR, 1.71; 95% CI, ). There was no significant difference in waitlist removal for death or deterioration, with 30 (5.7%) still awaiting transplant at the end of the study period. Sub-group Analysis of Infants Supported by ECMO The sub-group of patients on ECMO at initial listing consisted of 128 infants listed to receive ABO-C organs

5 1258 Everitt et al. The Journal of Heart and Lung Transplantation December 2009 Figure 2. Probability of competing outcomes is shown stratified by ABO-incompatible (ABO-I) and ABO-compatible (ABO-C) listing mode. (p 0.14 for transplant; p 0.37 for death or deterioration; p 0.62 for improvement). and 94 infants listed as eligible to receive ABO-I organs. For infants listed to receive ABO-C organs, 30.5% underwent transplantation compared with 39.4% of patients listed for ABO-I organs (p 0.17). There was not a significant difference in time to transplant between the ABO-I and ABO-C groups in the unadjusted competing risks analysis. After adjustment for other baseline covariates, infants listed as eligible to receive ABO-I organs did have a shorter expected wait time for transplant than infants listed to receive ABO-C organs only (HR, 1.70; 95% CI, ). There was no significant difference in waitlist removal for death or deterioration, with 6 patients (2.7%) still awaiting transplant at the end of the study period. DISCUSSION ABO-I heart transplantation for infants without established isohemagglutinin production is increasingly performed worldwide with favorable post-transplant outcomes. 7,13,14 These favorable results led to the acceptance of ABO-I organ transplantation in 2001 by the UNOS, which governs transplantation in the United States. Our study shows that although the number of infants listed as eligible for ABO-I transplant in the United States has steadily increased, such that approximately half of all infants listed for heart transplant are now eligible for an ABO-I organ, the number of ABO-I heart transplants performed in the United States remains low. Only 8% of infant heart transplant recipients received an ABO-I organ between years 2001 and Although we found a shorter waiting time for heart transplantation in infants listed as eligible for an ABO-I organ compared with infants listed as eligible for an ABO-C organ, we found no difference in waitlist mortality between groups. Thus, the intended benefit of reducing pre-transplant death through ABO-I organ acceptance and improved organ use has not been achieved. The most notable factor to explain our findings is the method of organ allocation in the United States. Al-

6 The Journal of Heart and Lung Transplantation Everitt et al Volume 28, Number 12 Table 3. Cumulative Incidence of Outcomes in First 6 Months After Listing Days from listing Outcomes a Still waiting ABO-C ABO-I Transplant ABO-C ABO-I Death/removal for deterioration ABO-C ABO-I Removal for improvement ABO-C ABO-I ABO-C, ABO compatible; ABO-I, ABO incompatible. a Other category is not presented in the table so the percentages do not total 1.0. The other category included the reasons for removal: refused transplant (n 10) and other not specified (n 34). though ABO-I heart transplantation is now possible in the United States, the current algorithm is heavily weighted towards ABO identical and compatible transplantation. The sequence of organ allocation dictates preferential distribution of donor hearts to identical ABO blood type recipients, followed by ABO compatible recipients (type O to O first, and then to B, A, and AB; type A to A; type B to B), and lastly to incompatible recipients once compatible candidates across all geographic zones have been considered. 15 This is in contradistinction to organ allocation in Canada, whereby the first available organ is allocated to the infant with the longest waitlist time at the highest medical urgency, without preferential allocation to an identical or compatible ABO recipient. 6 It is probably for that reason that despite an increase in the number of infants listed as eligible for an ABO-I organ, few ABO-I heart transplantations are ultimately performed in the United States and a decrease in waitlist mortality has not been realized. The preferential allocation to ABO-C recipients not only decreases the number of organs eventually offered for ABO-I heart transplant but also adversely affects the number of organs accepted for ABO-I transplant. When an organ has been declined for all potential ABO-C recipients across the United States before the organ is offered for ABO-I transplantation, it is plausible that the donor organ is then less than optimal, which results in the organ also being declined for the potential ABO-I recipient based on quality. In addition, donor organ quality coupled with a potentially longer ischemic time further decreases the likelihood that the organ will be accepted for ABO-I transplantation. Alternatively, organ allocation to the infant of highest medical urgency irrespective of blood type compatibility would encour- Table 4. Results of Multivariable Competing Risks Regression Analysis of Time to Death and Time to Transplant Occurrence Time to transplant Time to death or waitlist removal for deterioration Patient characteristic a HR b (95% CI) p-value HR (95% CI) p-value Listed as eligible for ABO-I transplant vs ABO-C only 1.26 ( ) ( ) 0.43 Weight (kg) at initial listing 1.07 ( ) ( ) 0.01 Use of prostaglandins 1.16 ( ) ( ) 0.32 Use of intravenous inotropes 0.98 ( ) ( ) 0.07 Need for mechanical ventilation 0.80 ( ) ( ) 0.01 Need for ECMO 0.59 ( ) ( ) 0.01 Medical urgency status 1A vs 1B 1.04 ( ) ( ) 0.04 ABO-C, ABO compatible; ABO-I, ABO incompatible; CI, confidence interval; ECMO, extracorporeal membrane oxygenation; HR, hazard ratio. a N 1021; 8 cases were excluded due to missing values. b A hazard ratio 1.0 is indicative of a shorter time to the specified outcome.

7 1260 Everitt et al. The Journal of Heart and Lung Transplantation December 2009 age more widespread ABO-I listing when applicable, increase the timeliness of donor-recipient matching, minimize distance as a potential cause for organ refusal, and provide life-saving treatment to the sickest of patients. With respect to waitlist time for transplant and likelihood of death, there are several reasons why a decrease in waiting list time for patients listed as eligible for an ABO-I transplant did not result in a reduction in waitlist mortality. As mentioned, the number of ABO-I transplants that were performed was relatively low, and therefore, the study might not have sufficient power to show the beneficial effect of the shorter waiting time on mortality. We adjusted for differences in clinical acuity, such as the need for mechanical ventilation, inotropic support, and ECMO, but we did not control for other variables related to medical urgency such as the need for high dose or multiple inotropes and the degree of end organ dysfunction that portend a worse outcome. In addition, listing practices varied widely among the 11 UNOS geographic regions, and the degree of disparity widened during the study period. It may be that regional variations with respect to donor organ availability, number of infants awaiting transplantation, access to mechanical circulatory support other than ECMO, and donor selection criteria interact with regional variations in ABO-I organ acceptance practices such that waitlist times and outcomes are affected by center-specific variables other than ABO-I listing practices. Our study was limited by its retrospective nature and the inherent limitations of using a public database wherein the completeness and accuracy of the information cannot be readily verified. Moreover, we did not examine the effect of an ABO-I listing strategy across all acceptable ages; the upper recipient age under UNOS policy is now 2 years old in the absence of blood type-specific antibodies. Although this age group was not included, it is unlikely that outcomes are different than those reported here given the same allocation system. In conclusion, despite evidence for ABO-I transplantation resulting in decreased waitlist mortality and increased organ use in Canada, waitlist mortality has not been significantly affected by ABO-I transplant in the United States, where blood group compatibility is favored for donor-recipient matching. Consideration should be given to revising the current UNOS allocation methods to place less emphasis on blood group compatibility in this age group. Only with equitable listing practices and organ allocation irrespective of blood group compatibility will the benefits of ABO-I transplantation be fully realized in the United States. DISCLOSURE STATEMENT This work was supported in part by Health Resources and Services Administration contracts and C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. REFERENCES 1. Canter CE, Shaddy RE, Bernstein D, et al. 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