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Erythropoiesis Stimulating� Agent

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Outline

History of EPO

Mechanism of action of erythropoietin

EPO for anemia

EPO for neuroprotection in preterm infants

EPO for neuroprotection in term infants

Summary

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Content prepared by

�Dr. Benjamin Courchia MD

&

Dr. Daphna Yasova Barbeau MD

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The discovery of EPO

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Paul Carnot

1869 - 1957

Clotilde Camille Deflandre

1871 - 1946

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Physiology and mechanism of action

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In Polin, R. A., In Abman, S. H., In Rowitch, D. H., In Benitz, W. E., & In Fox, W. W. (2017). Fetal and neonatal physiology.

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https://en.wikipedia.org/wiki/File:HIF_Nobel_Prize_Physiology_Medicine_2019_Hegasy_ENG.png

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EPO stimulation of endothelial cells activates eNOS and NO production, particularly at reduced oxygen to modulate vascular tone and BP.
In Animal models epogen has been shown to have a protective effect in ischemic injury in particular for the myocardium, improving cardiac function after coronary occlusion and improving neovascularization in chronic heart failure. In skeletal muscle, it increases myoblast proliferation and survival.

Animal studies suggest that EPO may improves glucose tolerance, reduce insulin resistance and regulate fat mass accumulation.
Epo has also been shown to have effects in wound healing and bone remodeling both in normal bone metabolism and after fractures.

When it comes to neuroprotection, epogen is induced by hypoxia in neurons and astrocytes. Animal models showed that lack of epogen showed reduced neuronal proliferation and increased susceptibility to glutamate damage and to stroke. They have also demonstrated that preconditioning with epogen reduced ischemic injury and that epogen reduced neuronal apoptosis in the face of cytokine mediated inflammation.
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EPO for anemia of prematurity

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Maier, R. F. et al. The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. New Engl J Medicine330, 1173--1178 (1994).

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Maier, R. F. et al. The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. New Engl J Medicine330, 1173--1178 (1994).

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Maier, R. F. et al. The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. New Engl J Medicine330, 1173--1178 (1994).

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

Intervention: Treated infants received 400 U/kg Epo 3 times weekly. initiated within 4 days after birth.

Epo or placebo was administered by the research nurse as a 1-hour intravenous infusion or subcutaneously when intravenous access was not available.

Treatment continued until discharge, transfer, death, or 35 completed weeks’ PMA.

All infants received supplementation with Iron, Folate and vitamin E

�

Criteria for Withholding/Stopping the Study Drug:

neutropenia(ANC <500/µL)

hematocrit of45% (not attributable to trans-fusion) with a reticulocyte count>200 000 cells/µL

hypertension

The study drug was restarted when these conditions resolved. Treatment was stopped when clinical seizures occurred or when hypertension or neutropenia persisted.

�They did weekly CBC and followed a multitude of clinical variables.

They had a strict transfusion protocol:

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

84% of treated infants and 87% placebo/control infants received a transfusion (P = 0.56)

The average number of transfusions received by each infant during the study was similar for treated and placebo/control infants (4.3+/-3.6 vs 5.2 +/-4.2;P=0.09) as was the total volume per infant who received a transfusion

Timing of transfusions, by adding the number of transfusions received during each week of the study for each infant separately and then calculating the average cumulative number of transfusions per infant among those who were alive at each week (Fig 1,above). By study week 7, the cumulative number of transfusions was significantly higher for placebo/control infants (P<.05 at each time point, weeks7–10)

Fourteen treated infants (16%) and 11 placebo/control infants (13%) received no transfusions during the study period

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

Hematocrits decreased somewhat from baseline levels in both groups and remained below baseline during the study

Starting at week 2, hematocrits were significantly greater in treated infants at each week except for week 5 (P<.05 at weeks 2–4, 6–10).

Platelet counts were significantly lower during weeks 1, 3, and 8 in the treated group (P.05) but remained>200 000/µL in all infants.

Three infants in the placebo/control group and 3 in the treated group had their study medication held for 1 week because of neutropenia.

All study infants were followed for morbidity and mortality through their hospital stay up to 120 days. By hospital discharge or 120 days, 15 treated infants (17%) and 15 placebo/control infants (18%) had died(P1.0).

There were no significant differences between treated and placebo/control infants in medical morbidities or length of hospital stay

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

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Ohls, R. K. et al. Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial. Pediatrics 108, 934–942 (2001).

Mortality and morbidity were similar between groups.

CONCLUSION

"Despite evidence of significantly increased erythropoiesis, the administration of Epo and supplemental iron did not decrease the average number of transfusions or donor exposures per infant in infants of 1000 g birth weight or decrease the percentage of infants who had a birth weight of 1001 to 1250 g and received a transfusion. There were no statistically significant differences in neonatal morbidities be-tween groups in either trial, and no adverse effects of Epo or iron supplementation were noted.We conclude that the combination of Epo and iron stimulates erythropoiesis, maintains hematocrits at a higher level, and is safe in very low birth weight infants. However, when conservative transfusion guidelines are followed, the combination of Epo and iron as used in this trial does not have a significant impact on the number of transfusions administered to very low birth weight infants. On the basis of the results of this study, the early use of Epo and iron to reduce transfusion number and exposure of infants to the risks of multiple blood transfusions is not warranted."

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Ohlsson, A. & Aher, S. M. Early erythropoiesis‐stimulating agents in preterm or low birth weight infants. Cochrane Db Syst Rev 2, CD004863 (2020).

So in 2006 we have a tandem of Cochrane reviews that are published by Ohlson and Aher on the use of EPO and the prevention of PRBC transfusions. One of them reviewed EARLY admin of EPO, the other LATE admin.

Let us start with the early review first.

The aim was to assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants.

The selection criteria included randomised or quasi‐randomised controlled trials of early (< 8 days of age) initiation of EPO treatment vs. placebo or no intervention in preterm and/or low birth weight neonates.

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Ohlsson, A. & Aher, S. M. Early erythropoiesis‐stimulating agents in preterm or low birth weight infants. Cochrane Db Syst Rev 2, CD004863 (2020).

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Ohlsson, A. & Aher, S. M. Early erythropoiesis‐stimulating agents in preterm or low birth weight infants. Cochrane Db Syst Rev 2, CD004863 (2020).

- Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639infants). The quality of the evidence was moderate.

The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced.

Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.

Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL).

Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI-0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants).

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Aher, S. M. & Ohlsson, A. Late erythropoiesis‐stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Db Syst Rev 2020, CD004868 (2020).

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Aher, S. M. & Ohlsson, A. Late erythropoiesis‐stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Db Syst Rev 2020, CD004868 (2020).

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Aher, S. M. & Ohlsson, A. Late erythropoiesis‐stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Db Syst Rev 2020, CD004868 (2020).

They obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. They looked at high vs low doses in the following way, high dose was considered > 500 IU /kg/week and low dose was < 500 IU/kg/week.

There was no significant reduction in the total volume(mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants).

There was a significant reduction in the number of transfusions per infant (11 studies enrolling817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (IP = 94%).

Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (IP = 83%)and RD (IP = 82%). The quality of the evidence was very low. Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (IP = 18%) but high heterogeneity for RD (IP = 79%). The quality of the evidence was very low.

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Aher, S. M. & Ohlsson, A. Late erythropoiesis‐stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Db Syst Rev 2020, CD004868 (2020).

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Aher, S. M. & Ohlsson, A. Late erythropoiesis‐stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Db Syst Rev 2020, CD004868 (2020).

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Aher, S. M. & Ohlsson, A. Late erythropoiesis‐stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants. Cochrane Db Syst Rev 2020, CD004868 (2020).

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EPO for neuroprotection (preterm infants)

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Neubauer, A. P., Voss, W., Wachtendorf, M. & Jungmann, T. Erythropoietin improves neurodevelopmental outcome of extremely preterm infants. Ann Neurol 67, 657--666 (2010).

EPO treated

Untreated

Neubauer and colleagues (43) evaluated 148 children at 10 to 13 years of age who as preterm infants had been randomized to receive Epo or placebo (control) in various multicenter Epo studies (Table 1). Children who received Epo during their initial NICU stay scored signiﬁcantly better than untreated children in overall developmental assessment (55% [Epo] vs 39% [controls] were normally developed; P<.05) as well as in measures of cognition (mean composite Hamburg-WechslerIntelligenztests für Kinder-III [HAWIK-III] IQ score, 90.8 [Epo] vs 81.3 [controls]; P<.005). The greatest difference was found in children who had brain injury due to intraventricular hemorrhage (IVH): those who were randomized to receive Epo scored signiﬁcantly better than placebo-treated children with IVH (52% vs 6% developed normally; composite HAWIK-III IQ score, 90.3 vs 67.0; P < .005). Based on these observations, Epo seemed to be a potential treatment for extremely low birthweight (ELBW; birthweight <1,000 g) infants, particularly for those with brain injury as a result of IVH.

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Bierer, R., Peceny, M. C., Hartenberger, C. H. & Ohls, R. K. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics 118, (2006).

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Ohls, R. K. et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics 133, 1023--1030 (2014)

Dr. Robin Ohls and colleagues reported in 2014 on neurodevelopmental outcomes of very low birthweight infants (birthweight <1,500 g) enrolled from 2006 to 2010.

A total of 99 infants were randomized to receive subcutaneous (SC) Darbe (10 mg/kg once per week), Epo (400 U/kg 3 times per week), or placebo through 35 weeks’ postconceptual age.

Of the 99 infants evaluated during the hospital phase of the study, 80 (29 Epo, 27 Darbe, 24 placebo) returned for follow-up at 18 to 22 months of age.

Mean – SD BSID-III cognitive scores were signiﬁcantly higher in Darbe (96.2 – 7.3) and Epo (97.9 – 14.3) recipients compared with placebo recipients (88.7 – 13.5; P ¼ .01 versus ESA recipients). In addition, Darbe and Epo recipients had a signiﬁcantly higher test score for object permanence compared with placebo recipients (P ¼ .05), which provided a first look at improved early executive function w ESA. (46) No infants in the ESA groups had cerebral palsy compared with 5 in the placebo group (P < .001). There were no differences in either visual or hearing impairment; overall neurodevelopmental impairment was signiﬁcantly less in the ESA groups compared with the placebo group (odds ratio, 0.18; 95% conﬁdence interval [CI], 0.05–0.63).

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Juul, S. E. et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. New Engl J Med 382, 233--243 (2020).

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Juul, S. E. et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. New Engl J Med 382, 233--243 (2020).

Intervention: administration of erythropoietin or placebo occurred within 24 hours after birth. Infants received erythropoietin at a dose of 1000 U per kilogram or placebo (saline) intravenously every 48 hours for a total of six doses; thereafter, infants received maintenance subcutaneous injections of erythropoietin at a dose of 400 U per kilogram of body weight or sham injections, three times per week through 32 weeks 6 days of postmenstrual age

Babies were supplemented with iron.

Transfusion anarchy: "Site-specific transfusion practices were allowed. The transfusion strategies used by the trial sites ranged from liberal to restrictive, which reflects the current lack of consensus regarding guidelines for transfusion strategies."

The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. severe

Secondary outcome: death or moderate-to-severe neurodevelopmental impairment. Other prespecified secondary outcomes were adverse events and death or severe neurodevelopmental impairment assessed according to sex.

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Juul, S. E. et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. New Engl J Med 382, 233--243 (2020).

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Juul, S. E. et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. New Engl J Med 382, 233--243 (2020).

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Juul, S. E. et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. New Engl J Med 382, 233--243 (2020).

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EPO for neuroprotection (term infants)

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Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124(2):e218–e226

Initial studies evaluating Epo for neuroprotection in term infants with HIE were performed on infants who did not receive therapeutic hypothermia (TH). A trial from china 🇨🇳 published in 2009 in Pediatrics by Zhu and colleagues (62) randomized 167 term infants with moderate or severe HIE to either conventional treatment (n = 84) or Epo, 300 U/kg (52 infants) or 500 U/kg (31 infants) every other day for 2 weeks (n= 83). The ﬁrst dose was administered SC and subsequent doses were administered IV.

In the control group, 35 of the 80 infants (44%) had moderate/severe disability or death at 18 months compared with the Epo group (25%; P =0.017). The primary outcomes were similar with both Epo doses. In infants with moderate to severe HIE, the response to Epo was comparable with the response to TH reported in previous trials (Shankaran) in that an overall 20% decrease in death or disability was identiﬁed.

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Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6):e20160191

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Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6):e20160191

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Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6):e20160191

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Garg, B., Sharma, D. & Bansal, A. Systematic review seeking erythropoietin role for neuroprotection in neonates with hypoxic ischemic encephalopathy: presently where do we stand. J Maternal-fetal Neonatal Medicine 31, 1–28 (2017).

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Garg, B., Sharma, D. & Bansal, A. Systematic review seeking erythropoietin role for neuroprotection in neonates with hypoxic ischemic encephalopathy: presently where do we stand. J Maternal-fetal Neonatal Medicine 31, 1–28 (2017).

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Summary

EPO production declines rapidly after birth, contributing to the physiologic anemia of infancy.
Administration of ESA to preterm infants with anemia significantly improved hematologic factors such as hematocrit and reticulocytes.
ESA administration is associated with a reduction in the number of transfusions administered to preterm infants.
EPO has not been shown to increase rates of severe ROP
The PENUT trial recently demonstrated the absence of neuroprotective effects of EPO in preterm infants.
Initial clinical studies of ESA administration for neuroprotection in term infants have demonstrated promising results. The results of several additional trials on this topic are expected soon.

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