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Erythropoietin Therapy in Critically Ill and Acute Kidney Injury Patients
Objectives
This chapter will:
- 1.
Describe the issues with and treatment options for critical care patients with anemia.
- 2.
Discuss the risks and benefits of transfusions versus erythropoiesis-stimulating agents (ESAs) treatment.
- 3.
Present results of clinical trials of critical care patients treated with ESAs.
- 4.
Evaluate hypotheses associated with organ protection by ESAs.
Anemia and Transfusion in the Intensive Care Unit
U.S. studies report that almost all patients are anemic by day 3 after admission to an intensive care unit (ICU). Despite controversies regarding the benefits, approximately 50% of patients in the United States are transfused, usually early in the course of the admission. Similarly, a multicenter European study showed that 63% of ICU patients had a hemoglobin less than 12 g/dL, and 29% less than 10 g/dL, at the time of admission and 37% were transfused during their ICU stay. However, transfusions have been associated with longer hospital lengths of stay and an increase in mortality.
Factors contributing to anemia in ICU subjects include direct causes such as hemorrhage or hemolysis associated with the initiating events such as trauma, infarction, and stroke. Additional factors include coagulopathies, occult blood loss, and the large amount (perhaps 40 to 60 mL daily) of blood removed during repeated diagnostic phlebotomy in the ICU. Indirect factors blunt the erythropoietic response to anemia. These include activation of proinflammatory cytokines that directly inhibit erythropoiesis (by blunting the response to erythropoietin) including IL-1, TNF-α, and IL-6. The latter upregulates the acute phase protein hepcidin. By mediating degradation and internalization of the iron transport protein, ferroportin-1, hepcidin-1 limits availability of iron absorption in the gut and release from stores. IL-6 thus indirectly limits erythropoiesis by impairing heme synthesis. Additional factors include shortened red cell survival from pathogen and immune-mediated hemolysis. The resultant anemia in critically ill subjects is usually normocytic and normochromic as in subjects with chronic kidney disease.
Publication in 1999 of the Transfusion Requirements in Critical Care study (TRICC), when there was a liberal approach to transfusion in the ICU, resulted in a reassessment in use of transfusions in critical care patients. The TRICC trial demonstrated that a restrictive approach to transfusion (Hb threshold for transfusion <70 g/L) had similar or even superior mortality outcomes to a more liberal approach (Hb <90 g/L), with better outcomes in younger, less critically ill subjects) but with the possible exception of patients with acute myocardial infarction and unstable angina. Similar results were obtained in a large randomized controlled trial of liberal (Hb <100 g/L) versus restrictive (Hb <80 g/L) transfusion in 2016 patients undergoing surgery for hip fracture. A liberal transfusion strategy (a hemoglobin threshold of 100 g/L), as compared with a restrictive strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <80 g/L), did not reduce rates of death or inability to walk independently (across a room) on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk.
Further studies of transfusion in subjects with myocardial ischemia suggest that the benefits of transfusion outweigh the risks when Hb is below 70 g/L. The results of transfusion are even more controversial in anemia associated with sepsis. Although some studies show no benefit of transfusion on tissue oxygenation, others suggest that because the microcirculation is improved by blood transfusion but not by crystalloids or colloids, that transfusion remains a useful option, perhaps particularly in sepsis.
Erythropoietin-Stimulating Agent Administration in the Critical Care Setting; Comparison to Transfusions
Erythropoietin (EPO) is the primary regulator of red blood cell formation. Because EPO is produced mainly by the kidney, patients with kidney disease can have severe anemia because of decreased EPO production. The preferred treatment option for patients with end-stage kidney disease (ESKD) is renal transplantation, which not only restores renal function but also alleviates the symptoms of anemia. The next most frequent treatment option, for renal patients and also other ICU patients, is to administer transfusions with the associated problems noted earlier. In long-term treatment settings, such as with ESKD patients, transfusions also could result in iron overload and produce allosensitization, which will reduce the number of suitable donor kidneys for a given individual with ESKD, or increase the risk of rejection of the transplanted kidney. With the approval of the first erythropoiesis-stimulating agent (ESA, epoetin alfa) there was a potentially practical alternative to transfusion, which offered pharmacologic treatment of anemia in multiple patient populations.
It is tempting to assume that the process of raising Hb with an ESA would be physiologically similar to that of transfusion. However, ESA treatment provides a slow rather than instantaneous (transfusion) rate of rise in Hb, and it may be desirable to have a fast or slow increase depending on conditions. For example, immediate correction is warranted with severe blood loss. For less severe conditions, a slower rise in Hb may be desirable because of the ability of the body to adapt. With ESA administration, iron is mobilized to support Hb synthesis. In the absence of administered iron, there can be depletion of iron stores, which has been hypothesized to promote a prothrombotic state.
The major rationale for use of ESAs was that administration would not only treat symptoms of anemia but also reduce the number of transfusions and thereby avoid their negative impacts. Thus a number of clinical trials were initiated to determine if ESA treatment would reduce transfusion rates and improve outcomes.
Erythropoietin-Stimulating Agents and Anemia Correction
In clinical trials with patients having heart and kidney disease, ESAs were shown to increase Hb levels in a dose-dependent manner and reduce blood transfusion rates ( Tables 224.1 and 224.2 ). There also was evidence that anemia symptoms could be improved, especially in cardiac patients (dyspnea, exercise tolerance) ( Fig. 224.1 ) but with little or no improvement in quality of life. Some studies showed an improvement in outcomes (e.g., mortality or rehospitalization rates), such as in patients after trauma ( Fig. 224.2 ). However, in larger trials and in meta-analysis of the combined results of the small trials, the benefits disappeared. In addition, there was evidence of increased risk of thrombotic events and ischemic stroke in some settings, but without an increase in mortality.
TABLE 224.1
Outcomes in Randomized Controlled Trials to Prevent or Correct Anemia
| REFERENCE | GROUP | ESA TREATMENT | SUBJECTS | OUTCOMES IN ESA/HIGH Hb ARMS |
|---|---|---|---|---|
| Ghali 2008 | Cardiac failure and anemia | DA (0.75 ug/kg/SC/2 wks) with dose adjusted to target an Hb of 130–150 g/L | N = 319: ESA (162), placebo (157) | Increased Hb. No improvement in exercise duration, NYHA class, or quality of life score |
| Abraham 2010 | Cardiac failure and anemia | Pooled analysis of 2 studies. DA (0.75 ug/kg/SC/2 wks or 50 ug/kg/SC/2 wks) with adjustments to target an Hb of 130–150 g/L | N = 475: ESA (266), placebo (209) | No difference in composite of all-cause mortality and rate of first hospitalization for cardiac failure. Improvement in composite for the ESA subgroup that had a Hb increase > 10 g/L |
| Swedberg 2013 | Cardiac failure and anemia | DA (0.75 ug/kg/SC/2 wks) with dose adjusted to target an Hb of 130 g/dL | N = 2278: ESA (1136), placebo (1142) | Increased Hb, reduced blood transfusion rate. No effect on all-cause mortality or first hospitalization for worsening cardiac failure. Increased rate of ischemic stroke, embolic, and thrombotic events |
| Roger 2004 | CKD and anemia | Epoetin α administered weekly (SC) with dose adjusted to target an Hb of 105–115 or 130–150 g/L | N = 152: high Hb (75), low Hb (78) | Increased Hb. No difference in LVMI or eGFR or creatinine at 2 yr |
| Levin 2005 | CKD and anemia | Epoetin α with dose adjusted to target an Hb of 90–105 or 120–140 g/L. Starting dose 2000 U/wk/SC then titrated | N = 152: high Hb (78), low Hb (74) | Increased Hb. No difference in LVMI, NYHA level, or rate of change in creatinine clearance |
| Drueke 2006 | CKD and anemia | Epoetin β with dose adjusted to target a Hb of 110–125 or 130–150 g/L. Median weekly dose 5000 U in high Hb and 2000 U in low Hb median dose/wk | N = 603: high Hb (301), low Hb (302) | Increased Hb. No difference in deaths or cardiovascular event (sudden death, myocardial infarction, acute heart failure, stroke, transient ischemic attack, angina pectoris, prolongation of hospitalization, amputation, necrosis, or cardiac arrhythmia). No difference in cardiac (LVMI, time to increased NYHA class) or renal function (eGFR) |
| Singh 2006 , Inrig 2012 | CKD and anemia | Epoetin α with dose adjusted to target an Hb of 105–110 g/dL or 130–135 g/dL. Average dose 11,215 U/wk/SC (high Hb) and 6,276 U/wk/SC (low Hb) | N = 1432: high Hb (715), low Hb (717) | Increased Hb. More rapid progression of composite end point (death, myocardial infarction, hospitalization for CHF) and kidney disease (composite of doubling of serum creatinine, RRT, or death). No difference in myocardial infarction or stroke |
| Ritz 2007 | CKD, diabetes, and anemia | Epoetin β (2,000 U/SC - initial dose) with adjustments to target high (130–150 g/L) or low Hb (105–115 g/L) | N = 160: high Hb (85), low Hb (75) | Increased Hb. No effect on cardiac function (LVMI, FS, or LVEF) or renal function (rate of creatinine clearance or eGFR decrease) |
| Pfeffer 2009 | CKD, diabetes, and anemia | DA monthly (average 176 ug/SC) targeted to Hb of 130 g/L | N = 4038: high Hb (2012), control (2026) | Increased Hb, reduced transfusion rate. No effect on time to first fatal or nonfatal cardiac failure or myocardial infarction, hospitalization for myocardial ischemia, or progression to ESKD. Increased risk of stroke |
| Still 1995 | Critical illness: Burns | Epoetin α (300 U/kg/IV) within 72 hr then daily × 7, then 150 U/kg alternate daily to 30 d | N = 40: ESA (19), control (21) | No differences in Hb, transfusion rate, or mortality |
| Corwin 1999 | Critical illness | Epoetin α (300 U/kg/SC) on d3, daily × 5 then alternate daily until Hct > 38% | N = 160: ESA (80), placebo (80) | Increased Hb, reduced blood transfusion rate. No differences in mortality, DVT, adverse events |
| Corwin 2002 | Critical illness | Epoetin α (40,000 U/SC) on d3 and continued weekly (×3). Added dose on ICU day 21 | N = 1302: ESA (650), placebo (652) | Increased Hb, reduced blood transfusion rate. No differences in 29-day mortality, morbidity, or hospital length of stay. Reduced mortality in trauma patients |
| Georgopoulos 2005 | Critical illness | rHuEpo (not specified) 40,000 U/SC 1×/wk or 3×/wk for 1–3 wks targeted to Hb of 120 g/L | N = 148: ESA (100), control (48) | Dose-dependent increase in Hb, reduced blood transfusion rate. No differences in ICU length of stay, hospital length of stay, incidence of adverse events, or mortality |
| Silver 2006 | Critical illness: Long-term care | Epoetin α (40,000 U/SC) before d7 then weekly up to 12 doses | N = 86: ESA (42) placebo (44) | Increased Hb, decreased transfusion rate. No differences in mortality or serious adverse clinical event |
| Corwin 2007 | Critical illness | Epoetin α (40,000 U/SC) on day 1, then weekly (×3) | N =1460: ESA (733) placebo (727) | Increased Hb, no difference in transfusion rate. No difference in mortality, ICU, or hospital length of stay. Reduced mortality in trauma patient subgroup. Increased thrombotic events |
| Lundy 2010 | Critical illness: Burns | rHuEPO (not specified) (40,000 U) within 72 hrs post admission then weekly for 1–35 wks (mean 10 wks) | N = 105: ESA (25), no ESA (27), historical control (53) | No reduction in transfusion rate. No differences in Hb, mortality, thrombotic events |
| Luchette 2012 | Critical illness: Blunt trauma and anemia | Epoetin α (10,000–40,000 U/SC) weekly for up to 12 wks after discharge or until Hb ≥120 g/dL (mean 3.1 wks) | N = 192: ESA (97), placebo (95) | Increased Hb. No difference in transfusion rate, patient health (SF-36, APACHE II, SOFA) or neurologic function (COG) |
| Weber 2005 | Surgery: Orthopedic moderate/no anemia | Epoetin α (40,000 U/SC) for 3 wks before (×3), at surgery then weekly (×3) | N = 733: ESA (487), control (237) | Increased Hb and reduced transfusion rate. No effect on time to ambulation or time to discharge. In both groups transfused patients had a longer time to discharge. |
| Cladellas 2012 | Surgery: Cardiac valve replacement and anemia | Epoetin β (500 U/kg/d/IV) and iron sucrose (IV) weekly, fifth dose 48 hrs preoperatively | N = 134: ESA (75), control (59) | Increased Hb and reduced transfusion rate. Decreased hospitalization, morbidity, in-hospital mortality, acute kidney injury, and cardiac failure |
| Talving 2010 | Traumatic brain injury and anemia | Epoetin α (100 U/kg/SC weekly) or DA (0.45 mcg/kg/SC weekly) for 30 d | N = 286: ESA (89), no ESA (178) | Increased Hb, no difference in transfusion rate. Decreased in-hospital mortality. No difference in morbidity but increased length of stay in hospital |
| Talving 2012 | Traumatic brain injury and anemia | DA (0.40 µg/kg/SC weekly) for 30 days | N = 150: ESA (75), no ESA (75) | Increased Hb, no difference in transfusion rate. Decreased in-hospital mortality but longer stay in the ICU and hospital. No difference in complications or neurologic outcome (GCS) |
APACHE II, Acute physiology and chronic health evaluation II; CHF, congestive heart failure; CKD, chronic kidney disease; COG, cognitive function test; d, day; DA, darbepoetin alfa; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; ESA, erythropoiesis stimulating agent; ESKD, end-stage kidney disease; FS, fractional shortening; GCS, Glasgow Coma Scale; hr, hour; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; min, minute; mo, month; NYHA, New York Heart Association; RRT, renal replacement therapy; SF-36 PF, 36 -item short form health survey; SOFA, sepsis-related organ failure assessment; wk, week.
TABLE 224.2
Outcomes in Randomized Controlled Trials to Prevent or Correct Anemia (Meta-Analysis)
| REFERENCE | GROUP | ESA TREATMENT | SUBJECTS | OUTCOMES IN ESA/HIGH Hb ARMS |
|---|---|---|---|---|
| Alghamadi 2006 | Surgery: cardiac | ESA (40–800 U/SC/IV) and iron (IV/oral) administered at least 1 wk before surgery and 1–3×/wk for 1–4 wks | 11 trials, N = 7 08: ESA (471), control (237) | Reduced risk of transfusion |
| Alsaleh 2013 | Surgery: knee and hip arthroplasty | ESA (40,000–120,000 U total) 0–28 days before surgery | 26 trials, N = 3450: ESA or ESA + ABD (2059), ABD, placebo or iron (1391) | Increased Hb and reduced transfusions. No difference in thromboembolism |
| Desai 2010 | Chronic heart failure and anemia | ESA 1–3×/wk for 2–72 mos to raise Hb to target | 9 trials, N = 2039: ESA (1023) control (1016) (TREAT HF subset) | Neutral for mortality and nonfatal heart failure events |
| Kotecha 2011 | Chronic heart failure and anemia | ESA to raise Hb to higher target (epoetin α or β - 1–3× wk/4000–15,000/weekly total, DA - q2wk-qMonthly/1.5–2.0 ug/kg monthly total) | 11 trials, N = 794: ESA (430), control (placebo or no ESA, 352) (does not include RED-HF ) | Increased Hb, improved exercise tolerance (exercise duration, peak O 2 consumption), cardiac function (NYHA class, ejection fraction, B-type natriuretic peptide), and quality-of-life. Reduced CHF-related hospitalization and reduction in all-cause mortality. No difference in stroke or thrombotic events |
| Kang 2016 | Chronic heart failure and anemia | ESA (epoetin - 1–3× wk/4000–15,000/weekly total, DA - 1/0r 2×/mo/1.5–5.0 ug/kg monthly total) to raise Hb to higher target | 13 trials, N = 3172: ESA (1609), control (1523) (includes RED-HF ) | Increase in Hb. No effect on all-cause mortality or rehospitalization. Improved dyspnea, NYHA grade, and quality-of-life measured by subjective questionnaires. Increased risk for thromboembolic events |
| Zarychanski 2007 | Critical illness: Mixed medical, surgical | Medium-term ESA (rHuEpo - daily-weekly/40,000–140,000/weekly total) for 3–12 wks | 9 trials, N = 3314: ESA (1695), control (placebo or no ESA (1619) | Reduced risk of transfusion. No effect on overall mortality or length of stay in hospital or intensive care unit. |
| French 2016 | Critical illness: traumatic brain injury, mixed medical, surgical | Epoetin α or β within 6 hr to 6 d of injury, 1–10 doses with total/mo of 20,000–160,000 U | 9 trials, N = 2607: ESA (1221), control (placebo or no ESA, 1184) | No difference in transfusions. No difference in functional neurologic outcome. Reduced mortality overall but no difference in patients with traumatic brain injury. No difference in thrombotic events |
| Parfrey 2009 | CKD, ESKD, and anemia | ESA to increase Hb to target (ESA, dose and schedule not disclosed) | 15 trials: N = 1731: high (>120 g/L) vs. low (<120 g/L) Hb target | Reductions in LVMI when starting at low (<100 g/L) but not moderate (>100 g/L) Hb |
| Palmer 2010 | CKD and anemia | Epoetin α, epoetin β, or DA to target low (95–120 g/L) vs. high (120–150 g/L) Hb (dose and schedule not disclosed) | 27 trials, N = 10,452: high (>120 g/L) vs. low (<120 g/L) Hb target. (includes TREAT ) | No differences in mortality, serious cardiovascular events, or progression to ESKD with higher Hb target. Increased risks for hypertension, stroke, and vascular access thrombosis |
| Koulouridis 2013 | CKD, ESKD, and anemia | Epoetin α, epoetin β, or DA to raise Hb to higher target (epoetin α or β - starting dose 5,500–44,000 U) | 31 trials: N = 12,956 (includes TREAT ): high Hb (100–150 g/L) vs. low (range 8.2–11.5) | Reduced transfusion risk. No association between ESA dose and annual eGFR change, progression to ESKD, or cardiovascular events. Increase in all-cause mortality, stroke, and thrombotic events but decreased serious adverse events with increased dose |
| Elliott 2017 | CKD and anemia | Epoetin α, epoetin β, or DA (epoetin - 1×–3× wk/20,000–80,000 total/wk, DA - 1×–4×/mo, 120–200 ug total/mo) to correct anemia | 18 trials, N = 8020: targeted to high (3964) or low Hb (4056) | No difference in progression to RRT |
ABD, Autologous blood donation; CHF, congestive heart failure; CKD, chronic kidney disease; ESKD, chronic kidney disease; DA, darbepoetin alfa; eGFR, estimated glomerular filtration rate; ESA, erythropoiesis stimulating agent; ESKD, end-stage kidney disease; LVMI, left ventricular mass index; NYHA, New York Heart Association; RRT, renal replacement therapy.
Clinical trials to test the possibility that ESA treatment may improve cardiac function or reduce progression of renal disease produced mixed results ( Tables 224.1 through 224.4 ), with meta-analysis showing no benefit in slowing the rate of progression of chronic kidney disease, but there was evidence of improvement in cardiac function. For example, there were reports that anemia correction may reduce left ventricular mass index and improve cardiac failure (NYHA class). The benefit of anemia correction in improving heart function was greater in patients at a lower starting Hb level.
TABLE 224.3
Tissue Protection with Short-Term ESA Treatment
| REFERENCE | GROUP | ESA TREATMENT | SUBJECTS | OUTCOMES IN ESA/HIGH Hb ARMS |
|---|---|---|---|---|
| Binbrek 2009 | Cardioprotection: STEMI | Epoetin β (30,000 U/IV) before thrombolysis | N = 236: ESA (115), no ESA (121) | No difference in Hb. No difference in cardiac function (enzymatically estimated infarct size, ECHO, mitral flow, EF, LV end systolic volume or LV wall motion score index) |
| Liem 2009 | Cardioprotection: Non-STE-ACS | Epoetin α (40,000 U/IV) within 8 hr of diagnosis | N = 51: ESA (26) placebo (25) | No effect on troponin or infarct size (CK-MB release) |
| Ott 2010 | Cardioprotection: STEMI | Epoetin β (3× 33,300 U) immediately after PCI, 24, and 48 hr | N = 138: ESA (68), Placebo (70) | No difference at 3 mos of LVEF or infarct size. No difference at 6 mos of death, recurrent myocardial infarction, stroke, vessel revascularization, LVEF measured by MRI, or infarct size |
| Ludman 2011 | Cardioprotection: STEMI | Epoetin β (50,000 U/IV) before PCI and 24 hr later | N = 51: ESA (26), placebo (25) | No difference in length of hospital stay, LVEF, troponin T or infarct size (CMR). Increased LVEDV, LVESV, and LV mass |
| Najjar 2011 | Cardioprotection: STEMI | Epoetin α (15,000, 30,000 or 60,000 U/IV) within 4 hrs of reperfusion | N = 222: ESA (125) placebo (97) | No difference in Hb. infarct size (CMR), LV mass, LVEF, death, stroke, or thrombosis. Increase in adverse events and composite outcome (death, MI, stroke, or stent thrombosis) |
| Suh 2011 | Cardioprotection: STEMI | Epokine (50 U/kg/IV) immediately before PCI | N = 57: ESA (29), control (27) | No difference in infarct size (CK, CK-MK, MRI), or LVEF |
| Prunier 2012 | Cardioprotection: STEMI | Epoetin β (1,000 U/kg/IV) immediately after PCI | N = 107: ESA (53), placebo (44) | At d5 no difference in peak CK release but decreased incidence of MVO, reduced LV volume, mass, and function impairment. At 3 mos no difference in infarct size, LV mass, volume, or function |
| Roubille 2013 | Cardioprotection: STEMI | DA (150 ug/intracoronary) after PCI | N = 51: ESA (27), control (24) | No difference in creatinine kinase or infarct size (by CMR) |
| Fokkema 2013 | Cardioprotection: STEMI | Epoetin α (60,000 U/IV) within 3 hr after PCI | N = 529: ESA (263), control (266) | No difference in composite end point (all-cause mortality, re-infarction, target vessel revascularization, stroke, or heart failure) or thrombotic events |
| Yoo 2011 | Cardioprotection: valvular heart surgery with anemia | ESA (epocain, 500 U/kg/IV) 16–24 hrs before surgery | N = 74: ESA (37) control (37) | Reduced transfusion risk and risk of AKI. No difference in mortality |
| Dardashti 2014 | Cardioprotection, renoprotection, neuroprotection: Surgery (CABG), patients with impaired renal function | ESA (Retacrit 400 U/kg/IV) preoperatively | N = 70: ESA (35) placebo (35) | No difference in Hb, transfusions. No difference in markers of renal function (cystatin C, NGAL, creatinine, eGFR), incidence of AKI, heart function (BNP, CK-MB), brain damage (S100B), or adverse events |
| Joyeux-Faure 2012 | Cardioprotection, neuroprotection: Surgery (CABG) | Epoetin β (800 U/kg/IV) 1–3 hrs before CPB | N = 50: ESA (25), placebo (25) | No difference in cardiac function ejection fraction and markers (troponin T, NT-proBNP, creatine kinase MB), cerebral (S100B) markers, inflammation markers (TNF-α, IL-6, IL-10. No difference in mortality |
| Springborg 2007 | Neuroprotection: Stroke (subarachnoid hemorrhage) | Epoetin α (500 U/kg IV) immediately after randomization and at 24 and 48 hr | N = 53: ESA (24) placebo (30) | No difference in Glasgow outcome score, markers of brain damage (S-100B and NSE), surrogate markers of secondary ischemia (glutamate, lactate/pyruvate), blood–brain barrier integrity (CSF:serum ratio of albumin) or brain injury (mean maximum flow velocities in the middle or anterior cerebral arteries) |
| Ehrenreich 2009 | Neuroprotection: Stroke (ischemic) | Epoetin α (40,000 U/IV) within 6 hr of symptom onset, and at 24 and 48 hr | N = 522: ESA (238), placebo (253) | No difference in MRI imaging (d7), Barthel Index, or NIHSS on d30 or d90. Increased mortality and intracerebral hemorrhage. Increased deaths |
| Tseng 2009 | Neuroprotection: Stroke (subarachnoid hemorrhage) | Epoetin β (30,000 U/IV) on day of recruitment and every 48 hr (90,000 U total) | N = 80: ESA (40) placebo (40) | No difference in vasospasm or ischemia (THRT). Reduced severe vasospasm. No difference in overall mRS or GOS score at discharge or 6 mos. No difference in thromobembolisms |
| Yip 2011 | Neuroprotection: Stroke (ischemic) | Epoetin β (5000 U/SC) at 48 and 72 hr after stroke | N = 167: ESA (83) placebo (84) | No change in Hb. Improvement in 90 d clinical outcome (MANE). No difference in NIHSS, mRS. or Barthel index |
| Pang 2013 | Neuroprotection: CO 2 poisoning | rHuEPO (10,000 U/SC) within 12 hr of poisoning, then daily for 1 wk | N = 103: ESA(54), placebo (49) | Improved NIHSS score and Barthel index (30 d) and S-100β levels decreased |
| Cramer 2014 | Neuroprotection: Stroke (ischemic) | Epoetin α (escalating dose 4000–20,000 U/IV, d7, 8, 9) and β-hCG (10,000 U/IV) on d1,3,5) initiated 24–48 hr after stroke onset | N = 96: ESA (72), placebo (24) | No difference in neurologic recovery (NIHS baseline to d90, Barthel index or mRankin), adverse events or death |
| Robertson 2014 | Neuroprotection: TBI | Epoetin α (500 U/kg/IV) within 6 hr of injury, daily for 2 d, then weekly for 2 wks (74 patients) or 1 dose within 6 hr of injury (126 patients) | N = 200: ESA (102), placebo (98) | No difference in transfusions. No difference in mortality or neurologic outcome (GOS) at 6 mos. Higher Hb transfusion threshold (70 vs. 100 g/L), had increased thrombotic events |
| Nichol 2015 | Neuroprotection: TBI | Epoetin α (40,000 U/SC) 1×/wk, up to 3× starting within 24 hr of injury | N = 606: ESA (308), placebo (298) | No difference in proportion of patients with a GOS (extended) level of 1–4, 6-month mortality, lesion mass, or occurrence of lower limb DVT |
| Cariou 2016 | Neuroprotection: Cardiac arrest | Epoetin α (40,000 U/IV) ×5 every 12 hr immediately postresuscitation | N = 476: ESA (234), No ESA (242) | No difference in CPC, irreversible brain damage, or mortality. Increased SAEs and thrombotic events in ESA group |
| Endre 2010 | Renoprotection: AKI | Epoetin β (500 U/kg/IV to a maximum of 50,000 U) within 6 hr and a second dose 24 hr later | N = 163: ESA (84) placebo (78) | No difference in incidence of AKI, dialysis, length of hospital stay, or deaths |
| de Seigneux 2012 | Renoprotection: Cardiac surgery | Epoetin α (20,000 U or 40,000 U/IV) 1 to 4 hr after surgery | N = 80: ESA (40) placebo (40) | No difference (0–48 hr) in Hb, incidence of AKI, creatinine, cystatin C and urinary NGAL levels, mortality, or hospital stays |
| Tasanarong 2013 | Renoprotection: Cardiac surgery | Epoetin β (200 U/kg/IV) 3 d before CABG and 100 U/kg at surgery | N = 100: ESA (50) or saline (50) | No difference in Hb. At 1–3 d, there was reduced incidence of AKI. Improvement in eGFR and urine NGAL |
| Oh 2012 | Renoprotection: Coronary artery bypass grafting | Epoetin β (300 U/kg/IV) before CABG | N = 71: ESA (36), saline (35) | Reduced incidence of AKI |
| Olweny 2012 | Renoprotection: Partial nephrectomy | Epoetin α (500 IU/kg/IV) 30 min before hilar occlusion | N = 106: ESA (52), control (54) | No difference in adverse events or eGFR at 3 wks or 12 mos |
| Kim 2013 | Renoprotection: Valvular heart surgery | Epocain (300 U/kg/IV) after anesthetic induction | N = 98: ESA (49) control (49) | No difference in Hb, incidence of AKI, SCr levels, eGFR, creatinine clearance, or biomarkers of renal injury (cystatin C and NGAL) |
| Kim 2016 | Renoprotection: Thoracic aorta surgery | Epocain (500 U/kg/IV) before surgery | N = 63: ESA (31) Saline (32) | No difference in incidence or severity of AKI, NGAL (0–48 hr), creatinine (0–7 d), time in ICU or hospital, or mortality |
ACS, Acute coronary syndrome; AKI, acute kidney injury; CABG, coronary artery bypass graft; CMR, cardiac magnetic resonance; CPB, cardiopulmonary bypass; CPC, cerebral performance category; d, day; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; GOS, Glasgow outcome score; hr, hour; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; MANE, major adverse neurologic event; min, minute; mo, month; mRS, modified Rankin score; NGAL, neutrophil gelatinase-associated lipocalin; PCI, percutaneous coronary intervention; SCr, serum creatinine; TBI, traumatic brain injury; THRT, transient hyperemic response test; wk, week.
TABLE 224.4
Tissue Protection with Short-Term ESA Treatment (Meta-Analyses)
| REFERENCE | GROUP | ESA TREATMENT | SUBJECTS | OUTCOMES IN ESA/HIGH Hb ARMS |
|---|---|---|---|---|
| Gao 2012 | Cardioprotection: STEMI | ESA (1–3×, 4,000–100,000 U total), 1 d before or up to 2 d after event | 13 RCTs N = 1564 | No difference in LVEF, infarct size, creatinine kinase, risk of heart failure, risk of stent thrombosis |
| Ali-Hassan 2015 | Cardioprotection: STEMI or AMI | 1–3 ESA doses (epoetin 14,000–60,000 U, or DA 300 ug) before or within 3 hrs of PCI, with additional doses 24–48 hrs post PCI | 5–14 trials depending on end point: N = 525–2044 | No difference in cardiac function (LVEF, LVESV, LVEDV, incidence of heart failure, infarct size, creatinine kinase), all-cause mortality, or incidence of stroke or thrombosis |
| Tie 2015 | Renoprotection; Cardiac surgery | Single dose of epoetin (20,000–40,000 U/IV) before or immediately post surgery | 5 trials: N= 423 | No difference in incidence of AKI or hospital mortality |
| Zhao 2015 | Renoprotection: Trauma and surgical | 1–4 doses (14,000–40,000 U) before surgery or up to 3d after admission to the ICU with additional doses for up to 3 wks | 10 trials, N = 2759: ESA (1391), placebo or no treatment (1368) | No difference in incidence of AKI, requirement for dialysis or mortality |
| Elliott and Endre 2016 | Renoprotection: AKI - trauma and surgical or kidney transplant | AKI trials: 14,000 U–40,000 U preoperatively or within 6 hrs of event, or 7000 U within 14 d of AKI (1 trial).Transplant trials: 7,000–100,000 U at time of surgery with additional doses up to 14 days postsurgery. In 2 trials lower-doses 10,000–17,000 U were given within 1 wk and continued for 1–3 mos | 7 AKI trials, N = 1020: ESA (490), placebo or no ESA (530). 7 transplant trials, N = 450: ESA (223), placebo or no ESA (227) | No difference in incidence of AKI in patients at risk for AKI or delayed graft function/renal recovery in kidney transplant patients |
AKI, Acute kidney injury; AMI, acute myocardial infarction; d, day; ECHO, echocardiogram; ESA, erythropoiesis stimulating agent; hr, hour; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; LVEDV, left ventricular end diastolic volume; mo, month; STEMI, ST segment elevated myocardial infarction; wk, week.
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