Impact of Delayed Erythropoietin Treatment in Critically Ill Patients

Anemia of critical illness is characterized by reduced tissue oxygenation and further complicated by end-organ dysfunction. Allogeneic red blood cell (RBC) transfusion is a primary method of treating anemia of critical illness in intensive care unit (ICU) patients. In 2002, a large, randomized controlled trial (RCT) showed that recombinant human erythropoietin (rHuEPO) promotes RBC production and reduces transfusions in ICU patients. However, the clinical benefits of rHuEPO remain to be determined, and the effects of RBC transfusions on rHuEPO efficacy are not well understood. In addition, general use of rHuEPO commonly deviates from protocols and patient populations of controlled trials. Thus, a recent study evaluated rHuEPO use for anemia of critical illness at a medical center where delayed initiation is frequent. The study evaluated rHuEPO use and RBC transfusion during the ICU stay as primary endpoints.

In this retrospective study of 126 patients, the average age (SD) and APACHE II score were 56.5 (18.6) years and 25 (7.8), respectively. The median ICU (IQR) and hospital length of stay (LOS) were 24 (11.25, 39) and 29 (17, 44.75) days, respectively. Eighty percent of patients were transfused with an average total of 5.42 +/-5.08 units received. On average, patients were treated with rHuEPO 12.5 days after ICU admission, and were given 3.8 doses (120,000 units of rHuEPO per dose) during the stay. RBC exposure inversely correlated with a lower mean hemoglobin (Hb) response to rHuEPO. ICU LOS (p less than 0.0001), Hb level at 24 hours (p = 0.055), transfusion within 48 hours of admit (p less than 0.0001), and postoperative status (p = 0.019) were the best predictors of transfusion requirements (r2 = 0.37).

In contrast to the large RCT, this study initiated rHuEPO treatment nearly ten days later after patients had been admitted to the ICU. The extended length of stay resulted in a 30% higher incidence of transfusions and an average of 1.24 additional doses of rHuEPO compared to the RCT. However, the average change in Hb levels was similar to RCT despite substantial differences in administration timing. Although rHuEPO has been shown to increase Hb levels in patients with anemia of critical illness, Duby et al concluded more studies are needed to determine if higher incidences of transfusion have a blunting effect on rHuEPO efficacy.

Please reference the source article:
Impact of delayed initiation of erythropoietin in critically ill patients. Duby JJ, Erstad BL, Abarca J, Camamo JM, Huckleberry Y, Bramblett SN. BMC Blood Disord. 2007 Oct 4;7:1.

NAAC Expert Commentary:
The authors reported four independent variables that had statistical significant relationship with allogeneic blood transfusions (ABT). These include: ICU stay, Hospital stay, APACHE II scores and the number of rHuEPO doses given. Predictors of ABT also included ICU length of stay, hemoglobin (Hb) concentration, and post-operative clinical status of the patient. Although the authors claim that rHuEPO is widely used in this population, data from pharmaceutical companies on prescriptions in this population shows very little use of these agents as treatment for anemia.

On average, between 7 to 10 days are required for rHuEPO to enhance red cell mass with the doses given in the critical care setting. A delay in initiation of therapy would result in a lower hemoglobin level at the time of rHuEPO administration. Low Hb levels are the result of a combination of frequent phlebotomies, bleeding and suppressed rHuEPO production and response. Data from other surgical and non-surgical populations shows that low hemoglobin levels are a strong predictor for ABT.

In this study, the population of critically ill patients was not stratified to eliminate the bias of transfusion based on the clinical condition of the patients. The absence of a control group enhances this shortcoming. In their analysis of the data, the presence of rHuEPO resistance or failure to respond was attributed to ABT. In fact, it could be a sub population of 25-30% of the non-responders that ended with higher numbers of ABT. Non-response, although not substantiated, could be associated with worse clinical status of the patients generally reflected with higher APACHE scores.

In conclusion, this small and retrospective study raises an interesting point weighing the use of rHuEPO in the critically ill as it relates to the time of administration. The investigators found that “late” administration of rHuEPO was not helpful in reducing these patients exposure to ABT. The optimal time and Hb level as a trigger for rHuEPO have not been clearly established and need further investigation. In addition, it is unclear if the “sicker” patients received (more) rHuEPO than a healthier cohort. As such, ABT rates could not be accurately assessed.

Based on previously published data in randomized control studies, early administration with a target hemoglobin level of approximately 10 g/dL may reduce exposure to ABT and result in higher Hb levels despite more ABT in the control group.

Lastly, newer studies suggest the rHuEPO administration in the critically ill is associated with higher incidence of deep vein thrombosis (DVT). This relationship is overcome with the use of proper prophylaxis. It would be interesting to see if delayed (not late) initiation of rHuEPO is associated with higher or lower DVT rates.

Role of Erythropoietin Treating Anemia in Chronic Heart Failure

Anemia is a strong predictor of adverse outcome in chronic heart failure (CHF). According to the World Health Organization, anemia is defined as a hemoglobin (Hb) level less than 12 g/dL in women and less than 13 g/dL in men. In CHF, deterioration of cardiac function and an insufficient supply of oxygen to the heart may lead to elevated levels of erythropoietin (EPO). Epoetin is an essential hormone that regulates plasma Hb concentrations in the body, and some recent studies have focused on the efficacy of recombinant EPO (rHuEPO) and erythropoiesis-stimulating proteins (ESP) in CHF treatment. These studies have shown promising results, and a larger morbidity and mortality trial in CHF has recently begun enrolling patients.

In 2000, an open-label study of 32 anemic CHF patients showed that administering rHuEPO resulted in significant improvement of cardiac function. A subsequent study examining the effects of rHuEPO therapy revealed significant improvements in exercise capacity and oxygen consumption. More recently, several randomized, placebo-controlled trials using ESPs were conducted. In these trials, anemic CHF patients receiving darbepoetin alfa showed improvements in exercise duration, as well as significant associations between increased Hb levels and improved quality of life. A pooled analysis of these studies also revealed that rHuEPO treatment, compared with placebo, reduced the risk of CHF-related hospitalization and all-cause mortality.

These studies indicate that rHuEPO treatment in anemic CHF patients may enhance cardiac performance and overall quality of life by increasing oxygen supply to the heart, normalizing heart rate, and inhibiting myocardial apoptosis. Although earlier studies have raised questions about the safety of increasing Hb levels in patients with chronic kidney disease, those results do not have immediate impact on rHuEPO treatment in CHF patients. Before rHuEPO and other ESPs can be routinely applied in clinical practice, it is essential to obtain better assessment of the efficacy of rHuEPO therapy through larger, ongoing CHF studies.

Please reference the source article:
Erythropoietin in chronic heart failure. Belonje AM, Voors AA, van Gilst WH, van Veldhuisen DJ. Congest Heart Fail. 2007 Sep-Oct;13(5):289-92.

NAAC Expert Commentary:
Randomized trials have reported a remarkable reduction in the annual mortality rate to around 8 % from the use of beta-blockers and renin-angiotensin-aldosterone antagonists in patients with chronic heart failure (CHF) (1,2). However, in routine clinical practice, mortality remains very high (3,4). One reason for this disparity is the exclusion of patients from clinical trials with comorbid conditions that contribute to high mortality. Over the last few years, anemia has come to be recognized as an important comorbidity that is common in CHF patients and is strongly associated with poor clinical status and worse outcomes. Nevertheless, it remains unclear whether anemia is just a marker or a mediator of poor outcomes. If anemia is a mediator, correcting it could become an important and novel therapeutic target to improve long-term outcomes in such patients. Because the majority of CHF patients are considered to have anemia of chronic disease, and circulating levels of erythropoietin are insufficient to the degree of causing anemia (5,6), stimulating erythropoiesis with ESAs becomes a rational strategy. Belonje et al (7) have recently summarized the results of using ESAs in three preliminary, small, single-center studies and three more recent phase II trials published in 2007. Overall, these studies show potentially beneficial effects of treating anemia in heart failure. Indeed, the preliminary studies even found an improvement in cardiac function with the use of ESAs.

The problem is that we still do not know the ideal threshold at which therapy should be initiated nor the extent of correction considered safe and desirable in the individual patient with heart failure. These issues are more important because of increasing safety concerns that rHuEPO therapy for treating anemia may be associated with adverse cardiovascular outcomes in patients with chronic kidney disease (8), and may worsen cancer in patients receiving chemotherapy to treat various types of cancer (9). Moreover, because increased hemoglobin is associated with an elevation in the systemic vascular resistance (10), it is unlikely that correction of anemia by itself will improve impaired left ventricular function. Therefore, nonhemodynamic mechanisms may play a more important role if the use of ESAs for increasing hemoglobin is found to be beneficial. In their article, Belonje et al summarize the emerging data showing that ESAs have cardioprotective effects independent of any hematological effect. These exciting effects may contribute to the beneficial effects of ESA in CHF. Finally, because of the great clinical importance of anemia in CHF, it is imperative that we wait for the results of the ongoing large mortality and morbidity clinical trial before drawing any conclusions regarding treating anemia in HF

References in the commentary:
(1) Cohn JN, et al. N Engl J Med 2001;345:1667-75.
(2) Bardy GH, et al. N Engl J Med 2005;352:225-37.
(3) Disease Statistics. NHLBI FY 2005 Fact Book, 2005:37-56.
(4) Thom T, et al. Circulation 2006;113:e85 - e151.
(5) van der Meer P, et al. J Am Coll Cardiol 2004;44:63-7.
(6) Opasich C, et al. Eur Heart J 2005;26:2232-7.
(7) Belonje AM, et al. Cardiovasc Drugs Ther 2008;22:1-2.
(8) Information for Healthcare Professionals Erythropoiesis Stimulating Agents (ESA). FDA. November 8, 2007.
(9) Additional Trials Showing Increased Mortality and/or Tumor Progression with EPOGEN(R)/PROCRIT(R) and Aranesp(R). FDA. 2008.
(10) Anand IS, et al. Br Heart J 1993;70:357-62.

Anemia Management for Surgery and Bariatric Surgery Patients

Laparoscopic roux-en-y gastric bypass (LRYGBP) is a common and cost-effective bariatric procedure that leads to improvements in obstructive sleep apnea, diabetes, hypertension, and osteoarthritis. Due to reductions in small intestine absorption, patients receiving LRYGBP often risk nutritional deficiencies in iron, folate, and vitamin B12. Typically, patients undergo lifelong vitamin supplementation to avoid these nutritional deficiencies. A recent study assessed the success of vitamin supplementation to avoid iron, folate, and vitamin B12 deficiency anemia in LRYGBP patients.

The study included 25 women and 5 men (average age 41 years) who underwent LRYGBP between 2003 and 2005 at a major medical institution. These patients completed a minimum of 2 years follow-up at an outpatient facility; complete blood cell count, iron, folate, and cobalamin levels were recorded before surgery, 6 months, 1, 2, and 3 years after LRYGBP. Each patient was prescribed one tablet of centrum per day, and vitamin intake and occurrence of anemia caused by iron, vitamin B12, or folic acid was registered. Definitions of iron, vitamin B12, and folic acid deficiencies were as follows, respectively: transferrin saturation less than 15%, serum cobalamin less than 150 pg/ml, and serum folate less than 3 ng/ml. All patients regularly took the vitamin supplement throughout the course of the study.

After completion of the study, 40% of patients presented with iron deficiency at the 2-year follow-up, with an increase to 54% at 3 years. Commercial vitamins typically contain 10 to 20 mg of elemental iron, a level that is clearly insufficient to avoid iron deficiency after LRYGBP. In addition, vitamin B12 deficiency was reported in 27% of patients at the 3-year follow-up. Commercial vitamin B12 (6 to 25 ug/tablet) is also insufficient to treat B12 deficiencies after LRYGBP. Consistent with other published studies, no folate deficiencies were seen in any patients. However, folate deficiency could be exacerbated during pregnancy.

The results of this study indicate that current vitamin supplementation therapy at this institution is insufficient to treat iron and vitamin B12 deficiency anemia. Current published guidelines recommend 40 to 65 mg of iron per day and 350 to 500 ug of cobalamin per day. To effectively treat these patients, a more rigorous and intense prophylactic regimen will have to be implemented.

Please reference the source article:
Prevalence of iron, folate, and vitamin B12 deficiency anemia after laparoscopic Roux-en-Y gastric bypass. Vargas-Ruiz AG, Hernández-Rivera G, Herrera MF. Obes Surg. 2008 Mar;18(3):288-93.

NAAC Expert Commentary:
The authors point out that many patients are anemic following bariatric surgery. Unfortunately, this finding is not unique to bariatric surgery. The literature shows that over 50% of patients entering the hospital for elective surgery are anemic. We need to address three specific areas about anemia in the surgical patient: (1) early recognition of anemia; (2) consequences of anemia; and (3) appropriate and timely treatment of anemia. Because pre-surgical anemia does not develop overnight, physicians should have known about the anemia before the day of surgery. Unfortunately, many pre-admission testing programs in place are not effective in alerting the admitting physician that a patient is anemic. The anemia is typically first noted when the lab results are reviewed by surgery and anesthesia on the day of surgery. Most physicians do not understand the consequences of anemia in the surgical patient. In this study, the authors point out, some patients do not respond to oral therapy for post-operative anemia. The use of intravenous iron and intramuscular B12 are a better choice for these patients.

In general, studies have shown that anemia is a stand-alone risk factor for worse outcomes. Moreover, it is the primary reason for red blood cell transfusion in these patients. Transfusion compounds the risk of worse outcomes. We have relied traditionally on transfusion as the way to treat anemia in surgical patients, in part because less attention is paid to anemia as a risk factor and in part because we have become complacent about transfusion. The first step is early recognition of anemia. Recognition of anemia and treatment with iron and ESA therapy has been proven to be an effective way to avoid transfusion exposure and to increase patient safety.