Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial

Corwin HL, Gettinger A, Rodriguez RM, et al.

Crit Care Med. 1999;27:2346-50. [abstract]

Reviewed by Chalikonda B. Prasad MD, Lutheran General Children's Hospital, Park Ridge, IL

Review posted January 5, 2001

I. What is being studied?:

The study objective:

Whether administration of recombinant human erythropoietin (rHuEPO) to critically ill patients in the intensive care unit would reduce the need for red blood cell transfusions.

The study design:

This is a prospective, randomized, double-blind, placebo controlled, multicenter trial

The patients included:

A total of 160 patients admitted to the ICU and who met the following criteria were enrolled:

• Age 18 years or older
• Male or female. Females must be post-menopausal for at least 1 year or surgically sterile; females of childbearing potential must have a negative pregnancy test immediately before study entry.
• No deficiency of B12 (< 200 pg/ml) or folate (< 2.5 ng/ml)
• No iron deficiency (transferrin saturation < 15% and ferritin < 50ng/ml)
• Hematocrit < 38 %
• Subject or next of kin must read and sign the informed consent form.

The patients excluded:

Exclusion Criteria:

• Presence of any primary hematological disease or B12 (< 200 pg/ml), folate (< 2.5 ng/ml) or iron deficiency (transferrin saturation < 15% and ferritin < 50ng/ml)
• Risk of hospital death > 80% (APACHE)
• Neutropenia (< 500 neutrophils) or thrombocytopenia (< 20,000 platelets)
• Vasopressors to maintain blood pressure other than dopamine at < 5mcg/kg/min
• Severe respiratory compromise (FiO2 > 60% and or PEEP > 10)
• Chronic renal failure on maintenance dialysis
• Liver failure, cirrhosis, varices or hepatic encephalopathy
• Seizures within prior 6 months
• Hypertension not controlled on medications (systolic > 200, diastolic > 110)
• Severe head injury
• Recent neurosurgical procedure or cerebrovascular accident within 1 month
• Recent androgen therapy within 1 month
• Recent cytotoxic or immunosuppressive therapy within one month
• Autoimmune hemolysis (Coombs test positive)
• Subjects who had received an experimental drug within 30 days before this study
• Previous involvement in prior recombinant human erythropoietin clinical study
• Subjects prohibited from receiving blood transfusions
• Pregnancy or lactation
• Human immunodeficiency virus positive
• Active collagen vascular disease
• Recent thromboembolic disease within 6 months
• Active bleeding

The interventions compared:

The patients were randomized to receive either rHuEPO or placebo. The study drug (300 u/kg of rHuEPO or placebo) was administered by subcutaneous injection beginning on ICU day 3 and was given daily until ICU day 7. The subsequent dosing was every other day to achieve a hematocrit (Hct) of > 38%. The drug was temporarily withheld if Hct was > 38% until it dropped to < 38%. The study drug was given for a minimum of 2 weeks or until discharge (for subjects with an ICU length of stay > 2 weeks), up to a total of 6 weeks post-randomization. The study drug was given intravenously if the platelet count was < 20,000. All patients received > 150 mg elemental iron either by mouth or nasogastric tube starting on day 1 of study. Those patients not able to take iron enterally were given parental iron. The attending physician determined the need for blood transfusion. No specific transfusion protocol was followed.

The outcomes evaluated:

1. The cumulative blood transfusion requirement from study day 1
2. Transfusion independence between study day 8 and study day 42

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

No. There is no strong, independent and consistent association between the surrogate and clinical end points.

In this study the authors are looking at the transfusion requirements or transfusion independence as the surrogate outcomes and mortality and morbidity as the true clinical outcomes. So far the studies have definitely proven that repeated transfusions are a risk for certain blood-borne diseases. However, in these days of excellent screening techniques, the incidence of these infections is significantly lower. One study (8), has pinned the incremental cost of preventing one hepatitis C infection by using erythropoetin and autologous blood transfusion at $ 888,000,000.

On the other hand, in the last few years, we have seen some studies that report an increased incidence of infections secondary to immunomodulation resulting from blood transfusions (7). These effects are however unproven and seem to be lesser with leukocyte depleted blood transfusions.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

There are no other drug classes that result in increased RBC production by the bone marrow that have been investigated.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Since there are no other drugs in this class, the question is not applicable.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The patients were randomly assigned to either the treatment or placebo group by a set of computer generated random numbers. Randomization was stratified by site.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Yes. All the patients entering the study were accounted for at the end of the study. All patients were followed for a period of 42 days unless death occurred earlier. Final lab studies were obtained on day 42 or at hospital discharge for those patients discharged before day 42.

Yes. The patients were analyzed in the groups to which they were randomized. There were no crossovers.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes, control patients received a placebo. However, there is no mention of how the study drug/placebo was dispatched or received.

4. Were the groups similar at the start of the trial?

Yes. No significant differences in age, gender, APACHE score, hematocrit, reticulocyte count and erythropoietin levels were noted between the two groups.

5. Aside from the experimental intervention, were the groups treated equally?

No mention is made of how the two groups were treated for the primary condition responsible for admission. The subjects' attending physicians decided on the need for blood transfusion. There was no specific transfusion protocol used. This has face validity in that it probably represents "real world" practice. However, it would be reassuring to see evidence that there was no systematic difference in the "transfusion triggers" between the two groups.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

1) Cumulative transfusion requirements:

	Recombinant Human Erythropoietin group	Placebo group
Total units transfused a	166	305
Hct change (baseline to final)b	4.8 (95% CI, 3.8, 5.9)	1.4 (95% CI, 0.3, 2.8)
Final Hct c	35.1 +/- 5.6	31.6 +/- 4.1
Reticulocyte % change (baseline to final)b	2.5 (95% CI, 1.9, 3.0)	0.8 (95% CI, 0.3, 1.3)

a - p < .002 ; b - p < .001 (analysis of covariance); c - p < .01

The data demonstrate a decrease in the cumulative transfusion requirements and increase in hematocrit and reticulocyte counts for patients receiving erythropoietin.

2. Transfusion independence between study day 8 and 42:

	Transfused	Not transfused	Totals
rHuEPO	36	44	80
Placebo	44	36	80
	80	80

 

 

Clinical Significance Measure	Value	Lower 95% Confidence boundary	Upper 95% Confidence boundary
Relative Risk	0.8	0.6	1.1
Absolute Risk Reduction (ARR)	0.10	-0.05	0.25
Relative Risk Reduction (RRR%)	18%	-12%	40%
Number Needed to Treat	10	4	infinity

As noted by the authors themselves, the sample size is not adequate to confirm with precision the 0.8 relative risk observed; the treated patients might have been between 60% less likely to receive a transfusion or 10% more likely.. The sample size to prove a significant RR of this degree should be at least 300 patients in each group.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

At this stage, I will be a little cautious in applying the outcomes of this study to my patient population as this study involved an adult population. However, there have been previous studies that reported the efficacy and safety of erythropoeitin in preterm babies (4) and in children with chronic renal failure (5).

2. Were all clinically important outcomes considered?

Clinically important outcomes were considered, although not as primary outcome measures. The primary outcome of reducing blood transfusions in those receiving erythropoeitin has been considered.

3. Are the likely treatment benefits worth the potential harms and costs?

In the United States of America, the current risk of transfusion related infections by viruses are very rare. The risks for contamination of a single unit of blood with HIV, hepatitis C and hepatitis B are 1:493,000, 1:103,000 and 1:63,000 respectively (9). Given the NNT of 10, one needs to treat a huge number of patients to prevent one episode of transfusion related infection. This would cost a tremendous amount of money (8). However, I think that the potential harm resulting from transfusion related infection, though rare, is reason enough to consider rHEPO, particularly when there is a need for multiple units of blood.

References

1. Cazzola M, Mercuriali F, Brugnara C. Use of recombinant human erythropoietin outside the setting of uremia. Blood. 1997 15;89(12):4248-67. [citation only]
2. Dunphy FR, Dunleavy TL, Harrison BR, et al. Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. Cancer. 1997; 79(8):1623-8. [abstract]
3. Jamal R, Fadzillah G, Zulkifli SZ, Yasmin M. Seroprevalence of hepatitis B, hepatitis C, CMV and HIV in multiply transfused thalassemia patients: results from a thalassemia day care center in Malaysia. Southeast Asian J Trop Med Public Health. 1998;29(4):792-4. [abstract]
4. Donato H, Vain N, Rendo P, Vivas N, et al. Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics. 2000;105(5):1066-72.5. [abstract] [full-text for subscribers/AAP members]
5. Brandt JR, Avner ED, Hickman RO, Watkins SL. Safety and efficacy of erythropoietin in children with chronic renal failure. Pediatr Nephrol. 1999;13(2):143-7.6. [abstract]
6. Vitale MG, Stazzone EJ, Gelijns AC, Moskowitz AJ, Roye DP Jr. The effectiveness of preoperative erythropoietin in averting allogenic blood transfusion among children undergoing scoliosis surgery. J Pediatr Orthop B. 1998;7(3):203-9.7. [abstract]
7. Petranyi GG, Reti M, Harsanyi V, Szabo J. Immunologic consequences of blood transfusion and their clinical manifestations. Int Arch Allergy Immunol. 1997;114(4):303-15. [abstract]
8. Woronoff-Lemsi MC, Arveux P, Limat S, Morel P, Le Pen C, Cahn JY. Erythropoietin and preoperative autologous blood donation in the prevention of hepatitis C infection: necessity or luxury? Transfusion. 1999;39(9):933-7. [abstract]
9. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med. 1996 27;334(26):1685-90. [abstract]

 

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