Parameters
Yes
No
Comment
Validity
Is the Randomization Procedure well described?
−1
Method of randomization was not clearly described
Group stratification prior to randomization was explained in detail
Double blinded?
+2
Open-labeled, phase III, randomized, controlled trial. The outcome measure is a laboratory result which is unlikely to be affected by unblinding
Is the sample size calculation described/adequate?
−1
It was based on 25 % event rate difference between both arms (40 % vs. 15 %). In reality, the difference was around 16 %, which should require bigger sample size. This is to achieve two-sided significance level at 0.05 and a power of 90 % with expected 10 % failure rate during observation. This requires 160 subjects in total for both arms. There was no account for dropout rate (22 %)
Does it have a hard primary endpoint?
+1
Increase in Hb of at least 1.0 g/dL at any time between baseline and either the end of study or withdrawal
Is the endpoint surrogate?
0
Is the follow-up appropriate?
−1
8 weeks which may be appropriate for efficacy but not for safety?
Was there a Bias?
−1
The inherent nature of open-labeled design without clear explanation of randomization method raises the risk of selection and performance bias
Is the dropout >25 %?
+1
Is the analysis ITT?
+3
Utility/usefulness
Can the findings be generalized?
−1
Relatively short follow-up period and small sample size question the power of the study and outcome results. The study was restricted on predialysis patients and Hb <11 g/dL
Score
13 %
Comments and Discussion
Iron deficiency is one of the main causes of resistance to erythropoietin treatment in CKD patients [1]. These patients have a unique feature of poor gastrointestinal iron absorption due to various reasons including the use of gastric acid-lowering tablets, common use of phosphate binders, and the persistent inflammatory state characteristic of CKD [2]. Therefore, this study was designed to address the important question whether intravenous iron is superior to oral iron therapy in this group of patients and whether it is safe or not. It also downgraded the value of serum ferritin and transferring saturation as predictors of bone marrow iron stores [3].
The study has a number of limitations:
1.
The study design was open-labeled, thus raising the potential of observer: selection and performance bias.
2.
The primary outcome in this trial was a laboratory result (increase in Hb concentration by 1 g/dL). While this satisfies the purpose of the clinical trial, it does not necessarily translate to patient’s improved quality of life, morbidity, or mortality.
3.
The study may well be underpowered due to a small sample size (anticipated difference was 25 % and actual difference was 16 % between arms) with no account or allowance for the dropout rate (22 %). Participants who completed the study and actually received the study intervention were around 66 %; hence, it would be of interest to know the difference between ITT and per protocol analyses.
4.
Follow-up period was too short (56 days) to assess safety and effect on eGFR. Cumulative hemoglobin response curve was on steady rise until the end of the study for both arms. Increasing the study duration to 12 weeks rather than 8 weeks might have increased the number of participants in the oral arm who achieved the target hemoglobin; it seems that the 56-day study duration was chosen arbitrarily. Of relevance, serum ferritin levels in the oral arm were still rising until the end of the study, albeit to a lesser extent than the IV iron arm.
5.
Multiple subgroup analyses for such a small sample size are inconclusive and at best hypothesis generating.
It was hard to explain the significant decline of eGFR (−4.4 ml/min/1.73 m2) based only on two readings within the relatively very short interval of 2 months [4] with patients receiving a drug (oral iron) routinely used in daily practice without such huge detrimental effect.
Conclusion
It has become acceptable practice in CKD4-5 to administer iron intravenously, rather than orally, to correct iron-deficiency anemia. There is little doubt that the US trial described above had a major influence on such practice. However, it is worth noting its limitations and also the fact that those given oral iron supplementation had a progressive improvement of their serum ferritin levels, albeit at a lower and slower rate than those who received parenteral iron.
Target Hemoglobin Level with Erythropoietin Treatment in CKD
CREATE study
Title: Normalization of hemoglobin level in patients with chronic kidney disease and anemia
Title Acronym: Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE)
Authors: Drüeke TB, Locatelli F, Clyne N, Eckardt K, Macdougall IC, Tsakiris D, Burger H, and Scherhag A, for the CREATE Investigators
Journal : NEJM. 2006;355(20):2071–84
Abstract
Background: Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established.
Methods: We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0–35.0 ml per minute per 1.73 m2 of body surface area and mild-to-moderate anemia (hemoglobin level, 11.0–12.5 g/dL) to a target hemoglobin value in the normal range (13.0–15.0 g/dL, group 1) or the subnormal range (10.5–11.5 g/dL, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g/dL (group 2). The primary endpoint was a composite of eight cardiovascular events; secondary endpoints included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.
Results: During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95 % confidence interval, 0.53–1.14; P = 0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P = 0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P = 0.03). General health and physical function improved significantly (P = 0.003 and P < 0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1.
Conclusions: In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events.
ClinicalTrials.gov number, NCT00321919
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the Randomization Procedure well described? | +1 | Randomization method was described in detail. There was no statistical difference between baseline variables of both groups | |
Double blinded? | −2 | Open-labeled, randomized, controlled trial | |
Is the sample size calculation described/adequate? | +3 | It is an event-driven trial, based on an event rate of 15 % in the control group to achieve 80 % power and 5 % significance with a projected reduction in the hazard ratio for a first cardiovascular event by one-third. This requires 200 events to happen within the recruitment and follow-up period | |
Does it have a hard primary endpoint? | +1 | Time to a composite of eight cardiovascular events including sudden death, fatal or nonfatal myocardial infarction, acute heart failure, angina pectoris or cardiac arrhythmias requiring hospitalization for 24 h or more, fatal or nonfatal stroke, transient ischemic attack, peripheral vascular disease (amputation, necrosis) | |
Is the endpoint surrogate? | 0 | ||
Is the follow-up appropriate? | +1 | Recruitment period of 2 years and follow-up 2 years after enrollment of the last patient | |
Was there a Bias? | −1 | There is a potential risk of selection and performance bias with the open-labeled design. This is particularly important with the primary hard endpoint | |
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | It was a multicenter study including participants from 94 renal units in 22 European, Asian, and Latin American countries | |
Score | 53 % | ||
Comments and Discussion
Hemoglobin target is one of the controversial areas in anemia management in chronic kidney disease [5]. In conjunction with CHOIR, both studies were the first efforts to identify the appropriate hemoglobin levels in chronic kidney disease patients not yet on dialysis. Their results were long-awaited by the guideline working groups to provide them with robust evidence [6]. The study has had a clear design with hard endpoints.
The study has some limitations:
1.
A number of factors reduced its power. For instance, sample size calculation relied on a single reference from a population with an event rate far higher than actual event rate (15 % vs. 6 %). The reasons behind the low event rate they encountered in their cohort were due to improved patient care for cardiovascular risks and the better-than-usual performance of participants in control arm of clinical trials [7]. This obviously resulted in a smaller sample size. This was further compromised when it was not clear whether they accounted for the dropout rate in the initial calculation or not (25 and 17 % in both arms).
2.
The number of participants who left the study to start dialysis was high (238). This should be expected when the lower limit of eGFR accepted for participation was 15 ml/min and study duration was expected to last for 2 years after the last randomized patient. The relatively higher number of patients who required dialysis in the higher-hemoglobin arm should be understood in the context of dialysis initiation which was not protocolized (controlled) and the study was not powered for this outcome.
3.
The risk of performance and selection bias cannot be ignored with the open-labeled design of this trial.
4.
The use of composite endpoint is usually justified by the assumption that the effect on each of the components will be similar and that patients will attach similar importance to each component. This is not necessarily the case with the eight cardiovascular endpoints chosen. The validity of composite endpoints depends to a large extent on similarity in patients’ importance (weighting), treatment effect, and number of events across components [8]. This may not be the case with those chosen in this trial.
Conclusion
CREATE was primarily a negative study that shaped subsequent practice of hemoglobin correction and related guidelines [9] in CKD. It showed no advantage of normalization of hemoglobin levels beyond a hemoglobin level >12 g/dl.
CHOIR Study
Title: Correction of anemia with epoetin alfa in chronic kidney disease
Title Acronym: Correction of Hemogloblin and Outcomes in Renal Insufficiency (CHOIR)
Authors: Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, and Reddan D, for the CHOIR Investigators
Journal : NEJM. 2006;355(20):2085–98
Abstract
Background: Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined.
Methods: In this open-labeled trial, we studied 1,432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g/dL and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g/dL. The median study duration was 16 months. The primary endpoint was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke.
Results: A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95 % confidence interval, 1.03–1.74; P = 0.03). There were 65 deaths (29.3 %), 101 hospitalizations for congestive heart failure (45.5 %), 25 myocardial infarctions (11.3 %), and 23 strokes (10.4 %). Seven patients (3.2 %) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5 %) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event.
Conclusions: The use of a target hemoglobin level of 13.5 g/dL (as compared with 11.3 g/dL) was associated with increased risk and no incremental improvement in the quality of life (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].
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