Erythropoiesis-stimulating agents (ESAs) -
Initially, the optimal degree of anemia correction in patients with chronic kidney disease by erythropoiesis-stimulating agents ESAs relied mainly on the results of observational studies.
Many of these studies supported full anemia correction. Subsequently, randomized controlled trials of small sample size examined intermediate outcomes, but only trials with hard outcomes could settle this issue convincingly.
In contrast to expectations based on epidemiological studies, the randomized controlled trials of large sample size performed in patients with chronic kidney disease in the last two decades have convincingly shown that full anemia correction, as compared to partial anemia correction, is associated with increased risk of adverse events and mortality and that the increased risk outweighs potential benefit.
Although transfusion needs decrease and quality of life increases with actively raised hemoglobin levels in severely anemic patients with chronic kidney disease, any benefit of increasing hemoglobin levels above As some of these patients may experience improvement in physical and mental health and overall well-being above this level, individualization of therapy may be chosen in those who are prepared to accept the associated risks.
Future, adequately powered, and blinded randomized controlled trials of anemia treatment using patient-reported outcomes as primary rather than secondary endpoints are needed to answer the question of the optimal hemoglobin target as regards the quality of life.
Anemia is a major complication of chronic kidney disease CKD. This type of anemia generally develops from CKD stage 3 onwards, and its degree of severity increases with the progression of renal disease [ 1 , 2 ]. It significantly contributes to patient mortality and morbidity including impaired physical and cognitive function, reduced quality of life, increased need for blood transfusions, higher frequency of hospitalizations, and an increase in cardiovascular events [ 3 , 4 , 5 ].
The main cause of the CKD-associated anemia is the insufficient production of erythropoietin EPO by the diseased kidneys, due to deranged renal oxygen sensing and subsequently reduced renal tissue mass [ 6 , 7 ]. Another major contributor is abnormal iron metabolism, which is related to inflammation, oxidative stress, and hepcidin excess [ 8 , 9 ], with reduced iron availability for red blood cell production.
The treatment of insufficient circulating concentrations of endogenous EPO or resistance to its action by recombinant human EPO alfa in patients with CKD has been a major breakthrough in nephrology [ 10 ].
Subsequently, many different types of erythropoiesis-stimulating agents ESAs have been developed and tested in the clinical arena.
At present, all clinically available ESAs are EPO derivatives [ 7 ]. In addition, two different classes of ESAs have been developed and undergone clinical evaluation. The first class is represented by peginesatide, a synthetic peptide-based ESA. It was shown to be as effective as epoetin and darbepoetin in hemodialysis-dependent and non-dialysis-dependent patients with CKD, respectively [ 11 , 12 , 13 ].
However, it was subsequently withdrawn from the market because of major adverse events [ 14 ]. The second new ESA class is represented by prolyl hydroxylase domain inhibitors PHI which inhibit HIF-α ubiquitination and proteasomal degradation.
Clinical trials with at least six different PHIs have been conducted so far in humans and have demonstrated effective anemia correction and improved iron metabolism in patients with CKD in the absence of serious side effects [ 15 ]. The results of phase III clinical studies, which are underway at present, need to be known before the potential introduction of PHIs into clinical practice.
The initial clinical use of ESAs was limited to anemia correction in patients with end-stage renal disease ESRD receiving dialysis therapy, mainly due to cost issues.
Subsequently, ESA treatment was extended to patients with non-dialysis dependent CKD. The question then arose whether the anemia should be corrected entirely or only partially [ 16 ]. Although the correction of severe anemia generally was associated with lower blood transfusion rates and improved quality of life, observational studies made it progressively clear that too rapid increases in hemoglobin could induce high blood pressure or aggravate preexisting hypertension and in a rare instance even lead to seizures [ 17 , 18 ].
In the initial decades after the introduction of ESAs into clinical practice, numerous studies were conducted to examine the issue of the optimal benefit-harm ratio of higher versus lower degrees of anemia correction in CKD. Since the majority among these studies were observational in nature, they were unable to solve this issue definitively.
Only randomized clinical trials RCTs can provide a convincing answer, reflecting an acceptable balance of benefits and risks. Several studies were done which were aimed at limiting the degree of hemoglobin variability and hopefully improving cardiovascular morbidity and mortality.
A study done in the USA found an association of hemoglobin variability and mortality in a cohort of 34, prevalent hemodialysis patients in [ 19 ]. The magnitude of the association increased when restricting the analysis to hemoglobin subgroups in order to address time-dependent confounding.
However, an analysis of a smaller, more recent incident cohort by same investigators failed to confirm an association between hemoglobin variability and risk of mortality [ 20 ]. In a subsequent European study, hemoglobin variability was determined in hemodialysis patients treated by ESAs over 2 years [ 21 ].
The authors used several different assessment methods of variability, including standard deviation, residual standard deviation, time-in-target, fluctuation across thresholds, and area under the curve.
Thus, hemoglobin variability probably does not play a major role in patient outcomes, in contrast to initial claims to the contrary. Up to the year , the results of approximately 30 prospective RCTs were reported, with a total of approximately patients included, as shown in Fig.
Initially, nearly all of them were placebo-controlled and had relatively low hematocrit or hemoglobin targets. The majority of the trials were of small sample size. Five more recently conducted trials included more than patients, and only four among them had hard outcome endpoints.
The first RCT with a high anemia correction target and large sample size done in chronic hemodialysis patients was reported in [ 23 ]. Subsequently, at least 12 additional RCTs were done testing the hypothesis that complete—or near complete—anemia correction in patients with CKD led to better intermediate outcomes such as cardiac dimensions and function, physical activity, and decline in kidney function than partial anemia correction, as shown in upper part of Fig.
None of the more recent RCTs had a placebo arm except one [ 26 ]. It is noteworthy that in nearly all of the more recent RCTs, the achieved mean hemoglobin value was either at the lower end of or even below the predefined higher hemoglobin target and either at the higher end of or above the predefined lower hemoglobin target, respectively.
This demonstrates the difficulty to obtain a prespecified degree of anemia correction despite major efforts to have investigators and patients strictly adhere to study protocol.
The practical consequence is that the difference in mean hemoglobin levels between the higher and the lower hemoglobin target groups is less marked than anticipated, which in turn makes it more difficult, if not impossible, to observe statistically significant outcome differences between the lower and the higher anemia correction arm.
Randomized controlled trials RCTs with erythropoiesis-stimulating agents ESAs in patients with chronic kidney disease CKD. For each published trial, the figure shows sample size, effectively achieved mean hemoglobin Hb levels in lower and higher anemia correction arms, and lower versus higher Hb targets, respectively.
References of articles quoted in the figure: Suzuki M et al. Here is a brief summary of the four partial versus full anemia correction RCTs which examined hard patient outcomes and were of sufficiently large sample size. The patients received epoetin alfa for 29 months, at which time the trial was prematurely stopped by the data monitoring board because there was no clear benefit of the higher hematocrit target and because of major concerns of a progressively increasing mortality risk.
In the CREATE trial, patients with non-dialysis-dependent CKD were randomly assigned to epoetin beta treatment to achieve a hemoglobin target of either Follow-up time was 3 years. Full anemia correction did not reduce the risk of cardiovascular events. There was even a non-significant trend to an increased risk for death in the higher hemoglobin target group, and dialysis treatment was required in more patients of this group.
On the positive side, there was evidence for a quality-of-life benefit. The CHOIR trial involved 1, patients with non-dialysis-dependent CKD. They were treated with epoetin alfa to achieve a hemoglobin target of either Median study duration was 16 months. Patients in the higher hemoglobin target group were found to have a higher risk for cardiovascular events and death than those in the lower target group.
The adverse outcome was associated with increased risk for congestive heart failure and hospital admissions. There was no between-group difference in quality-of-life scores.
TREAT included 4, patients with type 2 diabetes mellitus and non-dialysis-dependent CKD [ 26 ]. After a mean follow-up of Of major concern was the observation of an increased risk for stroke in the high hemoglobin group. Blood transfusions were needed more frequently in the placebo-treated patients.
There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. In accord with the KDIGO anemia guideline [ 4 ], one can summarize the main lessons from the RCTs of anemia correction by ESAs in patients with CKD as follows.
The most important lesson of the recent RCTs with hard outcomes is that in patients with CKD, full anemia correction, as compared to partial anemia correction, is associated with increased risk of adverse events and mortality and that the increased risk outweighs the potential benefit.
Figure 2 shows the progressive increase in risk and decrease in benefit with actively raised anemia correction values. Higher hemoglobin correction targets are associated with less transfusion needs than lower hemoglobin correction targets, but the optimal hemoglobin value at which both transfusion needs and cardiovascular and other risks are reasonably low is not known.
Moreover, this value probably varies from one patient to the other. The results of the recent RCTs, with a particularly strong impact of TREAT, led the workgroup of the KDIGO anemia guideline to recommend major changes in the approach of anemia treatment [ 4 ].
Since often high to very high doses of ESAs are needed to raise hemoglobin levels towards the normal range and iron deficiency is known to induce ESA hyporesponsiveness, the KDIGO workgroup advised to first refill iron bone marrow stores by the oral route in CKD stage 3—5 patients and by the intravenous IV route in in CKD stage 5D patients.
Since oral iron compounds are generally ineffective in these patients and not well tolerated by them, with the exception of the subsequently introduced oral iron phosphate binder ferric citrate [ 27 , 28 , 29 ], this recommendation led to a marked increase in IV iron supplementation in the USA in the years following the release of the KDIGO guideline [ 30 ].
In this prospective cohort study, high ferritin levels relative to region-specific medians were associated with elevated mortality in all three regions. The irony is that there are no hard evidence-based RCTs to support recurrent high dose IV iron administration, with its potential for long-term risks of iron overload and adverse patient outcomes [ 31 , 33 ].
Thus, at present, we still ignore which amount of iron supplementation is too much in patients with CKD [ 34 ]. Hopefully, the PIVOTAL study will bring a convincing answer to this issue [ 35 ]. PIVOTAL is a multicenter RCT conducted in more than chronic hemodialysis patients in the UK.
It compares proactive high-dose and reactive low-dose IV iron regimens with respect to all-cause mortality and incidence of non-fatal CV endpoints as well as ESA dose requirements, the need for transfusions, the incidence of infections and other complications of hemodialysis and indicators of quality of life.
The trial has been terminated recently Iain Macdougall, personal communication. Its results should be known by the end of the year The KDIGO anemia guideline of suggested a drastic lowering of target hemoglobin levels, more cautious initiation of ESA treatment, and lower maintenance ESA doses as compared to prevailing practice in Western countries at that time.
This suggestion was not only influenced by the observation of increased risk of cardiovascular and cerebrovascular events and mortality with anemia correction to high hemoglobin targets, but also by the observation of a higher incidence of vascular access loss and of higher mortality risk in patients with a history of cancer.
It is interesting to note that patients who achieved higher hemoglobin levels in these RCTs had better outcomes than those with lower hemoglobin levels.
Thus, not higher hemoglobin concentrations but higher ESA doses correlated most strongly with adverse outcomes. This would suggest that high ESA doses might have detrimental off-target effects [ 7 ]. However, high doses are needed to overcome ESA hyporesponsiveness and this is linked to many different mechanisms, including iron deficiency and inflammation, which may be the real culprits [ 36 , 37 ].
In , the authors of a meta-analysis of 27 trials concluded that the evidence for effects on quality of life was limited by selective reporting and that trials reported insufficient information to allow analysis of the independent effects of ESA dose on clinical outcomes [ 38 ].
However, it is well known that the majority of severely anemic patients with CKD experience substantial physical and mental health benefit in response to a rise in hemoglobin level. The question above then is which degree of anemia correction should be used to further quality of life benefit.
To answer this question, the participants of an NKF and FDA sponsored symposium in the USA proposed to design adequately powered, blinded randomized controlled trials of anemia treatment using patient-reported outcomes as primary rather than secondary endpoints [ 39 ].
The mean difference of achieved hemoglobin levels between the patient groups allocated to higher and lower anemia correction targets was 1.
In the latter trial, the physical function score on the quality of life questionnaire at 12 months showed a clinically meaningful increase of 7. However, this study was done in relatively disabled chronic hemodialysis patients with congestive heart failure or ischemic heart disease. Among the subsequent three RCTs done in non-dialysis-dependent CKD patients with less comorbidities, only CREATE found significant quality-of-life benefit, in response to an achieved mean hemoglobin increase of 1.
Patients randomly assigned to the higher hemoglobin target experienced improved general health and physical function scores. In contrast, TREAT and CHOIR with lower achieved mean hemoglobin level differences found either no [ 25 ] or only one [ 26 ] improvement among several quality-of-life scores tested.
Another issue is that the response to ESAs varies considerably from one CKD patient to the other and that the subjective perception of improvement probably fades away after prolonged time periods. Therefore, KDIGO anemia guideline says that individualization of therapy is reasonable and ESA therapy may be started in selected patients above a hemoglobin value of Moreover, it admits that individualization of therapy is necessary as some patients may have improvements in quality of life at hemoglobin concentration above The main lesson learnt from randomized controlled trials in patients with CKD is that on the average full anemia correction, as compared to partial anemia correction, is associated with increased risk of adverse events and mortality and that the increased risk outweighs the potential benefit.
There is no question that raising hemoglobin levels in severely anemic CKD patients is extremely beneficial for physical and mental health and overall well-being. It remains unclear at present which patients may experience improved quality of life when hemoglobin is actively increased above Individualized therapy is probably the answer, weighing the potential benefit against potential harm Fig.
a , b Potential risks and benefits with full versus partial anemia correction in patients with CKD in response to treatment with erythropoiesis-stimulating agents ESAs.
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Yokoyama K, Fukagawa M, Akiba T, Nakayama M, Otoguro T, Yamada K, Nagamine Y, Fishbane S, Hirakata H. The NCCN guidelines for reflected the lifting of the REMS strategy by removing the need to consult REMS when considering ESA use National Comprehensive Cancer Network [NCCN], Recently, the ESMO Clinical Practice Guidelines for the management of anemia and iron deficiency in patients with cancer Aapro et al.
Backed by evidence from more than 2, ESA-treated patients, the guidelines also highlight that epoetin alfa is now indicated by the EMA for the treatment of anemia in low- or intermediaterisk primary myelodysplastic syndrome patients.
The similar safety and efficacy of EMA-approved originator ESA products and biosimilars is also mentioned. The first ESA approved in Europe for dialysis and non-dialysis patients with CKD was Eprex ® epoetin alfa, Ortho Biotech in , and the first ESA approved for the United States dialysis market was Epogen ® epoetin alfa, Amgen, Thousand Oaks, CA, United States , in The longer-acting ESA, Aranesp ® darbepoetin alfa, Amgen , was licensed in the United States in Luksenberg et al.
Following intensive investigation, it was considered that a switch to a new stabilizing agent polysorbate 80 in might have resulted in increased immunogenicity through interaction with leachates from uncoated rubber stoppers of prefilled syringes, and possible protein denaturation or aggregate formation resulting from the polysorbate 80 formulation being more susceptible to stress conditions such as insufficient attention to the cold supply chain McKoy et al.
By , the contraindication for subcutaneous administration of Eprex ® in CKD patients had been lifted Macdougall et al. Throughout the s, clinical practice guidelines for ESAs were developed and evolved through a focus on evidence-based medicine.
In , the Cooperative Multicenter EPO Clinical Trial Group reported a Phase 3 trial including more than dialysis patients Evans et al. Treatment with epoetin alfa resulted in improvements in many QoL measures, with benefits beyond the avoidance of transfusion and iron overload, including improvements in energy, sleep, and well-being Evans et al.
A number of studies in the nephrology arena have been pivotal in further shaping guidelines. In a double-blind study, Parfrey et al. Although the group with higher Hb levels had a greater incidence of cerebrovascular events, this group showed an improved QoL outcome in terms of vitality Parfrey et al.
The Correction of Hemoglobin and Outcomes in Renal Insufficiency CHOIR study of randomized 1, CKD patients to target Hb levels of At follow-up, composite cardiovascular endpoints including mortality were significantly increased in the high-level Hb group.
Although improvements in QoL were seen on correction of anemia, there was no difference in QoL between the two groups.
The authors concluded that targeting higher Hb levels was associated with increased risk, with no incremental improvement in QoL. There were no differences between groups in primary cardiovascular and survival outcomes, although patients in the high-level Hb group showed hastened progression to dialysis, more hypertensive episodes, and improved QoL scores Drueke et al.
This trial was stopped early as a result of the expectation that patients in the normal arm would not have better outcomes than those in the low-level arm. In its analysis of CHOIR and the Normal Hematocrit Trial, the FDA reported an inverse relationship between achieved Hb level and cardiovascular events, finding that ESAs increased adverse outcomes when Hb levels changed at a rate greater than 0.
A secondary analysis of CHOIR actually found ESA dose to be the major predictor of AEs, when the data were adjusted for ESA dose and patients not achieving their Hb target Szczech et al. Those patients achieving target Hb levels had better outcomes than those who did not, and no increased risk of higher Hb levels was observed Szczech et al.
Although there was a significantly higher incidence of stroke in Group 1, cardiovascular events, death, and QoL scores were similar for both groups Pfeffer et al. For maintenance therapy an upper limit of In a non-graded recommendation, KDIGO suggested that individualization of therapy will be necessary because some patients may have improvements in QoL at Hb concentrations above More recently, the NICE guidelines National Institute for Health and Care Excellence [NICE], , and the Renal Association clinical practice guidelines on anemia of CKD Mikhail et al.
Despite changes in guidance, the question of whether focus should be directed on avoiding high Hb levels or avoiding high ESA doses in ESA-resistant patients remained.
A meta-regression analysis published in examined the association of ESA dose with adverse outcomes in CKD, independent of the target or Hb level achieved Koulouridis et al.
In 12, patients, all-cause mortality was associated with higher total-study-period mean ESA dose and higher firstmonth mean ESA dose. Total-study-period mean ESA dose and firstmonth ESA dose remained significant after adjusting for target Hb or firstmonth mean Hb, respectively.
Hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events, were increased with higher total-study-period mean ESA dose Koulouridis et al. Data continue to be published in the nephrology literature regarding ESA dose vs.
Hb concentration on patient outcomes. In , data from a prospective, non-interventional, multinational cohort study of 1, consecutive patients with advanced or end-stage renal disease receiving epoetin theta was published Lammerich et al. Intermediate Hb concentrations were associated with the lowest incidence of RAEs, and the incidence of ischemic stroke was 0.
The authors concluded that the lowest approved, effective dose of epoetin theta should be used Lammerich et al. Figure 3. Relationship between reportable adverse events RAEs and the combined effects of hemoglobin Hb concentration and dose of epoetin theta therapy in patients with anemia associated with chronic kidney disease.
RAEs were predefined cardiovascular events selected from the Medical Dictionary for Regulatory Activities classification system and included cardiac disorders, cardiac failure, myocardial infarction and ischemic stroke, and respective subterms.
Hb, hemoglobin. Reprinted from Lammerich et al. Although the appropriate risk-benefit ratio of ESAs has been established based on the current labeling and guidelines, access remains a significant problem in many areas of the world, with barriers including issues related to insurance coverage, drug availability, and cost Lammers et al.
However, biosimilars have reduced development costs as a result of a less extensive trial program in comparison to originator products, bringing potential cost savings for patients and healthcare providers Blackstone and Joseph, ; Singh and Bagnato, An analysis in compared the cost efficiency of various originator epoetins vs.
a biosimilar, Binocrit ® epoetin alfa , across the EU G5 countries France, Germany, Italy, the United Kingdom, and Spain Aapro et al. The savings from treating patients with biosimilar epoetin alfa 40, IU were Biosimilar competition in the market not only brings lower prices but can also reduce the cost of originator products.
reference product Quintiles IMS, The cost savings associated with biosimilar use could be reallocated to enhance patient access to other therapies. For example, a simulation of the budgetary impact of ESA use in EU G5 countries involved a hypothetical panel of , patients, with three models estimating the number of patients who could be provided with rituximab, bevacizumab, or trastuzumab therapy from the cost savings of using biosimilar erythropoietin Abraham et al.
As with any ESA, for safety and economic considerations, biosimilar ESAs should be used according to the latest guidance and label. In Europe there are two biosimilar ESAs marketed by different license holders: epoetin alfa Abseamed ® , Medice, Iserlohn, Germany; Binocrit ® , Sandoz, Holzkirchen, Germany; Epoetin Alfa Hexal ® , Hexal AG, Holzkirchen, Germany , and epoetin zeta Retacrit ® , Hospira, Lake Forest, IL, United States; Silapo, Stada Arzneimittel, Bad Vilbel, Germany.
Retacrit ® , for example, was one of the earliest biosimilar epoetins launched in Europe; post-marketing and clinical studies have demonstrated clinical efficacy and safety in oncology and nephrology indications, and exposure data reveal a growing population receiving this treatment Michallet and Losem, Now finally approved in the United States, biosimilar ESAs may, as in Europe, provide cost savings and increase patient access to other novel treatment approaches Aapro et al.
Erythropoiesis-stimulating agents have transformed the management of anemia in patients with CKD, cancer, and other indications, with some studies suggesting they improve QoL in certain subsets of patients with anemia Evans et al. Although target Hb levels have been a key component of guidance, evolving data suggest that ESA dose and the speed at which Hb levels change in response to ESAs are also important considerations when treating anemic patients US Food and Drug Administration, a.
Indeed, the latest product labeling no longer specifies a target Hb level, but use of the lowest ESA dose sufficient to reduce the need for transfusions.
Biosimilar ESA products have been used successfully for many years outside the United States, with safety and efficacy comparable to originator products, bringing cost savings to patients and healthcare systems, and increased access to ESAs and other expensive drugs due to reallocation of resources.
Further research will provide guidance on individualization of ESA therapy for different patients and indications so that the optimal benefit to risk ratio may be achieved.
Figure 4. Timeline of key clinical trials and interventions between and MA, PG, KP, GR, SF, LA, and JW contributed to the conception, content and writing of this review article.
All authors contributed to manuscript revisions, and read and approved the final version. KP is a consultant for and has attended advisory boards for Pfizer Inc. GR is a consultant for Pfizer Inc.
SF and LA are employees of Pfizer Inc. and hold stock in Pfizer. JW is a consultant for Pfizer Inc. Medical writing support was provided by David Sunter, Ph. Aapro, M. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines.
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Erythropoiesis-stimulating agemts ESAs are a group of medications that Natural anti-inflammatory remedies take the place Erythropoiesis-stimulating agents (ESAs) a hormone called erythropoietin Coffee bean extract. Erythropoiesis-syimulating with chronic kidney disease Eyrthropoiesis-stimulating may not have enough EPO coming from Erythropoiesis-stimulating agents (ESAs) kidneys to tell their xgents to Erythropoissis-stimulating more red blood cells. This pamphlet explains how to take and store this medication, and lists possible side effects. Service Statuses and Closures Contact. PRIMARY CARE AND FAMILY MEDICINE Accessing Primary Health Care Need a Family Practice Registry Virtual Care NS Community Pharmacy Primary Clinics Urgent Treatment Centres Mobile Primary Care Clinics Home and Community Care Long-Term Care Respite and Caregiver Support Health Equipment Protecting Vulnerable Adults Covid Symptoms Testing I Tested Positive COVID Vaccines Living with COVID Erythropoiesis-stimulating agents (ESAs) Eryturopoiesis-stimulating agents also called ESA coffee bean extract are Erythropoiesis-stimulatihg to treat anemia caused by chronic kidney Erythropoiesis-stimjlating or chemotherapy for cancer treatment. They may also be used to treat anemia caused by taking medicines for human immunodeficiency virus HIV. Or they may be given for certain types of surgeries. The kidneys make a hormone called erythropoietin. It helps the body make red blood cells.
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