Anemia Management: Update and Best Practices
Transcript of Anemia Management: Update and Best Practices
Ajay K. Singh, MBBS, FRCP, MBA
Attending Nephrologist, Brigham and Women’s Hospital
Senior Associate Dean for Postgraduate Medical Education, Harvard Medical School
Anemia Management: Update and Best Practices
Ajay K. Singh Bio
• Attending Nephrologist, Brigham and Women’s Hospital
• Senior Associate Dean for Postgraduate Medical Education, Harvard Medical School
• Research interests: Anemia of CKD and CKDu
• Clinical interests: managing patients with CKD
Disclosures• Consultant – GSK, Chair of Ascend program
for HIF stabilizer (PHI) Daprodustat
• Stock: Gilead
Case History
• 62-yo woman with 10-year history of CKD from diabetes; slowly worsening renal function. Past medical history of a right CVA stroke. She sees you in the office. Feels great. Working, exercising, eating well. Lab data shows BUN 48, Cr 4.2, eGFR 18, Hb 8.9 g/dL, Tsat 30%, ferritin 282.
• What do you do?
A. Start patient on an ESA –darbepoetin alfa 40 mcg/week
B. Empirically treat her with a course of intravenous iron
C. Check stool guaiac, and if all right, continue to observe her
Case History
• 62-yo white woman with 10-year history of CKD from diabetes; slowly worsening renal function. Past medical history of a right CVA stroke. She sees you in the office. Feels great. Working, exercising, eating well. Lab data shows BUN 48, Cr 4.2, eGFR 18, Hb 9.1 g/dL, Tsat 30%, ferritin 282.
• What do you do?
A. Start patient on an ESA –darbepoetin alfa 40 mcg/week
B. Empirically treat her with a course of intravenous iron
✓ Check stool guaiac, and if all right, continue to observe her
Should One Treat?
• In our case = no
• She’s not symptomatic; doing fine
• Also, h/o stroke!
• Would work up the anemia and make sure that she is not bleeding
• Remember: No evidence that mild anemia treatment is a disease-modifying treatment. Treat for symptoms.
US FDA ESA label: 12/11❑For patients with CKD not on dialysis:
• Consider initiating ESA treatment only when
the hemoglobin level is less than 10 g/dL….
3.2: In initiating and maintaining ESA therapy, we recommend
balancing the potential benefits of reducing blood transfusions
and anemia-related symptoms against the risks of harm in
individual patients (e.g., stroke, vascular access loss,
hypertension). (1B)
We recommend using ESA therapy with great caution, if at all, in
CKD patients with active malignancy—in particular when cure is
the anticipated outcome—(1B), a history of stroke (1B), or a
history of malignancy (2C).
The KDIGO Anemia GuidelinesKI supplement Aug 2012
Hb Target
• Target for treatment should be?
– KDIGO < 11.5 g/dL
– FDA<11 g/dL
• What about the lower number?
– KDIGO>9 g/dL
– FDA>10 g/dL
• Why 9 g/dL
• In dialysis patients, evidence from the Normal Hematocrit Study
• In non dialysis patients, evidence from the TREAT study
• Why 11.5 g/dL
– Normal Hematocrit study (9-11), CREATE, CHOIR (11.3 vs. 13.5), TREAT (>9 vs. 13)
Trials of Anemia Targets in CKD
• Normal Hematocrit
• CHOIR study
• TREAT study
Worrisome safety signals
Normal Hematocrit Study
Besareb A et al NEJM 339:584-590, 1998
N=1233 HD patientsDeath or MI10 g vs. 145 g
No Improvement in hrQOL
Algorithm for Anemia Management
Hb <11 g/dL
Major causes: Iron deficiency, erythropoietin deficiency and inflammation
Likely iron deficiencyFerritin <100 ng/mL and/or Tsat <20%
Treat with oral iron for at least 3
months, if tolerated
Stool positive for occult blood
Likely inflammationAlbumin <3.5 g/L
ferritin >500 ng/mLhsCRP >2
Likely ESA deficiency stateNormal iron storesNormal folate/B12
No evidence for inflammation
No evidence of occult blood loss
Establish Hb trigger for ESA initiation<11 g/dL, patient symptomatic or transplant candidate
9-10 g/dL, most patients<9 g/dL prior stroke, active malignancy
Inflammation inducerameliorated
Case (cont.)
• 62-yo woman …
• 2 years following initial presentation, she feels fatigued with minor tasks; has difficulty getting out of bed. Hb is 8.9 g/dL; iron stores replete. She is started on ESA (darbepoetin alfa 40 mcg q week). Her Hb responds and she feels better. 6 months later, she develops an ulcer on her foot. Her Hb starts to drift down, despite a gradual 3-fold increase in her darbepoetin alfa dose (now at 120 mcg q weekly)
QuestionWhich one
of the following
statements is correct?
A. The patient should be treated with a course of IV iron.
B. The patient requires a blood transfusion in order to get her Hb into the 11–12 g/dL range recommended by the NKF.
C. The most likely cause of her ESA resistance is the diabetic foot ulcer. You should not escalate her ESA dose; instead focus on treating her foot ulcer.
D. She should be treated with an anabolic steroid.
QuestionWhich one
of the following
statements is correct?
A. The patient should be treated with a course of IV iron.
B. The patient requires a blood transfusion in order to get her Hb into the 11–12 g/dL range recommended by the NKF.
✓ The most likely cause of her ESA resistance is the diabetic foot ulcer. You should not escalate her ESA dose; instead focus on treating her foot ulcer.
A. She should be treated with an anabolic steroid.
ESA HyporesponsivenessESA resistance, or hyporesponsiveness, patients who do not achieve the desired hemoglobin (Hb) concentration despite higher than usual doses of ESAs or who require increasingly higher ESA doses to maintain an Hb concentration1
• KDOQI Definition: A failure to achieve and/or maintain
target hemoglobin levels at an erythropoietin dose of
450 IU/kg/week when administered intravenously, or 300 IU/kg/week when administered subcutaneously
1SOURCE: Berns J. https://www.uptodate.com/contents/hyporesponse-to-erythropoiesis-stimulating-agents-esas-in-chronic-kidney-disease
Causes of ESA Hyporesponsiveness
• Iron deficiency
• Inflammation – infectious and chronic microinflammatory
– Failed kidney allograft
– Chronic infection (TC, diabetic ulcer, amputation stump infection)
• Inadequate dialysis
• Hyperparathyroidism
• Carnitine deficiency
• Drugs: ACE-I/ARB
• Aluminum overload
• Nutritional: Folate, vitamin B12, vitamin C deficiency
• Malignancy
• Hematological disorders
Risk Factors for ESA Hyporesponsiveness*
Singh AKS et al, ASN 2020
*Primary definition of ESA hyporesponsiveness included a two-part definition: a baseline ESA Resistance Index
(ERI) ≥2 U/kg/week/g/L, or treatment at baseline with a very high standardized ESA dose ≥450 U/kg/week.
ESA Hyporesponsiveness
Singh AKS et al, ASN 2020
CKD
Iron Supplementation
InflammationVitamin D Deficiency
Reduced GFR
Reduced Iron Releasefrom Cells of RES
Reduced Gut Iron Absorption
Iron Restricted Erythropoiesis
↑ HEPCIDIN
Panwar B, Gutiérrez OM. Semin Nephrol. 2016.
Pathophysiology of CKD Anemia
Babitt JL, Lin HY. J Am Soc Nephrol. 2012.
*ESA = Erythropoietin stimulating agent
Iron Regulation by Hepcidin
Therapeutic Plan for ESA Hyporesponsivess
Diagnose ESA Hyporesponsivess
Avoid repeated escalations in ESA Dose
Identify correctable vs non correctable causes
Easily correctableAbsolute iron deficiencyVitamin B12/folate deficiencyHypothyroidismACEi/ARBNon-adherence
Impossible to correctHemoglobinopathiesBone marrow disorders
Potentially correctableFunctionalIron deficiency
InfectionInflammation
UnderdialysisBleedingHyperparathyroidis,MalignancyMalnutritionPRCA
Empirically treat with iron
Empirically treat with iron
Where are We Now?
Despite Epo therapy costing billions of dollars each year, anemia is sub-optimally treated in CKD patients
– Normalization of Hb associated with increased mortality and CVD risk
• No consistent and meaningful improvement in quality of life
• Patients treated to subnormal Hb target of 10-11 g/dL
– Patients require SC/IV injection, increased visits to health care provider
– Higher health systems costs
USRDS 2016 Annual data report. www.USRDS.org.
Guidelines
CHOIR
TREAT
Bundled Payments
HbUnmetneed
CKD Anemia – the Unmet Need
HIF Biology
• In 1991 HIF-1 discovered, a protein with DNA binding activity to the erythropoietin gene
• The two isoforms or subunits of HIF-1 regulate target gene in response to hypoxia
• HIF-1α is mainly under the control of oxygen sensing prolyl-4-hydroxylase enzymes) 2,3
• 2019 Nobel Prize in Physiology or Medicine awarded to William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability.”
1Proc Natl Acad Sci U S A. 1991;88:8725-8729. 2Proc Natl Acad Sci U S A. 1995;92: 5510-5514. 3Nat Rev Drug Discov. 2009;8:139-152.
ProlylHydroxylase
HIFα
STOP
No epo genetranscription
Translocate to nucleus
+ epo genetranscription
HIFα
O2
HIFα
VHL
Attaches to von Hippel-Lindau (pVHL)
Normoxia
Hypoxia
OH
OH
OH
OH
degradation by 26S Proteosome
PHI Agents“HIF stabilizers”e.g., Roxa, Vada, Dapro
HIF stabilized
HIFα/ßcombine to
form heterodimer
HIF Mechanism
Oxygen sensing and the HIF system
HIF
1α /2 α
VHL
HIF-dependent genes
HIF
1α /2 α
HIF β
regulators of
cell-specific
expression
O2
OH
oxoglutarate CO2
succinate PHD-1
PHD-2
PHD-3 FIH
degradation
EPO
3
1
2
4
Rare mutations causing HIF
activation lead to polycythemia
• PHD-2
• HIF-2
• VHL
- VHL-syndrome (cancer)
- Chuvash polycythemia
Percy et al., PNAS 2006
Ladroue et al., NEJM 2008
Percy et al., NEJM 2008
Percy et al., Blood 2008
Gale et al., Blood 2008
Furlow et al., JBC 2009
Chuvashia – a Russian Republic
Chuvash polycythemia • endemic in Chuvash population
in Russia
• majority likely originated
from a single founder event
• 598 C > T mutation in VHL;
R200W (Arg Trp)
Mild inhibition of HIF-2α
Degradation
• Polycythemia
• No enhanced tumor incidence
• Reduced life expectancy
(due to polycythemia ?)
• Mild organomegaly
• Pulmonary hypertension
Slide source – K.-U. Eckardt
Erlangen-Nürnberg
Example of Mutations in Oxygen Sensing Apparatus
Single dose study with a PHD-I in humans
(FG 2216)
time (h)
pla
sm
a E
PO
(m
U/m
l)
healthy controls
time (h)
anephric HD patients
extrarenal (hepatic)
EPO production
time (h)
nephric HD patients
extrarenal (hepatic)
+ renal
EPO production
preserved EPO production capacity
Bernhardt et al.
J Am Soc Nephrol 2010
Single Dose Study of PHI in HumansFG2216
Slide source – K.-U. Eckardt
Erlangen-Nürnberg
523
6637
PH2B RHEPO CONTROL (5000 U IV/WK)
CLIMBERS AT 4500 M PH2B DAPRODUSTAT
Peak Epo levels in Epo treated and PHI treated dialysis patients
Peak EPO 14x higher in rhEPO vs climber
Peak E
PO
conce
ntr
ations
(IU
/L)
rEPO 5000u Climber 4500m PHI
3 leading PHIs
RoxadustatDaprodustat Vadadustat
(Yeh et al, 2017)30
• Similar MOA, different biophysical properties, all oral agents
Attributes Daprodustat Vadadustat Roxadustat
Half life Short ( T1/2=1.5-4hr) Short (T1/2 ~5-7 hr) Long (T1/2 ~12-19 hr)
Metabolism Hydroxylation. Active metabolite Glucuronidation, Inactive metabolite Unknown, presumed inactive metabolite
Excretion Mostly liver metabolism Liver metabolism +Renal excretion Primarily liver (?)
Tissue Distribution(rodent)
Broad distribution (liver, kidney, lung, BM.Low in skeletal muscle)
Unknown Unknown
SOURCE: Provenzano, 2020, J. Clin. Pharm; Balzo et al, 2020, JPET; Zuk et al, 2019 ASN poster; Chavan 2019 ASN poster; Hara, 2015, Drug Metab. Pharm, Daprodustat IB
Dosing 1 mg-12 mg (QD), 6 mg- 48 mg TIW 150-400 mg (QD or TIW) 60-300 mg (QD or TIW
Phase 2a, 2b Dialysis and Non-dialysis all PHI agents
Special Interest (based on HIF-PHI Mechanism of Action)
• Cancer-related mortality and tumor
progression and recurrence
• Pulmonary artery hypertension (PAH),
Cardiomyopathy
• Proliferative retinopathy, macular edema,
choroidal neovascularization
• Exacerbation of rheumatoid arthritis
No Safety Signal
Phase 3 Program
• Roxa
• Chinese studies, NEJM 2019
• Approved in China and Japan
• ASN presentations 2019, 2020 ≈ 80 abstracts
• July 14, 2021 FDA Adcom
• Vada
• Approved in Japan
• NEJM, April 2021
• Dapro
• Japanese studies, CJASN 2020
• Approved in Japan
ASCEND-D, ASCEND-ND and ASCEND-ID Program
11
Non dialysis Dialysis Incident Dialysis
Randomized, open-label (sponsor-blind), active-controlled, parallel-group
Correction & maintenance* Maintenance* Correction &
maintenance**
n = 4500(945 events)
n = 3000(945 events)
n=300
1. ESA naïve2. Rx with ESA
Rx with ESA(HD &PD)
1. ESA naïve2. Rx with ESA
daprodustat vs darbepoetin alfa
daprodustat vs epoetin alfa (HD)
vs darbepoetin alfa ((PD)
daprodustat vs darbepoetinalfa
ASCEND CVOT Program
*Chair of Executive Steering Committee and Publication Steering Committee: Ajay K. Singh
*
ASCEND Program –Other Studies
• ASCEND-BP Study, N=88
• Randomized, open-label, parallel-group study in HD subjects with anemia of CKD
• Hypothesis: daprodustat would be associated with less effects on BP than rhEPO
• ASCEND-NHQ Study, N=614
• Randomized, Double-Blind, Placebo-Controlled study in (rhEPO) naïve non-dialysis participants
• Hb, Mean Change in SF-36 Vitality Domain, Common AEs, SAEs, and adjudicated MACE
• ASCEND-TD study, N= 270 Dapro, N=137 rhEPO
• Randomized, double-blind, active-controlled study of daprodustatadministered three-times-weekly in hemodialysis patient
Conclusions
• Current guidelines on anemia treatment
– FDA 10-11 g/dL goal
• ESA hyporesponsiveness is an important factor in anemia treatment
– Multifactorial
– Hepcidin and inflammation
• Unmet need in anemia treatment
– Discovery of oxygen sensing mechanism has led to development of PHIs
• 3 PHI’s under development
– Roxadustat
– Vadadustat
– Daprodustat
• PHIs non-inferior to Epo and its analogues for Hb. Safety similar to Epo
• More convenient oral dosing
• But are HIF stabilizers (PHIs) better?