Definition of Terms
Erythropoiesis Stimulating Agents
in Chronic Kidney Disease:
A Question of Quality versus Quantity
KAREN NG
PHARM D STUDENT (COHORT 07)
UNIVERSITY OF TORONTO
LESLIE DAN FACULTY OF PHARMACY
FEBRUARY 22, 2010
Outline
™ Background
™ Epidemiology and impact of anemia of chronic kidney disease
™ Clinical Controversy
™ Clinical question
™ The Evidence
™ CHOIR, CREATE, TREAT, Quality of life studies
™ Summary and Discussion
™ Evaluation of the evidence
™ Unanswered questions
™ Conclusions
™ Questions
Abbreviation
Definition
CHF
Congestive heart failure
CKD
Chronic Kidney Disease
ESA
Erythropoiesis-stimulating agent
ESRD
End stage renal disease
GFR
glomerular filtration rate
HRQOL
Health related quality of life
HgB
Hemoglobin
QOL
Quality of Life
RBC
Red blood cell
RRT
Renal replacement therapy
Epidemiology
y “.. prevalence of earlier stages of CKD is approximately 100
times greater than the prevalence of kidney failure, affecting
almost 11% of adults in the United States” KDOQI 2006
y In Canada, as of December 1, 2002, ESRD population reached
29,162, which represents a prevalence of 920 per million
population Manns el al, 2007
y Between 1998 and 2002, the prevalence of ESRD in Canada
increased 33%, while the incidence increased 17%. Manns el al, 2007
Components of CKD Care
Stages of CKD
Stage
Description
GFR
ml/min/1.73m2
1
Kidney damage with normal or GFR
≥90
2
Kidney damage with mild GFR
60-89
3
Moderate GFR
30-59
4
Severe GFR
15-29
5
Kidney Failure
<15 or dialysis
KDOQI 2006
Pathophysiology of Anemia
Factors that Contribute to Anemia
™ Deficient production of endogenous erythropoietin
™ Iron deficiency
™ Inflammatory conditions
™ Decreased RBC survival
™ Aluminum toxicity
™ Folate deficiency
™ Severe hyperparathyroidism
™ Hemoglobinopathies (ex. sickle cell anemia, α-thalassemia)
™ Hypothyroidism
Hodges VM et al. 2007
Impact of Anemia
How is Anemia Defined?
™ Anemia contributes to poor quality of life in patients with CKD
™ Uncorrected anemia is a risk factor for “adverse patient outcomes,
including hospitalization, ventricular volume overload, heart
failure, cognitive impairment and mortality” KDOQI guidelines 2006
™ Anemia is the clinical manifestation of a decrease in
circulating red blood cell mass
{
Detected by low blood Hgb concentration
y KDOQI and CSN
{
<13.5 g/dL males and <12.0 g/dL females
Levin A et al 1999
Current Therapies:
Erythropoiesis-stimulating Agents
Recombinant
erythropoietin
Mechanism of
action
Darbepoetin alfa
Erythropoietin is a hormone that binds to the erythropoietin
receptor on erythroid progenitor cells (erythrocyte burst-forming
and colony-forming units) in the bone marrow stimulating
differentiation into mature red cells.
Guideline Recommendations
NKFNKF-KDOQI 2006 and 2007 update
y In patients with CKD, Hb should be 11.0 g/dL or greater.
(MODERATELY STRONG RECOMMENDATION)
y …there is insufficient evidence to recommend routinely maintaining
Molecular weight
3 N-linked oligosaccharide
chains
30,400 Dalton
5 N-linked oligosaccharide
chains
37,100 Daltons
Half life (hours)
in CKD
IV: 4 - 13 hours
SQ: 27 hours
3x/week dosing
SQ: 70 hr (range, 35-139 hr)
Initial response
10 days
1 to 4 weeks
y Initiate ESA therapy when iron stores have been corrected, other
Peak response
2 to 6 weeks
7 to 10 weeks
48.7 ± 2.1
52.4 ± 2.0
reversible causes of anemia have been treated, and the hemoglobin
level is sustained below 100 g/l (Opinion).
y Target hemoglobin level of 110 g/L (no higher than 120g/l).
Volume of
distribution
(mL/kg)
•Additional carbohydrates
Hb levels at 13.0 g/dL or greater in ESA-treated patients.
CSN Practice Guidelines 2008
Q1-2 week dosing
Proposed Pros & Cons Associated with
Anemia Treatment with ESAs
Clinical Question
Controversy Defined
PROS
CONS
Enhanced quality of life
Increased blood pressure
Improvement in cardiovascular
outcomes and complications related
to left ventricular hypertrophy
Increase platelet adhesiveness
Reduced transfusion needs
Increase risks of thrombosis
Improved exercise tolerance through
increased muscle strength and
function
Increased cardiovascular events
Does improving morbidity through the use of
erythropoiesis stimulating agents to correct anemia in
non-dialysis dependent patients with stage 3-4 chronic
renal failure, outweigh the potential risks of CV events
and end-stage renal disease?
CHOIR Trial
Risks of Therapy
Singh AK, Szczech L, Tang KL et al 2006
Objectives
Design
Benefits
Patient
population
Risks
Intervention
Evaluate whether using epoetin alfa to achieve a higher HgB
decreases the risks of complications from CVS causes and death
compared to a lower HgB target
Open label, randomized, multi-centered
Industry sponsored.
N=1432 randomized (~700 completed trial)
>18yrs of age, HgB <11g/dL, GFR (15-50ml/min)
Epoetin alfa : HgB target 13.5g/dL versus 11.3g/dL
*protocol amendment Starting dose of 10,000 units SC 1x / week. After 3 weekly doses,
subsequent doses and dosing intervals of EPO adjusted based on an
Feb 2003
assessment of the two most recent HgB values.
Outcomes
measures
CHOIR Trial Results
CHOIR Trial Results
y Early termination of study by data and safety monitoring board
y Mean of 16 months follow-up, mean age 66, baseline HgB 10.1g/dL
Median achieved HgB
y Higher target: 12.6g/dL**target not reached! Lower target: 11.3g/dL
higher HgB
PEP: composite of death, MI, hospitalization for CHF
(excluding RRT), stroke
SEP: components of primary end points, time to RRT,
hospitalization for either CVS cause or any cause, QOL
lower HgB
Higher Hemoglobin versus Lower Hemoglobin target groups
PEP: 17.5% vs 13.5%, HR 1.34 (95% CI 1.03-1.74), p=0.03 (NNH=25)
SEP:
{
{
Hospitalization for CVS 32.6% vs 27.5%, HR 1.23 (1.01-1.48) p=0.03
Hospitalization any cause 51.6% vs 46.6% HR 1.18 (1.02-1.37) p=0.03
{ Component of death and hospitalization for CHF
Strong trend towards higher risks (p=0.07)
{ QOL measures (LASA, KDQ, SF-36) NS diff
Serious adverse events 54.8% vs 48.5% (p=0.02)
{
CHF occurring SIG more in the higher HgB group (11.2% vs 7.4%)
CHOIR Trial Conclusions
y Use of higher HgB targets increased risks
{ Differences in the groups were driven by higher number of
deaths and hospitalizations for CHF
y No incremental improvement in QOL measures
CHOIR Trial Limitations
y Pre-specified censoring of data on patients at initiation of RRT
y Protocol change and premature discontinuation of trial
y Large number of patient drop out
y Not double blinded
y Recommended new targets to be 11-12g/dL
y Unbalanced baseline characteristics
y Lack of information on how QOL were measured
CREATE trial
Drueke TB, Locatelli F, Clyne N et al 2006
Objectives
Design
Patient population
Intervention
Outcomes
measures
Evaluate whether complete correction of anemia in patients
with stage 3 or 4 CKD improves CVS outcomes as compared
with partial correction of anemia
Open-label, randomized, parallel group, multi-centered
Industry sponsored
N= 603
>18yrs of age, HgB 11-12.5 g/dL, GFR (15-35ml/min),
BP<170/95
CREATE Trial Results
y Mean of 3 years follow-up, mean age 59, baseline HgB 11.6g/dL
Median achieved HgB
y Higher target: 13.5g/dL
Lower target: 11.5 gdL
PEP: NS diff between groups (19.3% vs 15.6%)
SEP: Frequency & incidence of death from any cause: NS diff
y Mean time to worsening of NYHA class: NS diff
y Changes in left ventricular mass: NS diff
Epoetin beta: HgB target 13-15g/dL versus 10.5-11.5g/dL
y Hospital admission : NS diff
Starting dose of 2000 units SC 1x / week. Doses reviewed
q4weeks, if HgB increase <0.5g/dL dose increase 25-50%, if HgB
increased >1g/dL dose reduced by 25-50%
y Time to initiation of dialysis: SIG worse in group 1 than in group 2*
PEP: time to first cardiovascular event
SEP: death from any cause, CHF, hospitalization from any
cause, left ventricular mass index, progression of CKD, QOL
CREATE Trial Conclusions
y No added benefit to target HgB of 13-15g/dL in terms of
y Quality of life: SIG better in group 1 than in group 2 at year 1
Adverse Events: NS diff
CREATE Trial Limitations
y Event rate much lower than predicted
CVS endpoints
{
{
Complete correction does not improve outcomes
Recommend partial correction of anemia
y Significant benefit of higher hemoglobin targets on QOL
with regards to physical and social function, vitality,
mental health, however these benefits diminished over
time.
y Not double blinded
y Lack of information on how quality of life outcomes
were measured
TREAT Trial
Pfeffer MA, Burdmann EA, Chen CY et al. 2009
Objectives
Evaluate whether increasing Hgb with darbepoetin in type 2
DM/CKD patients would lower the rates of death, CVS events
and ESRD
Design
Randomized, double-blind, placebo controlled
multi-centered
Industry sponsored
Patient population
N=4038
DM2, HgB <11 g/dL, GFR (20-60ml/min), transferrin sat > 15%
Intervention
TREAT Trial Results
y Median of 29.1 months follow-up, mean age 68, baseline HgB 10.4g/dL
Median achieved HgB
y Darbepoetin group 12.5g/dL (12-12.8)
Placebo 10.6g/dL (9.9-11.3)
Darbepoetin
Placebo
P-value
Darbepoetin alfa (target HgB 12-13.5 g/dL)
versus
Placebo rescue darbepoetin if Hgb <9g/dL
Conservative dose adjustment using a computer algorithm
Outcomes measures
PEP: 1) time to composite outcome of death from any cause or a
CVS event (nonfatal MI, CHF, stroke, or hospitalization for
myocardial ischemia)
2) time to composite outcome of death or ESRD
SEP: time to death, death from CVS causes, components of PEP,
rate of decline in the estimated GFR, changes in FACT–Fatigue
instrument, SF-36*
TREAT Trial Results
TREAT Trial Results
QOL measures (change from baseline to 25 weeks)
FACT-Fatigue score: SIG greater change in darbepoetin group vs placebo
(4.2±10.5 points vs 2.8±10.3 points p<0.001)
36-SF: NS diff between groups (<3 points change in scores from baseline)
Adverse Effects
Venous thrombotic events: SIG more in the darbepoetin group vs
placebo (2% vs 1.1%, p=0.02) NNH=112
Arterial thrombotic events: SIG more in the darbepoetin group vs
placebo (8.9% vs 7.1%, p=0.04) NNH=56
Hypertension: NS diff
Cancer-related ADR: NS diff
TREAT Trial
Summary of the Evidence
CHOIR
Design
Conclusion
y Use of darbepoetin is no better than “placebo” in reducing death, renal
or cardiovascular events
y Use of darbepoetin is associated with increased risk of venous and
arterial thromboembolic events, including stroke (subgroup analysis)
y Modest improvements in patient reported fatigue with darbepoetin
y Reduction in red-cell transfusions with the darbepoetin group
Strengths
y Large size, long follow-up
Population
Intervention
Achieved
HgB
Results
CREATE
TREAT
Open label, randomized,
multi-centered
f/u 16 months
Open-label, randomized,
multi-centered
f/u 36 months
Randomized, double-blind,
placebo controlled
multi-centered
f/u 29.1 months
N=1432
Mean age 66
CKD (15-50ml/min)
50% DM, 94% HTN,
24% CHF, 10% stroke,
9% A.Fib, 15% MI
16% PVD
N=603
Mean age: 59
CKD (15-35ml/min)
25% DM, 90% HTN
32% CHF, 4% stroke
1% MI
2% PVD
N= 4038
Mean age: 68
CKD (20-60ml/min)
100% DM, HTN,
33% CHF, 11% Stroke,
10% A.Fib, 18.3% MI
21% PVD
Epoetin alfa (Eprex)
Epoetin beta
Darbepoetin alfa (Aranesp)
Higher HgB : 12.6g/dL
Lower HgB : 11.3 g/dL
Higher HgB 13.5g/dL
Lower HgB: 11.5 g/dL
Darbe: 12.5 g/dL
Placebo 10.6 g/dL
Stopped prematurely
in composite PEP
hospitalization CHF in
high-Hgb group
NS diff in CV events,
death, CHF,
hospitalization
QOL (SF-36), time to
dialysis in high-Hgb
group
NS diff in composite of
death or CV/renal events
QOL (FACT-fatigue),
cardiac revascularization,
stroke (SEP) in darbe
*more transfusions
Benefits of Therapy
Earlier Observational Trials
y Most trials supporting the QOL benefits in anemic patients treated
with EPO have been done in the dialysis population.
What about studies in non-dialysis CKD patients?
Risks
Benefits
Lefebvre and colleagues
In 1995, Revicki and colleagues compared changes in HRQOL in EPO-treated
and untreated pre-dialysis CKD patients with anemia.
y 35 pts randomized to EPO versus no EPO, followed for 48 wks
y Baseline HCT=28.6%, GFR= 10mls/min (stage 5 CKD)
y SIG changes in HCT were correlated with changes in HRQOL scores
y SIG improvements in energy, physical function, social activity, and
cognitive function in the EPO-treated group.
y The control group had a decrease in physical function
Lefebvre and colleagues: Results
Lefebvre P, Vekeman F, Sarokhan B et al. 2006
Objectives
Investigate relationships between
1) Absolute HgB levels and QOL
2) HgB changes and QOL
3) Impact of 1g/dL in HgB on corresponding QOL increase
Design
post hoc analysis of an open-label, non-randomized trial
16 weeks
Patient population
N=1044
>18 yrs of age, baseline HgB <10 g/dL, CKD
Scr: (Male: 133-530 umol/L, Female: 177-530 umol/L)
Dosed at 10000U/week potential increase to 20000U/wk at
week 5 if HgB was <1g/dL after 4 weeks of treatment
Intervention
Outcomes
measures
Epoetin alfa (single arm)
LASA (Linear analog scale assessment) and Kidney Disease
Questionnaire (KDQ) measured at baseline, week 8, 16.
Abu-Alfa and colleagues
Lefebvre and colleagues
Abu-Alfa AK, Sloan L, Charytan C et al 2008
Conclusions
y non-linear relationship btw HgB and QOL improvements
y Maximal incremental gain in QOL occurred when HgB
reaches 11-12g/dL
Limitations
y Post hoc analysis
y Open label with no control comparison
Objectives
Design
Evaluation of the effects of Q2W darbepoetin alfa treatment on
HgB concentration and health related quality of life endpoints
Subanalysis of the STAAR trial’s secondary endpoint
Patient population N=277 (30.4% of enrolled pts)
≥18 years of age, CKD with GFR ≤60mL/min/1.73m2, , TSAT≥20%,
ESA naïve, baseline HgB<11g/dL
Intervention
Darbepoetin alfa
Initial 0.75mcg/kg Q2W to maintain HgB <12g/dL.
If HgB approached 12g/dL, dose was 25%.
If HgB reached 12g/dL tx held & restarted at dose 25% lower than the
original dose once HgB<12g/dL.
If HgB <1g/dL in 4 weeks, dose of 25%.
A rate of rise ≤1g/dL every 2 weeks
Outcomes
measures
KDQOL-CRI mean at baseline, week 12, and 52, then change of
scores btw baseline to week 12 and week 12 to 52
Abu-Alfa and colleague’s Results
y Mean age 67
y Baseline HgB 10g/dL, mean HgB at 52 weeks 11.7±1.2g/dL
y 63% patients on iron therapy
y Clinically significant changes* in HRQOL scores at 12 weeks
improvement maintained through week 52 in 40-50% of patients
{
SIG increase in only some subscales of KDQOL-CRI (physical component scores, kidney
disease effect) per unit increase in HgB
Safety
HRQOL analysis (N=277)
Infections
7.6 %
Cardiac disorders
4.3 %
Renal and urinary disorders
2.2 %
General disorders ad administration site conditions
1.8 %
Discussion
What we know
Untreated anemia results in increased
morbidity
What we do not know
Unanswered Questions!
Affects of iron overload in higher HgB
target groups?
ESAs may make patients “feel better”
What is driving the CV risks???
However trials have only yielded modest •High dose of ESAs?
QOL benefits
•High absolute level of HgB itself?
•Drug itself (off target effect, class)?
ESAs will not make patients live longer
When to initiate ESA ,what HgB target?
Targeting a higher HgB with ESAs is not Optimal and safe dosing regimens?
associated with benefit but perhaps
•Oscillation/fluctuations in HgB levels
increased risk
Conclusions
™ Not a black or white answer
™ Depends on the perspective
™
Patient, practitioner, policymakers, payers
™ Treat the individual patient, not the numbers!
™ Balancing the tradeoffs
Abu-Alfa and colleagues
Conclusions
y Darbepoetin improved HRQOL in ESA naïve subjects
y Subjects with lower baseline HgB levels appeared to have SIG
improvements in some of the HRQOL measures
Limitations
y Single arm study, sub-analysis of a secondary endpoint
y Restricted analysis to patients who had KDQOL-CRI responses
at specific time points
y Less than 1/3 of enrolled subjects completed HRQOL scales
y Study not specifically designed to assess clinical outcomes
associated with changes in HRQOL parameters
Conclusions
™ Does improving morbidity through the use of
erythropoiesis stimulating agents to correct anemia in
non-dialysis dependent patients with stage 3-4 chronic
renal failure, outweigh the potential risks of CV events
and end-stage renal disease?
It depends…
depends…
Upcoming Trials..
Trial
Estimated
Completion Date
Study Evaluating Once Monthly Darbepoetin Alfa Dosing September 2011
for the Correction of Anemia in Non-dialysis Patients
With Chronic Kidney Disease-Phase III
October 2012
A Study of All-Cause Mortality and Cardiovascular
Morbidity in CKD Patients on Dialysis and Those Not on
Renal Replacement Therapy Receiving Mircera (methoxy
polyethylene glycol-epoetin beta) or Reference ESAs.
Effects Of Darbepoetin On Vascular Repair Mechanisms
In Kidney Disease The DARBEPC Study
October 2007 (still
recruiting)
Questions
References
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9)
References
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