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Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Welcome and Meeting Objectives
Great Fosters, UK28th -29th June 2006
David Goldsmith
Renagel Health Economics Advisory Board
Introduction
David Goldsmith
Aims and objectives 1
Strengths and gaps DCOR 2001-2004 CMS and RINDresults • Which data are compelling and why? What are the key conclusions
about Renagel? Which data are inconclusive?
• What are the remaining gaps and how can we explain these gaps using other existing evidence outside of DCOR (prospective trials, retrospective studies, epidemiologic data, etc)?
• What are the remaining gaps for future research?
Aims and objectives 2
Strengths and gaps of the DCOR/RIND costeffectiveness analysis• Is the overall framework of the model robust and supportable from
a clinical perspective?• Is the overall framework of the model robust, transparent and does
it meet the standards set by NICE?• Is the data used appropriately from DCOR and other sources, or
are there better sources of data • Are the assumptions of the model reasonable and accurate, or how
can we improve them further from a clinical perspective?
Aims and objectives 3
How best to communicate the evidence to NICE,reimbursement and guidelines authorities
• What are the key benefits of Renagel that should be communicated to reimbursement authorities and guidelines/listings?
• How should the Renagel clinical-economic story be told?• Is the evidence convincing enough and how simple/complex should
the story be made? What is the sequence of the critical messages and supporting data in that story?
• What targets (first-line, sub-groups, etc) should we be aiming for versus expect in the NICE CKD guidelines
What we know and what we don’t know
As we know, there are knownknowns. There are things we knowwe know. We also know there areknown unknowns. That is to say we know there are some things we donot know. But there are also unknown unknowns, the ones we don't know we don't know.
0
10000
20000
30000
40000
50000
60000
70000
2000 2005 2010 2015 2020 2025 2030
Transplant
PD
HD
Roderick et al 2004
No. of patients
Year
The CKD Forecast for England
Dialysis – TariffsFinancial envelope (a strait-jacket ?)
• Dialysis• Hospitalizations• Transport / outpatients• Drug costs
– EPO
– phosphate binders
– ACEI / ARB
– statins
DRUGS
FIXED DIALYSIS COSTS
DRUGS
ERYTHROPOIETINS £3000+
CINACALCET £3-9000
SEVELAMER / FOSRENOL £1500
FIXED DIALYSIS COSTS
DRUGS
ERYTHROPOIETINS £3000+
FIXED DIALYSIS COSTS
DRUGS
ERYTHROPOIETINS £6000+
CINACALCET £9000
SEVELAMER / FOSRENOL £3000
PARACALCITOL £2000
FIXED DIALYSIS COSTS
DCOR 2-year CMS data summary - Mortality
• Primary endpoint (all-cause mortality): No significant difference between sevelamer and calcium (22% vs 23%).
• All-cause mortality in patients aged ≥65 years: Significant difference in favour of sevelamer compared to calcium (28% vs 32%).
• Cardiovascular mortality: No significant difference between treatment groups (11.8% vs 11.7%).
DCOR 2 year summary - Hospitalization
• Trend towards fewer all-cause, CV and other hospitalizations with sevelamer vs calcium.
• Anderson-Gill regression models showed significantly lower relative risk of all-cause hospitalization with sevelamer vs calcium (RR 0.88, 95%, p=0.011) and for other hospitalization (RR 0.82, 95%, p=0.0045).
• Sevelamer patients had significantly fewer days hospitalized for other causes compared to calcium group and a trend toward fewer days hospitalized for all causes (p=0.0644) and CV causes (p=0.0582).
DCOR 2 year summary - Medicare expenditures and clinical events
• Sevelamer patients had lower mean total, inpatient, skilled nursing facility and other Medicare allowable expenditures vs calcium patients primarily due to a difference in inpatient costs ($1546 vs $1779 PMPM).
• Sevelamer patients used significantly more vitamin D.
• The incidence of clinical events was lower for sevelamer in 22/30 types of inpatient event and 17/19 types of outpatient event.
RIND Kidney International 2005
• Subjects with no evidence of coronary calcification at baseline showed little evidence of disease development over 18 months (independent of phosphate binder therapy), while subjects with at least mild calcification had significant progression at 6, 12 and 18 months.
• Subjects treated with calcium showed more rapid and more severe increases in coronary artery calcification score (CACS) compared to those on sevelamer (p=0.056 at 12 months; p=0.01 at 18 months).
RIND Mortality (Spiegel, Poster at NKF 2006)
• 114 patients from the primary RIND study were followed for up to 5 years to determine the relationship between phosphate binder and mortality in patients new to haemodialysis.
• Baseline CACS was a strong predictor of mortality.• Mortality was significantly lower in subjects randomized to
sevelamer vs calcium (p=0.0214).• There was a trend toward improved survival with sevelamer for all
levels of baseline CACS, even when adjusted for baseline CV risk using the Framingham Risk Index.
• Conclusion: The results provide strong evidence that phosphate binder selection and calcification are integrally linked with mortality in dialysis patients.
What we don’t know
• Where does new data take us?• Is the current model fit for purpose?• Is a new model needed and what should it be like? • Is DCOR strong enough alone or do other data need to
be combined with it (eg RIND) ? • Do DCOR and/or RIND change current clinical practice? • How can the rationale convince in the clinical setting, ie
can it support arguments of cost at the clinical level?
Deliverables
• What is the minimum/probable/best destination for sevelamer?
• What are the specific targets en route and how can they be reached?
• What specific actions are needed?
• What is a realistic timeframe?
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Business Overview
Doug JermasekSenior Vice President,
Global Marketing & New Product Development
The Genzyme Commitment
• Genzyme’s mission is to: – Address serious diseases with unmet medical needs – Provide breakthrough therapies and services that significantly improve patients’ lives
• Kidney disease is an illness in need of new solutions – The complexity and severity of kidney disease has lead Genzyme to focus on many
aspects of renal care
• Genzyme has made a long-term commitment to renal care– Clinical research– Product development – Education– Access– Support
Our Global Corporation
• Founded in 1981 • From small start up to more than 8,000 employees • Headquarters in Cambridge, MA, and presence in over
30 countries• Helping patients in more than 80 countries• 14 manufacturing sites• 9 genetic testing lab sites
Our Focus: Seeking Frontiers
Breakthrough therapies and services
Significant improvement to patients’ lives
Serious diseases with unmet medical needs =+ Patient-focused
Variety of technology platforms
Life-changing standard of care products
Creating sustainable value
Our Technology Platforms
• Protein therapies• Polymer therapeutics• Small molecule therapeutics• Biomaterials• Cell therapy• Gene therapy• Diagnostics products and services• Pharmaceuticals
Our Products
Cerezyme® imiglucerase for injection
Fabrazyme®agalsidase beta
Aldurazyme®laronidase
Campath®
alemtuzumab for injection
Clolar®
clofarabine
Thyrogen®
thyrotropin alfa for injection
Renagel®
sevelamer hydrochloride
Hectorol®doxercalciferol
Thymoglobulin®
Anti-thymocyte Globulin [Rabbit]
LSDs Renal
Synvisc®
hylan G-F 20
Carticel®
autologous cultured
chondrocytes
OrthopaedicsOncology/
EndocrinologyTransplant &
Immune Disease
Diagnostic Products and Services
Our Late-Stage Pipeline
Research Pre-Clinical Phase 1 Phase 2 Phase 3 Phase 4
Myozyme - Pompe disease
Synvisc - for hip U.S.
Tolevamer - C. difficile
Hylastan - OA of knee
Sevelamer Carbonate - kidney disease
DX-88 - hereditary angioedema
Campath - multiple sclerosis
Tasidotin HCL - cancer
Gene therapy - peripheral arterial disease
Cell therapy - ventricular restoration
Iron Chelator - iron overload diseases
Thyrogen - goiter
DENSPM - liver cancer
Renal Disease is a growing concern
CURRENTLY THERE ARE OVER 1 MILLIONDIALYSIS PATIENTS WORLDWIDE. THIS ISEXPECTED TO DOUBLE IN THE NEXT DECADE.2
Majority of CKD patients die before reaching Stage 5
1. U.S. Renal Data System, USRDS 2004 Annual Data Report; Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2004.
2. Lysaght MJ. Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol. 2002;13:S37-40.
3. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1-12.
4. U.S. Renal Data System, USRDS 1998 Annual Data Report. National Institutes of Health, Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998. Cited by: National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification—Quick Reference Clinical Handbook. New York, NY: National Kidney Foundation; 2002.
1
Our Growing Focus on Renal Disease
RBRTRBRT PKDPKD
FSGSFSGS
Bone & Mineral Disease & Product Synergies
↓ ↓ Renal FunctionRenal Function
↑ ↑ Phosphate RetentionPhosphate Retention↓ ↓ 1,25 D Production1,25 D Production
↑ ↑ PTHPTH ↓ ↓ Ca+Ca+Decreased VDR Decreased VDR expressionexpression
Altered Parathyroid Gland Function Altered Parathyroid Gland Function Hyperplasia SHPT➙ ➙ Hyperplasia SHPT➙ ➙
CONSEQUENCESCONSEQUENCESRenal Osteodystrophy Fractures Calcification CV DiseaseRenal Osteodystrophy Fractures Calcification CV Disease
MORBIDITY & MORTALITYMORBIDITY & MORTALITY
↑ ↑ POPO44
HyperphosphatemiaHyperphosphatemia
Genzyme Renal Continuum of Care
HTN
CKD ESRD
DN
Fabry
APKD
FSGS
Un
der
lyin
g D
isea
se
CV Death
Infection
Transplant
Internal dvpt
GC-1008
RenaMed Collaboration
Tolevamer
Renagel ®
Fabrazyme ®Sevelamer carbonate
Alternate Phosphate Binder
Deferitrin
Renagel ®
ESRD
Thymoglobulin ®
ESRDCKDRenagel ®
Progression
Acute Renal Failure
SHPT
Hectorol ®
LR-103BCI-202
Renal Division Pipeline
Pre-Clinical
Phase 3Commercialized
ProductsPhase 2Phase 1
BCI 202BCI 202SHPTSHPT
Vials
1.0 mcg
HectorolHectorol
GC 1008GC 1008FSGSFSGS
CyclacelCyclacelPKDPKD
RenaMedRenaMedRBRTRBRT RenagelRenagel
AlternateAlternatePhosphatePhosphate
BinderBinder
SevelamerSevelamerCarbonateCarbonate
CKDCKD
Once-a-day Powder
TolevamerTolevamer
Renal Replacement Therapy for ESRD
• From a health economics standpoint, caring for ESRD patients is cost ineffective relative to other healthcare investments– yet most societies routinely provide dialysis
• Why are we so inconsistent in the way that we evaluate the economics of dialysis-related services?
• Dialyzers
• Vascular access
• Anemia management
• Binders
• In for a penny, in for a pound?
Lest we forget…
• Behind the products…
…there are economics
• Behind the economics…
…there is disease
• Behind the disease…
…there are patients
Thank You!
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Renagel Clinical Overview
Great Fosters, UK28th -29th June 2006
Robert Guiberteau
Clinical Overview
Health EconomicsAdvisory Board
Great Fosters June 28-29th 2006
Robert Guiberteau MD VP Global Medical Programs
consequences of hyperphosphatemiafrom the 60’s to the 90’s
PiPiCa **Ca **
PTH ResistancePTH ResistanceCalcitriolCalcitriol
Calcitriol ResistanceCalcitriol Resistance
PTH SecretionPTH Secretion
Parathyroid Cell GrowthParathyroid Cell GrowthIncreased Risk Increased Risk of Bone Diseaseof Bone Disease
Increased RiskIncreased Riskof Bone Diseaseof Bone Disease
consequences of hyperphosphatemiasince 1998
P
MortalityRisk of Calcification
Parathyroid Cell Growth
PTH Secretion
PTH Resistance
Ca++
Calcitriol Resistance
Calcitriol
the history of the paradigm shift
– 1996 Rapid progression of Coronary calcifications Braun
– 1997 Negative Calcium Balance??? Hsu
– 1998 Hyperphosphatemia as independant RRF Block
– 1999 Hyperphosphatemia, a silent killer? Amann
– 2000 Oral Calcium load is an independant RRF Goodman
– 2001 Calcifications predict outcome Blacher
– 2002 Calcifications, a modifiable risk factor Chertow
– 2004 Increased S.Calcium as independant RRF DOPPS
– 2004 Low PTH > High PTH as an increased RRF Stevens
High Serum Phosphorus Increases Mortality Risk
Serum phosphorus >6.5 mg/dL in 39% of patients
Block, et al. Am J Kidney Dis. 31:607-17. 1998
0.5
1
1.5
2
1.1 - 4.5 4.5 - 5.5 5.6 - 6.5 6.6 - 7.8 7.9 - 16.9
Serum Phosphorus Quintile (mg/dL)
Relative Mortality Risk (RR)
REFERENCE
1.00 1.00
1.02
1.18*
1.39**
*P = 0.03** P < 0.0001
association between mortality risk and serum phosphate in CKD patients
Block et al. JASN 2004 15: 2208–18
Serum phosphorus (mg/dL)
Rel
ativ
e ri
sk o
f d
eath
< 3 3–4 4–5 5–6 6–7 7–8 8–9 > 90
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2 Reference group
Multivariable-adjusted RR of death
n=40538
relationship between serum phosphate and morbi / mortality in patients with normal GFR
Tonelli M. Circulation 2005 112:2627-33
the history of the paradigm shift
– 1996 Rapid progression of Coronary calcifications Braun
– 1997 Negative Calcium Balance??? Hsu
– 1998 Hyperphosphatemia as independant RRF Block
– 1999 Hyperphosphatemia, a silent killer? Amann
– 2000 Oral Calcium load is an independant RRF Goodman
– 2001 Calcifications predict outcome Blacher
– 2002 Calcifications, a modifiable risk factor Chertow
– 2004 Increased S.Calcium as independant RRF DOPPS
– 2004 Low PTH > High PTH as an increased RRF Stevens
coronary calcifications in young adults
Goodman WG et al. N Engl J Med. 2000;342:1478-1483.
0.1
1
10
100
1000
10000
0 5 10 15 20 25 30 35
Age (years)
Cal
cifi
cati
on S
core
0.0
0.8
1.7
2.5
3.3
4.2
5.0
0 1 2 3 4
Arterial calcification score
CaC
O3
(g C
a el
emen
t/d
ay)
P<0.0001
arterial calcification score and daily dose of Ca containing PO4 binders
Guerin et al NDT 2002
the history of the paradigm shift
– 1996 Rapid progression of Coronary calcifications Braun
– 1997 Negative Calcium Balance??? Hsu
– 1998 Hyperphosphatemia as independant RRF Block
– 1999 Hyperphosphatemia, a silent killer? Amann
– 2000 Oral Calcium load is an independant RRF Goodman
– 2001 Calcifications predict outcome Blacher
– 2002 Calcifications, a modifiable risk factor Chertow
– 2004 Increased S.Calcium as independant RRF DOPPS
– 2004 Low PTH > High PTH as an increased RRF Stevens
calcification score
• Probality of all-cause survival according to calcification score. Comparison (log-rank test) between curves was highly significant ( Chi D =42.66 ; P<0.0001).
Calcification score : 0Calcification score : 0
0.250.25
0.500.50
0.750.75
11
00
00 2020 4040 6060 8080
Calcification score : 1Calcification score : 1
Calcification score : 2Calcification score : 2
Calcification score : 3Calcification score : 3
Calcification score : 4Calcification score : 4
Duration of follow-up (months)Duration of follow-up (months)
Pro
bal
ity
of s
urv
ival
Pro
bal
ity
of s
urv
ival
Blacher et al Hypertension 2001
smooth muscle cell matrix mineralization
Adapted from Yang Kidney Int 2004 66:2293-9
0.0
8.3
16.7
25.0
33.3
41.7
50.0
0 1 2 3 4Arterial calcification score
CR
P (
mg/
l)
arterial calcification score and CRP in ESRD patients
London et al NDT 2003
P<0.0001
absorption of phosphate binder
• Calcium : up to 20 %
• Aluminium : 0.06 – 0.10 %1
• Lanthanum : 0.00003 %2
1 De Broe ME et al. NDT 19:114-118, 20042 Joy MS Am J Kidn Dis 42:96-107, 2003
renagel a new phosphate binder
N H2
N H3C l
N H2
O
PO H
-OO
N H
N H3+
N H2
HH3P O4
+ HCl
H
Combination of anionic and hydrogen bonding.
4.5
5
5.5
6
6.5
7
7.5
8
8.5
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks
Se
rum
P (
mg
/dl)
Ca (TTG)* Renagel (TTG)* Lanthanum** Ca (CARE)***
K/DOQI Limit
efficacy
* Chertow G. KI 2002 ** Hutchison A. WCN 2003Berlin*** Qunibi W. et al. KI 2004 65: 1914-1926
the history of the paradigm shift
– 1996 Rapid progression of Coronary calcifications Braun
– 1997 Negative Calcium Balance??? Hsu
– 1998 Hyperphosphatemia as independant RRF Block
– 1999 Hyperphosphatemia, a silent killer? Amann
– 2000 Oral Calcium load is an independant RRF Goodman
– 2001 Calcifications predict outcome Blacher
– 2002 Calcifications, a modifiable risk factor Chertow
– 2004 Increased S.Calcium as independant RRF DOPPS
– 2004 Low PTH > High PTH as an increased RRF Stevens
TTG: percentage change in coronarycalcification scores at 52 weeks
*Within treatment *Within treatment PP<0.0001; between treatment groups <0.0001; between treatment groups PP=0.02.=0.02.Patients with a baseline score >30.Patients with a baseline score >30.
0
5
10
15
20
25
30
35
Calcium Sevelamer
Me
dia
n P
erc
en
tag
e C
ha
ng
e
0
5
10
15
20
25
30
35
Calcium Sevelamer
Me
dia
n P
erc
en
tag
e C
ha
ng
e
25%*
6%
Chertow KI 2002
TTG: percentage change in coronary calcification scores at 2 years
p*: Wilcoxon signed rank test p**: Wilcoxon rank sum test -20
0
20
40
60
80
100
p*=0.99 p*=0.40
p*=0.108
p*=0.020p*=0.004
p*=0.000
p**=0.129
p**=0.239
p**=0.040
(%)
week 26 week 52 final (1.8-2 yrs)
Sevelamer (n=17)Calcium (n=23)
Asmus Nephrol Dial Transplant 2005 20:1653-61
0
20
40
60
80
100
120
140
Sevelamer Ca Salts
Me
dia
n I
nc
rea
se
CA
CS
0
20
40
60
80
100
120
140
Sevelamer Ca Salts
Me
dia
n I
nc
rea
se
CA
CS
RIND: Effects of Sevelamer and Calcium on Coronary Artery Calcification
The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the Sevelamer-Treated Group The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the Sevelamer-Treated Group
P=0.01P=0.01
In Patients New to HemodialysisIn Patients New to Hemodialysis
Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
*Wilcoxon signed rank test, within group P<0.05 **Wilcoxon rank sum test, between group P<0.05
Trabecular** Cortical
Sevelamer
Calcium
Per
cen
t ch
ang
e (m
edia
n)
*
*
TTG: sevelamer and bone density
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
Raggi et al. J Bone Miner Res. 2005;20:764–772
100
80
60
40
20
20
Change in coronary calcium score
Ag
atson
score
Change in trabecular bone attenuation
40
5
5
10
10
15
20
Ho
un
sfie
ld u
nit
s
TTG: change in bone attenuation and coronary calcium score
Sevelamer
Calcium salts
Raggi et al. J Bone Miner Res. 2005;20:764–772
0.0
7.5
15.0
22.5
30.0
0 1 2 3 4
Arterial calcification score
Ost
eob
last
su
rfac
e (%
) (%
)
London et al JASN 2004
P<0.0001
bone histomorphometry and arterial calcifications in ESRD
sevelamer hydrochloride restores bone in osteopenic OVX rats
BV/TV, Tr.nOsteocalcinMAR, BFR
BMDBV/TV
Boneformation
Restorationof lost bone
Boneresorption sC-telopeptide
Vukicevic Abstract ASN 2005
Reversal of the Adynamic Bone Disorder and Established Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy
• “The LDLR-/- high fat fed mouse exhibits an adynamic bone disorder in the presence of CKD characterized by decreased osteoblast surface, decreased bone formation rates and normal osteoclast surfaces similar to the excess representation of the ABD as the form of renal osteodystrophy observed in human diabetic nephropathy.
• Treatment with sevelamer significantly increased osteoblast surfaces and bone formation rates ameliorating the adynamic bone disorder of the LDLR-/- high fat fed animals with CKD.”
Hruska K. Submitted for publication
Sevelamer and bone: clinical data
Impact of phosphate binders on bone histomorphometry: results of a one-year bone biopsy study
A. Ferreira J. Frazao H.Malluche
A. Ferreira J. Frazao H.MallucheSubmitted for publication
Trends in Activation Frequency
RenagelN=33
Calcium
N=35
Away from normal
Towards normal
0 %
9 %
3 %
12 %
No change 67 % 54 %
Towards normal
Away from normal
21 %
3 %17 %
14 %
renagel a efficient phosphate binder with additional benefits……..
• Bioindicators– Lowering LDL C– Lowering biomarkers of inflammation– Lowering biomarkers of oxydative stress (animals)– Lowering uric acid– Lowering serum glucose– Binding to p cresol, indoxyl sulfate and indole (in vitro)– Increasing serum fetuin A
• Intermediate indicators– Preserving RRF (animals)– Halting progression of CV calcifications– Maintening / Improving bone health
• Improving patient outcomes
new terminologies and recommendationsfrom osteodystrophy to CKD-MBD
Moe, Drueke Am J Kidney Dis 2004 43:553
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Outcomes Evidence:DCOR Trial and CMS 3-Year results
RIND Trial Results
Great Fosters, UK28th -29th June 2006
Jose Menoyo
Patients New to Dialysis and Established PatientsPatients New to Dialysis and Established Patients
Prevalence of Vascular Calcification in CKD-IV
40%
57%
83%
0%
20%
40%
60%
80%
100%
Russo et al RIND TTG
40%
57%
83%
0%
20%
40%
60%
80%
100%
Russo et al RIND TTG
*Russo et al AJKD 2004 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265***Chertow et al KI 2002
*Russo et al AJKD 2004 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265***Chertow et al KI 2002
*
**
***
Effects of Sevelamer and Calcium on Coronary Artery Calcification in Patients New
to Hemodialysis
RIND TrialBlock, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Objective
• The primary aims of this study were to assess the degree of coronary artery calcification in a cohort of patients new to hemodialysis, and to compare the impact of sevelamer vs. calcium-based phosphate binders on the development and progression of coronary artery calcification
Study Design
Sevelamer Extended treatmentRANDOMIZEw/in 90 days
of HD
0 EBCT scan
Titrate doseP < 6.5 mg/dL
Ca2+ < 10.2 mg/dL
USUAL clinical practice
Calcium binder
Extended treatment
6 mo 12 mo 18 mo EBCT scans
Titrate doseP < 6.5 mg/dL
Ca2+ < 10.2 mg/dLPTH 150-300 pg/mL
Maintain dialysate Ca=2.5 mEq/L
•Renagel patients can receive Ca supplementation at night.•Dialysate Ca concentration was maintained at 2.5 mEq/l (1.25 mmol/l) throughout the study period.
Effects of Sevelamer and Calcium on Coronary Artery Calcification
Screened (N=385)Screened (N=385)Screened (N=385)Screened (N=385)
Declined/Screen Failures (N=237)Declined/Screen Failures (N=237)Declined/Screen Failures (N=237)Declined/Screen Failures (N=237) Randomized (N=148)Randomized (N=148)Randomized (N=148)Randomized (N=148)
Calcium (N=75)Calcium (N=75)Calcium (N=75)Calcium (N=75) Sevelamer (N=73)Sevelamer (N=73)Sevelamer (N=73)Sevelamer (N=73)
Adverse Event (N=1)Adverse Event (N=1)Transplanted (N=3)Transplanted (N=3)
Death (N=1)Death (N=1)Other (N=4)Other (N=4)
Lost to Follow-Up (N=1)Lost to Follow-Up (N=1)Transferred to PD (N=2)Transferred to PD (N=2)
Adverse Event (N=1)Adverse Event (N=1)Transplanted (N=3)Transplanted (N=3)
Death (N=1)Death (N=1)Other (N=4)Other (N=4)
Lost to Follow-Up (N=1)Lost to Follow-Up (N=1)Transferred to PD (N=2)Transferred to PD (N=2)
Adverse Event (N=1)Adverse Event (N=1)Transplanted (N=2)Transplanted (N=2)
Death (N=1)Death (N=1)Other (N=2)Other (N=2)
Transferred to PD (N=2)Transferred to PD (N=2)
Adverse Event (N=1)Adverse Event (N=1)Transplanted (N=2)Transplanted (N=2)
Death (N=1)Death (N=1)Other (N=2)Other (N=2)
Transferred to PD (N=2)Transferred to PD (N=2)
Available for Analysis (N=55)Available for Analysis (N=55)(at Least 1 Post Baseline EBCT)(at Least 1 Post Baseline EBCT)
Available for Analysis (N=55)Available for Analysis (N=55)(at Least 1 Post Baseline EBCT)(at Least 1 Post Baseline EBCT)
Available for Analysis (N=54)Available for Analysis (N=54)(at Least 1 Post Baseline EBCT)(at Least 1 Post Baseline EBCT)
Available for Analysis (N=54)Available for Analysis (N=54)(at Least 1 Post Baseline EBCT)(at Least 1 Post Baseline EBCT)
Baseline EBCT (N=67)Baseline EBCT (N=67)Baseline EBCT (N=67)Baseline EBCT (N=67) Baseline EBCT (N=62)Baseline EBCT (N=62)Baseline EBCT (N=62)Baseline EBCT (N=62)
In Patients New to Hemodialysis In Patients New to Hemodialysis
RIND Baseline Demographics
• Age: 59• BP: 149/80• Hg: 11.8• Ca+: 9.3• Phos: 5.3• Albumin: 3.6• PTH: 363• Creatinine: 7.4• Days from
1st HD to EBT: 84.6
• 42% Caucasian• 32% African-American• 62% Male• 57% Diabetic• 96% HTN• 23% History of CAD• 30% History of ASVD• 16% History of CHF
Effects of Sevelamer and Calcium on Coronary Artery Calcification
SevelamerSevelamer CalciumCalcium
PhosphorusPhosphorus 5.2 (0.9)5.2 (0.9) 5.1 (0.8)5.1 (0.8)
Corrected CalciumCorrected Calcium 9.1 (0.5)9.1 (0.5) 9.6 (.5)9.6 (.5) PP<0.05<0.05
Ca x PCa x P 47 (7)47 (7) 49 (8)49 (8)
PTHPTH 298 (152)298 (152) 243 (136)243 (136) PP<0.05<0.05
LDLLDL 60 (34)60 (34) 81 (26)81 (26) PP<0.05<0.05
AlbuminAlbumin 3.8 (0.3)3.8 (0.3) 3.8 (0.4)3.8 (0.4)
CRPCRP 9.1 (9.7)9.1 (9.7) 10.5 (10.3)10.5 (10.3)
Hypercalcemia Hypercalcemia (Ca>10.2mg/dl)(Ca>10.2mg/dl) 22%22% 54%54% PP<0.0001<0.0001
Severe Severe HypercalcemiaHypercalcemia(Ca>11mg/dl)(Ca>11mg/dl)
5%5% 24%24% PP<0.02<0.02
In Patients New to HemodialysisIn Patients New to Hemodialysis
Mean (SD)Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Mean (SD)Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Average Phosphorus Control by Binder
4.4
4.6
4.8
5.0
5.2
5.4
5.6
5.8
6.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Study Month
Se
rum
Ph
os
ph
oru
s
Renagel Calcium
4.4
4.6
4.8
5.0
5.2
5.4
5.6
5.8
6.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Study Month
Se
rum
Ph
os
ph
oru
s
Renagel Calcium
Mean Serum Phosphorus by Study MonthMean Serum Phosphorus by Study Month
Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Mean Serum Calcium by Study MonthMean Serum Calcium by Study Month
Mean Serum Calcium Level by Binder
8.5
8.7
8.9
9.1
9.3
9.5
9.7
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Study Month
Se
rum
Ca
lciu
m (
Co
rre
cte
d)
Renagel Calcium
8.5
8.7
8.9
9.1
9.3
9.5
9.7
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Study Month
Se
rum
Ca
lciu
m (
Co
rre
cte
d)
Renagel Calcium
Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Effects of Sevelamer and Calcium on Coronary Artery Calcification
0
50
100
150
200
250
300
350
Baseline 6 months 12 months 18 months
Me
dia
n C
AC
S
Sevelamer Calcium
N=54N=54 N=55N=55 N=51N=51 N=53N=53 N=45N=45 N=47N=47 N=40N=40 N=45N=45
In Patients New to HemodialysisIn Patients New to Hemodialysis
Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
0
20
40
60
80
100
120
140
Sevelamer Ca Salts
Me
dia
n I
nc
rea
se
CA
CS
0
20
40
60
80
100
120
140
Sevelamer Ca Salts
Me
dia
n I
nc
rea
se
CA
CS
Effects of Sevelamer and Calcium on Coronary Artery Calcification
The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the
Sevelamer-Treated Group
The Median Absolute Increase in CACS at 18 Months Was 11-Fold Greater in the Calcium Treated Group Compared to the
Sevelamer-Treated Group
P=0.01P=0.01
In Patients New to HemodialysisIn Patients New to Hemodialysis
Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005Block, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Percentage Among Subjects with Baseline Coronary Artery Scores >30Percentage Among Subjects with Baseline Coronary Artery Scores >30
Subjects With or Without Progression of Coronary Artery Calcium Scores
60
44
38
40
56
626 Months
12 Months
18 Months
Progression Regression/Stable
93
86
63
7
14
326 Months
12 Months
18 Months93
86
63
7
14
326 Months
12 Months
18 Months
Sevelamer Sevelamer Sevelamer Sevelamer CalciumCalciumCalciumCalcium
Progression of CACS = Greater Than 15% Increase from BaselineFisher Exact Test P Value <0.05 for Between Group Differences at 12 and 18 MonthsBlock, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Progression of CACS = Greater Than 15% Increase from BaselineFisher Exact Test P Value <0.05 for Between Group Differences at 12 and 18 MonthsBlock, GA, Kidney Int; Vol68(4): 1815-1824, 2005
Effects of Sevelamer and Calcium on Coronary Artery Calcification
• Substantially greater proportion of patients new to dialysis had no visible coronary calcification compared with previous reports of patients on chronic hemodialysis
• Subjects with no evidence of coronary artery calcification upon initiation of dialysis showed little evidence of coronary artery calcification development during follow-up
• While all subjects with evidence of baseline coronary calcification showed progression over time, patients randomized to calcium-based binders experienced significantly more rapid and severe progression of disease than sevelamer-treated patients
Block, GA et al. Kidney Int 2005; 68:1815-1824 Block, GA et al. Kidney Int 2005; 68:1815-1824
Calcium Containing Phosphate Binders are Associated with Increased Mortality Risk in
Hemodialysis Patients Compared to
Sevelamer
DM Spiegel, P Raggi, A Bellasi, L Kooienga, GA Block
NKF Spring Clinical Meeting 2006
Mortality Analysis Comparing Baseline Calcium Score
Months
0 6 12 18 24 30 36 42 48 54 60 66
Su
rviv
al D
istr
ibutio
n F
unctio
n
0.00
0.25
0.50
0.75
1.00
CCS=0 CCS< 400CCS >= 400
No. at RiskCCS = 0 43 41 41 38 32 18 4CCS < 400 35 34 33 29 25 14 1 CCS >= 400 36 34 32 28 23 15 4
Survival by Baseline Coronary Calcium Score
P = 0.0035
Mortality Analysis Comparing Calcium Versus Sevelamer
Months
0 6 12 18 24 30 36 42 48 54 60 66
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
0.00
0.25
0.50
0.75
1.00
No. at RiskCalcium 60 57 54 49 38 22 5Renagel 54 52 52 46 42 25 4
Calcium Renagel
10 Deaths
24 Deaths
P = 0.0214
Survival by Binder Randomization
Mortality by Baseline Calcification Score
Summary
• Sevelamer confers a survival benefit over calcium-based phosphate binders
• Within each strata of coronary artery calcification sevelamer demonstrated a improved survival
• Baseline CACS as measured by EBCT scan is a strong predictor of survival in patients new to dialysis
DCOR: Dialysis Clinical Outcomes
Revisited
Outcomes Studies in Hemodialysis
HEMO Study (n=1,846)– Standard or high dose of dialysis and a low or high flux dialyzer – Risk of death from any cause was same for both dialyzer doses
and both dialysis groups
U.S. Normal Hematocrit Trial (n=1,223)– Patients with clinical evidence of congestive heart failure or
ischemic heart disease– Study terminated after 29 months because the group targeted to
normal values had a higher mortality rate
4D (n=1,255)– Diabetic patients randomized to atorvastatin/day or matching
placebo– Atorvastatin had no statistically significant effect on
cardiovascular death, nonfatal myocardial infarction, and/or stroke in patients
• Largest prospective randomized clinical outcomes trial conducted in the hemodialysis population
• First large scale head-to-head trial comparing clinical outcomes in patients randomized to alternative phosphate binder therapies
• Real-world study design– Broadly applicable across clinical practice settings– Health economic outcomes data allow for
analysis of cost-effectiveness
The DCOR Trial
DCOR Study Objectives
• Primary Objective– To compare the association of sevelamer use versus
calcium-based phosphate binder use on all-cause mortality in hemodialysis patients
• Secondary Objectives– To compare the association of sevelamer use and
calcium-based phosphate binder use with:• Cause-specific mortality (cardiovascular, infection, other)• All-cause and cause-specific hospitalization and morbidity• Medicare expenditures
Study Design
• Multi-center, open-label, parallel design trial
• Patients randomized to receive sevelamer or a calcium-based phosphate binder in a 1:1 fashion
• Randomization stratified by age, race, gender and diabetic status
• 1,000 patients per arm
• Patients enrolled from March 2001 through January 2002
• The treatment period was scheduled to go through December, 2004 for a total duration of at least 3 years
Patient Enrollment
• Inclusion criteria– > 18 years– On dialysis for > 3 months– Required phosphate binder therapy– Had Medicare as their primary insurance
• Exclusion criteria– Current dysphagia, swallowing disorders, severe
gastrointestinal motility disorders, or bowel obstruction
– Hypersensitivity to sevelamer
Statistical Methods
• Sample Size Calculation:
– Assuming a mortality rate of 200 per 1000 patient years in the control group, a two sided test, and a preserved overall significant level of 0.05
– A total of 1000 patients per treatment arm would provide 80% power to detect a 22% decrease in all-cause mortality
Statistical Methods
• Survival probabilities (Kaplan-Meier curves) were calculated for time to death by treatment group overall
• Cox regression models were run to determine relative risks and 95% confidence intervals adjusting for the following pre-specified prognostic factors (age, race, gender, diabetes, cause of ESRD, and vintage)
• Treatment interactions with each of the prognostic factors were assessed
• A statistically significant interaction was required as a gating step prior to subset analysis
Results
* Completers either died or followed through the end of the study. All patients dispensed study medication were included in the data analysis.
Patient DispositionRandomized
N = 2,103
Renagel N = 1,053
Calcium N = 1,050
Never DispensedN = 20
DispensedN = 1,033
Never DispensedN = 43
DispensedN = 1,007
Terminated Early (N=491)• Consent Withdrawn (N=61)• Investigator Decision (N=141)• Lost to Follow-up (N=98)• Adverse Event (N=50)• Renal Transplant (N=46)• Changed Dialysis Modality (N=25)• Other (N=70)
Completed Study*N = 516
Terminated Early (N=484)• Consent Withdrawn (N=62)• Investigator Decision (N=90)• Lost to Follow-up (N=107)• Adverse Event (N=81)• Renal Transplant (N=59)• Changed Dialysis Modality (N=22)• Other (N=63)
Completed Study*N = 549
Demographics
VariableSevelamer(N=1033)
Calcium(N=1007)
p-value*
Race [N (%)]
Caucasian Black Asian Other
508 (49)482 (47)
6 (1)37 (4)
479 (48)470 (47)
11 (1)47 (5)
0.36
Age
[Mean ± SD, (years)]
[Median (years)]
60 ± 14
62
60 ± 15
62
0.69
Gender [N (%)] Male Female
562 (54)471 (46)
546 (54)461 (46)
0.96
Diabetes Status [N (%)]
No Yes
509 (49)524 (51)
499 (50)508 (50)
0.93
* Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables
Renal History
VariableSevelamer(N=1033)
Calcium(N=1007)
p-value*
Primary Cause of CKD [N (%)]
Diabetes Hypertension/Large Vessel Disease Glomerulonephritis Secondary GN/Vasculitis Interstitial Nephritis/Pyelonephritis Neoplasms/Tumors Miscellaneous Conditions Cystic/Hereditary/Congenital Disease
440 (43)342 (33)108 (10)
16 (2)24 (2)10 (1)66 (6)27 (3)
432 (43)338 (34)97 (10)22 (2)29 (3)8 (1)
47 (5)34 (3)
0.54
Dialysis Vintage [Mean ± SD, (months)]
[Median (months)]38 ± 39
24
38 ± 40
24
0.58
* Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables
Laboratories (Mean + SD)
0.11
< 0.0001
< 0.0001
< 0.0001
0.60
< 0.0001
< 0.01
p-value*
1.6 ± 0.31.6 ± 0.3Kt/V
84.9 ± 31.069.0 ± 25.9LDL Cholesterol
160.8 ± 34.7145.6 ± 33.8Total Cholesterol
226278iPTH ^
53.6 ± 12.953.7 ± 12.0Calcium x Phosphorus Product
9.5 ± 0.79.2 ± 0.7Calcium
5.7 ± 1.35.8 ± 1.3Phosphorus
Calcium(N=843)
Sevelamer(N=843)
Parameter
* Wilcoxon Rank Sum Test ^ Presented as median
Results
All-Cause Mortality
Time on Study (Years)
Cu
mu
lati
ve I
nci
de
nce
of
All
-Cau
se M
ort
alit
y
CalciumSevelamer
1007 640 430 161 1033 656 449 195
No. at Risk
1 2 3 40
0.0
0.1
0.2
0.3
0.4
0.5
0.6
SevelamerCalcium
Primary endpoint results inconclusive across entire
study population
Primary endpoint results inconclusive across entire
study population
p = 0.30
Pre-Specified Subset Analysis
Variable
Gender[male/female]
Race[black/non-black]
Age[< 65 or ≥ 65 years]
Diabetes[yes/no]
Dialysis vintage≤ or > 2 years
Cause ESRDdiabetes, hypertension, other
Co
x R
egre
ssio
n M
od
el
p-value
0.67
0.84
0.03
0.35
0.83
0.82
Of the pre-specified variables, only age
demonstrated a statistically significant treatment interaction
Subset analysis of patients < or ≥ 65 years
was undertaken in accordance with pre-
specified statistical plan
Time on Study (Years)
Cu
mu
lati
ve I
nci
de
nce
of
All
-Cau
se M
ort
alit
y
No. at RiskCalciumSevelamer
556 366 245 98 585 381 253 99
0 1 2 3 4
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
SevelamerCalcium
Sevelamer therapy resulted in
a statistically significant reduction in the relative risk
for all-cause mortality in pre-specified subset[RR 0.78 (0.62-0.97)]
Sevelamer therapy resulted in
a statistically significant reduction in the relative risk
for all-cause mortality in pre-specified subset[RR 0.78 (0.62-0.97)]
↓ 22% p = 0.03
All-Cause Mortalityin Patients ≥ 65 years
All-Cause Mortality Patients < 65 years
Time on Study (Years)
Cu
mu
lati
ve I
nci
de
nce
of
All
-Cau
se M
ort
alit
y
No. at RiskCalciumSevelamer
451 274 185 62 448 275 196 97
1 2 3 400.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
SevelamerCalcium
p = 0.31
Results inconclusive for patients <65 years
Results inconclusive for patients <65 years
All-Cause Mortality for Patients Other Than the Pre-specified Age Cut-point (< or ≥ 65
years)
Age Cut point (years)
All 25 30 35 40 45 50 55 60 65 70
Rel
ativ
e R
isk
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Statistically significant reduction of relative risk for all-cause mortality was observed for patients >45 years of age
treated with Sevelamer
Statistically significant reduction of relative risk for all-cause mortality was observed for patients >45 years of age
treated with Sevelamer
Cause specific Mortality
• Results for CV and infection mortality were similar to all-cause mortality
• With only 53% of deaths due to CV causes, the study is not powered to detect differences in CV death
All-Cause Hospitalizations
0.0917 ± 32 5.8
15 ± 285.0
Number of Days Hospitalized[per patient year] Mean ± SD Median
0.062.3 ± 4.91.3
2.1 ± 4.41.0
Number of Hospitalizations[per patient year] Mean ± SD Median
p-value*Calcium(N=1007)
Sevelamer(N=1033)
Variable
* Wilcoxon rank sum test
Conclusions
• Results of the DCOR trial failed to reach statistical significance for the primary end-point of all-cause mortality (RR 0.91; p = 0.3)
• Statistically significant reduction in all-cause mortality was observed for patients receiving sevelamer in a pre-specified subset analysis of patients ≥ 65 years of age (RR 0.78, p = 0.03)
• A strong trend toward reduced hospitalizations in sevelamer-treated patients was observed (p = 0.06)
QUESTIONS?
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
DCOR study: CMS-based data analysis
Jeremy Heaton
Outline
• CMS data used in analysis• Study rules
• Randomized versus dosed population
• 90-day versus study completion follow-up
• Baseline data• Mortality• Hospitalization• Morbidity• Costs
CMS data background
• Medicare tracks vital status (mortality)• Medicare pays for:
– Dialysis procedures– Hospitalizations– Physician visits, outpatient procedures– Some IV medications (EPO, iron, vitamin D, antibiotics
administered in dialysis unit)– Other treatments, excluding most oral medications
• All payments occur following adjudication by Medicare• Payments finalized over time• Data presented reflect up to December 31, 2004
What are CMS data?
CMS = Centers for Medicare and Medicaid Services
USRDS 2004 Annual Data Report
Structure of the CMS database
Methods – patient matching
• 2101 patients in CMS database were matched to patients in the Case Report Form (CRF) database ITT population
• Patients were matched based on:– SSN
– first/last name initial
– date of birth
– dialysis initiation date
– gender
– race
– primary cause ESRD
Data used in CDRG data analysis
CRF• Baseline age, race, gender,
diabetes, vintage, ESRD cause• Randomization date, drug
dispensed date, stop date, study completion date
CMS• Pre-study comorbidities (CHF,
ASHD, other cardiac, PVD, CVA/TIA; diabetes-by CRF)
• CVD history (0, 1, ≥1)• Baseline Hb, URR, Vit D use• Death date and cause• Hospitalization date and cause• Morbidity (inpatient and
outpatient) and cause• Costs (total, inpatient,
outpatient, skilled nursing facility, other)
Randomized versus Dosed populations
• Analyses were conducted for both randomized and dosed populations (majority):– Randomized population – followed from date of randomization
– Dosed population – followed from date of first dose of study medication
Four rules used
Randomizationor first dose date
Study completion12/31/0312/31/04
+90 days
Early termination: withdrawal pt consent, renal transplant, modalitychange; investigator decision, lost-to-follow-up, adverse event, other
EventDeath (mortality analysis only)
HospitalizationMorbidity
Cost
Early termination
Importance of data captured by CMS
• Support results from prospective DCOR trial
• Provide additional details otherwise impossible without great expense– Hospitalization dates, causes, costs
– Morbidity (inpatient, outpatient), dates, causes, costs
– Cost breakdown
• Follow more early termination patients– More death, hospitalization events
Risk factors adjusted for in analyses
• Clinical trial– Age – Race– Gender– Diabetes status (2 categories)– Vintage– ESRD Cause
• CMS analysis– Age – Race– Gender– Vintage– Pre-study comorbidities
• Diabetes (per CRF-3 categories)• CHF• ASHD• CVA/TIA• PVD• Other cardiac
CMS 3-year results
• New data– Haemoglobin– URR– Vitamin D use– Baseline co-morbidities
• CHF• PVD• ASHD• CVA/TIA• Other cardiac
• 90-day (mainly) and SC follow-up data
Baseline characteristics
VariableTotal
(n=2038)Sevelamer(n=1031)
Calcium(n=1007)
p value*
Haemoglobin, g/dL
Mean ± SD Median
11.9 ± 1.311.9
11.9 ± 1.411.9
11.8 ± 1.311.8
0.9289
URR, n (%) < 60 % 60- < 64 % 65- < 70 % 70- < 75 % ≥ 75% Unknown %
99 (5)123 (6)
371 (18)612 (30)706 (35)127 (6)
54 (5)61 (6)
198 (19)308 (30)343 (33)
67 (7)
45 (5)62 (6)
173 (17)304 (30)363 (36)
60 (6)
0.6696
Vitamin D use, n (%) No Yes
687 (34)1351 (66)
339 (33)692 (67)
348 (35)659 (65)
0.4261
* Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables
Baseline characteristics: Dosed populationHb, URR, vitamin D use
VariableTotal
(n=2038)Sevelamer (n=1031)
Calcium(n=1007)
p value*
Cardiovascular History #
[N (%)]
0.9269
0 co-morbidities 686 (33.7) 351 (34.0) 335 (33.3)
1 co-morbidity 491 (24.1) 248 (24.1) 243 (24.1)
> 1 co-morbidity 861 (42.2) 432 (41.9) 429 (42.6)
* Fisher’s exact test for categorical variables and Wilcoxon rank sum test for continuous variables
Baseline characteristics: Dosed populationCardiovascular comorbidities
Mortality
All-cause mortalityKaplan-Meier survival curves of time to all-cause mortality, by treatment (90-day follow-up rule, ITT population)
p = 0.5332
Hospitalization
Multiple hospitalizations (per 100 patient-years)
Sevelamer Calcium p value
All-cause 170 191 0.02
CV 55 60 0.05
Infection 25 30 0.11
Vascular Access 33 34 0.94
Fracture 3 3 0.21
Other 55 64 0.10
Hospital days (mean per patient-year)Dosed population, SC rule
12.1
3.7
2 2
0.38
3.9
13.9
4
2.72.2
0.48
4.6
0
2
4
6
8
10
12
14
All-cause CV Infection VA Fracture Other
Me
an
ho
sp
ita
l da
ys
pe
r p
ati
en
t y
ea
r
Sevelamer Calcium
p=0.052
p=0.06
p=0.1 p=0.85
p=0.21
p=0.155
p value: Wilcoxon rank sum test was usedFollow-up time calculated as total number of patient-years at risk of hospital admission including time in hospitalUnadjusted analyses
Relative Risk for Multiple Hospitalization
Adjusted for demographics and pre-study comorbidities, dosed population
0.4 0.6 0.8 1.0 1.2 1.4 1.6
All-cause
Fracture
Other
Sevelamer (Referent: Calcium)
Cardiovascular
Infection
Vascular access
p < 0.05Relative Risk
10.2.1.1Genzyme Corporation Protocol GTC-68-401Centers for Medicare and Medicaid Services Data Analysis
Multiple Hospitalizations (Anderson-Gill Regression Model)
Relative Risk for Days Hospitalized Per 100 Patient Years
Adjusted for demographics and pre-study comorbidities, dosed population
10.2.1.1
0.4 0.6 0.8 1.0 1.2 1.4 1.6
Sevelamer (Referent: Calcium)
All-cause
Cardiovascular
Infection
Vascular access
Fracture
Other
p < 0.05Relative Risk
Genzyme Corporation Protocol GTC-68-401Centers for Medicare and Medicaid Services Data Analysis
Hospitalization days per patient (Poisson Main-Effects Regression Model)
Morbidity
Morbidity analyses
• Categories– Cardiovascular (CV)
– Vascular access (VA)
– Infection
– Fracture
• Included both inpatient and outpatient events
• Rules were created to avoid counting same event twice
Morbidity results (adjusted analyses)
• First morbidity (Cox regression analysis)– Final Model: All RR (when no interactions) favour sevelamer, but all
are NS• CV: interaction with CVA/TIA (SC only)• VA: interaction with diabetes (90 d, SC)• Infect: interaction with dialysis duration (90 d only)
• Multiple morbidity (Anderson-Gill model)– Final model: All RR favour sevelamer, but all are NS
• VA: interaction with diabetes (90 d, SC), • Fracture: interaction with ASHD (SC only); too few events to
evaluate
Cost analysis
Mean Annual Medicare costsDosed population, 90-day follow-up
$66,348 $68,688
$18,528 $20,748
$44,760 $44,532
$960 $1,320 $2,088 $2,100
$0
$10,000
$20,000
$30,000
$40,000
$50,000
$60,000
$70,000
Total Inpatient Outpatient Skilled nursingfacility
Other
Sevelamer
Calcium
($2,340) ($2,220) $228 ($360) ($12)
(3.5%) (12.0%) 0.5% (37.5%) (0.6%)
Difference:
Inpatient actual annual cause-specific costsDosed population, 90-day follow-up
$6,240
$4,176
$5,316
$6,432
$5,916
$4,128
$2,592$3,372
$0
$5,000
$10,000
$15,000
$20,000
$25,000
Sevelamer Calcium
Other
Infection
Fracture
VA
CVD
Annual Medicare allowable expenditures: selected sub-groupsDosed population, 90-day follow-up
p = 0.034
$50,000
$55,000
$60,000
$65,000
$70,000
$75,000
$80,000
Total >=65 Diabetic Dialysis<2 yrs
Me
an
pa
tie
nt co
st p
er
ye
ar
Calcium
Sevelamer
p = 0.030
p = 0.028
p = 0.063
N 934 961 428 415 468 484 454 473
Total cost per patient shown
Summary – mortality
• All-cause and cause-specific mortality NS at 3 yrs
• Trend for sevelamer benefit is seen for all-cause and other cause mortality
• CRF and CMS results are consistent using 90-day rule, even though more deaths captured by CMS data
• Significant age interaction seen with all-cause mortality
Summary – hospitalization
Multiple hospitalization (Anderson-Gill)• Dosed population, 90-day rule
– Positive sevelamer effect on all-cause (RR=0.9, p=0.05) and ‘other’ (RR=0.85, p=0.02), but not CV hospitalization
• Dosed population, SC rule– Positive sevelamer effect on all-cause (RR=0.89, p=0.01), infection (RR=0.03) and
“other” (RR=0.86, p=0.02), but not CV hospitalization
• Diabetes: significant interaction in multiple analyses
Hospital days (Poisson regression)• All-cause: Positive sevelamer effect seen with both 90-d (RR=0.84, p=0.01) and
SC (RR=0.86, p=0.02)• Infection: Positive trend with 90-d (RR=0.78, p=0.06), positive effect with SC
(RR=0.76, p=0.02)• ‘Other’: Positive effect with 90-d (RR=0.81, p=0.04) only, trend with SC
(RR=0.86, p=0.11)
Summary – morbidity
• First morbidity (adjusted, Cox regression): – All RR (when no interactions) <1 favouring sevelamer, but all are NS
– Scattered interactions; not consistent
• Multiple morbidity (adjusted, Anderson-Gill model):– All HR < 1 favoring sevelamer, but all are NS
– Scattered interactions; not consistent
Conclusions
• There was no statistically significant difference for all-cause mortality overall.
– All-cause mortality was significantly reduced by 19% in patients over 65 years.
• All-cause hospitalisation was significantly reduced by 10 %.
• Overall, sevelamer resulted in less Medicare expenditure, reducing inpatient expenditure by 12.0% annually.
• Expenditures were consistently less for sevelamer in sub-groups, including:
– older patients
– diabetic patients
– patients on dialysis for at least 2 years.
DCOR study: CMS-based data analysis
Principal Investigator Wendy L. St. Peter, Pharm.D., FCCP, BCPS
Principal BiostatisticianJiannong Liu, Ph.D.
BiostatisticiansQiao Fan, M.S. and Eric Weinhandl, M.S.
Company Chronic Disease Research Group
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Discussion and Conclusions
Great Fosters, UK28th -29th June 2006
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Debrief Day OneWorkshop One: Weighing the Evidence
Great Fosters, UK28th -29th June 2006
Group A: Orangery Group B: Mowbray
Share Discussion from Workshop One
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Renagel Health Economics Advisory Board
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What Price Health?What Price Health?The case for sevelamerThe case for sevelamer
Heba Elgazzar MScHeba Elgazzar MSc
Global Health Outcomes GenzymeGlobal Health Outcomes Genzyme
OverviewOverview
ContextContext
Health Economic AnalysisHealth Economic Analysis
Conclusions and QuestionsConclusions and Questions
ContextContext
Health Care in CKDHealth Care in CKD
Health Care in CKDHealth Care in CKD
WHO Goal by 2015: Reduce mortality in chronic
diseases by 2% annually
Number of dialysis patients:
1.45 millionSource: WHO ‘Preventing chronic diseases: a vital investment’, 2006; Fresenius Annual Report, 2005.
Health Care in CKDHealth Care in CKD
Dialysis is the only treatment in the world for which all
governments pay.
Source: Jonssen, Pharmacoeconomics 2005.
Annual Resources Per Annual Resources Per CapitaCapita
WHO, 2003; Romão Jr, 2005; USRDS, 2003; IGES 2006; Grun et al, 2004.
$0
$10,000
$20,000
$30,000
$40,000
$50,000
$60,000
$70,000
Brazil USA Germany UK
General
Hemodialysis
Resources per patientResources per patient
Ploth et al, 2003; Romão Jr 2005; Grun et al, 2003.
1. Perceived Medical and Clinical Need: “Is it needed?”
2. Effectiveness: “Does it work?”
3. Budgetary impact and cost effectiveness: “Can we afford it and is it worth it?”
Key Questions asked by Key Questions asked by Health AuthoritiesHealth Authorities
Budgetary impact and cost effectiveness:
Health Economic Health Economic Analysis - AimsAnalysis - Aims
1.1. Demonstrate value-for-moneyDemonstrate value-for-money
2.2. Support reimbursement and Support reimbursement and patient access to health care patient access to health care coveragecoverage
Comparative evidence in Comparative evidence in ESRDESRD
Risk FactorRisk Factor Relative Relative Risk on Risk on
Mortality*Mortality*
InterventionIntervention
Kt/VKt/VVascular accessVascular access
1.161.161.231.23
Dialysis modeDialysis mode
Hg levelsHg levels 1.141.14 ErythropoeitinErythropoeitin
CholesterolCholesterol ---- StatinsStatins
Parathyroid Parathyroid hormonehormone
1.011.01 Vitamin D Vitamin D Cinacalcet Cinacalcet
PhosphatePhosphate 1.11 / 1/041.11 / 1/04 CalciumCalcium
LanthanumLanthanum
SevelamerSevelamer
*Port et al, 2004 DOPPS
Comparative evidence in Comparative evidence in ESRDESRD
Risk FactorRisk Factor Relative Relative Risk on Risk on
Mortality*Mortality*
InterventionIntervention MortalityMortality MorbidityMorbidity Quality Quality of Lifeof Life
Kt/VKt/VVascular accessVascular access
1.161.161.231.23
Dialysis modeDialysis mode ++++ ++++ ++
Hg levelsHg levels 1.141.14 ErythropoeitinErythropoeitin ---- ---- ++
CholesterolCholesterol ----
StatinsStatins ---- ---- ----
Parathyroid Parathyroid hormonehormone
1.011.01 Vitamin D Vitamin D Cinacalcet Cinacalcet
--------
+ + ----
--------
PhosphatePhosphate 1.11 / 1/041.11 / 1/04 CalciumCalcium ---- ---- ----
LanthanumLanthanum ---- ---- ----
SevelamerSevelamer ++ ++ ----
*Port et al, 2004 DOPPS
Health economics of Health economics of Sevelamer —Sevelamer —
Treat-to-Goal Predictive Treat-to-Goal Predictive modelmodelCVD events predicted per 100 patients in long-term:CVD events predicted per 100 patients in long-term:
Huybrechts et al. Value in Health 2005.
0
10
20
30
40
50
60
70
80
All CVD events Fatal CVD events
Ev
en
ts p
er
10
0 p
ati
en
ts
Sevelamer Calcium acetate
12%RR
12%RR
Treat-To-Goal Predictive ModelTreat-To-Goal Predictive Model
Huybrechts et al, 2005, Kidney International; Value-in-Health
Less CVD morbidity
Sevelamer predicted cost-effective
Predicted cost-effectivenessPredicted cost-effectiveness
Source: National Institute for Health and Clinical Excellence, 2002.
Sevelamer
DCOR: Economic DCOR: Economic ImplicationsImplications
Cause-specific hospitalizationsCause-specific hospitalizations ExpenditureExpenditure
DCOR All-cause DCOR All-cause HospitalizationsHospitalizations
0.090.0917 ± 32 17 ± 32 5.85.8
15 ± 2815 ± 285.05.0
Number of Days HospitalizedNumber of Days Hospitalized[per patient year][per patient year] Mean ± SD Mean ± SD Median Median
0.060.062.3 ± 4.92.3 ± 4.91.31.3
2.1 ± 4.42.1 ± 4.41.01.0
Number of HospitalizationsNumber of Hospitalizations[per patient year][per patient year] Mean ± SD Mean ± SD Median Median
p-value*p-value*CalciumCalcium
(N=1007)(N=1007)SevelamerSevelamer(N=1033)(N=1033)VariableVariable
* Wilcoxon rank sum testSuki et al, ASN 2005
Outcomes Benefit and ValueOutcomes Benefit and ValueConclusionsConclusions
50% less mortality over 5 years in incident patients
10% less hospitalisation in prevalent patients over 3 years
22% less mortality in patients over 65 years
34% less mortality in patients treated for at least 2 years
Net cost: - 4.0% to + 1.0% relative to calcium
Economic Evaluation Economic Evaluation QuestionsQuestions
Which treatment effects?Which treatment effects? Follow-up time?Follow-up time? Binder costs – compliance?Binder costs – compliance? Sub-groups?Sub-groups? Quality of life gains (due to less Quality of life gains (due to less
hospitalisation)?hospitalisation)? Sensitivity analysis parameters?Sensitivity analysis parameters?
Cost-Effectiveness Analysis (CEA)
Great Fosters, UK28th -29th June 2006
Jörgen Möller and Paul Trueman
Sevelamer (Renagel) in the Management of CKD: A NICE
Perspective
Paul Trueman29th June 2006
Items for Discussion
Overview Sevelamer and NICE DCOR & RIND for the UK setting Key issues Summary
Overview
Aims To demonstrate the cost-effectiveness of
sevelamer (Renagel) in the management of chronic kidney disease in a UK setting
To incorporate data emerging from the DCOR and/or RIND trials
To ensure that the revised economic model is tailored for use in submission to NICE
Overview
Key Issues for today Comparison of Sevelamer with similar technology
appraisals from NICE; Application of emerging evidence (DCOR/RIND); Utility measurement; Model parameters (population and horizon); Costs.
Case Study: Cinacalcet NICE Review
“Cinacalcet hydrochloride is not recommended for the routine treatment of secondary hyperparathyroidism in patients with ESRD on maintenance dialysis therapy”
Implications for sevelamer Similar patient group, so can we expect a similar decision?
Case Study: Cinacalcet Incremental cost-effectiveness ratio
Manufacturer’s submission = £35,600 Assessment Group’s model:
Base case = £61,900 Inclusion of dialysis costs = £72,000 Alternative assumption = £43,000 Best case = £38,900 Treatment discontinuation = £57,400
“The committee concluded that cinacalcet hydrochloride was unlikely to be a cost-effective use of NHS resources”
Case Study: Cinacalcet Key differences between sevalamer and cinacalcet
Incremental cost-effectiveness ratio Comparator (‘cinacalcet + standard care’ versus ‘standard care
alone’)
“…it did not replace the need for dietary restrictions and the use of other medications such as phosphate binders and vitamin D sterols”
Sevelamer positioned as an alternative calcium containing phosphate binders
Cinacalcet positioned as an adjuvant to other therapies – less potential for cost offsets
Case Study: Cinacalcet Implications for sevelamer
“…there was a lack of data relating to long-term treatment”
“…there was considerable uncertainty in the extent to which intervening to correct derangements in the levels of PTH, calcium and phosphate (in particular by lowering PTH levels) was effective in reducing the risk of adverse events”
“…people on dialysis have many other factors that contribute to their risk of serious adverse events, and these add to the uncertainty in predicting clinical benefits from changes in surrogate markers”
Case Study: Cinacalcet Implications for sevelamer
Reviewing HTA report to determine how utilities, costs and mortality were addressed.
Patient Demographics Applying the DCOR and RIND results to the UK
population
UK (Renal Registry)
DCOR RIND
Age (years)
64.7 60.5 58.0
Male 62.0% 54.4% 63.0%
Patient Demographics
EthnicityUK (Renal Registry)
DCOR RIND
Caucasian 84% 48% 42%
Black 4% 47% 31%
Asian 10% 1% -
Other 3% 4% 27%
Patient DemographicsPrimary cause of ESRD
UK (Renal Registry)
DCOR RIND
Glomerulonephritis 10.4% 10.1% 7.0%
Pyelonephritis 7.0% 2.6% -
Diabetes 18.0% 42.7% 53.0%
Reno-vascular disease
7.5% - -
Hypertension 5.5% 33.3% 20.0%
Polycystic kidney disease
5.4% - -
Patient Demographics
Median vintage (prevalent patients)
UK (Renal Registry)
DCOR RIND
Vintage (years) 2.70 3.16 -
Discussion Point – Outcomes
Key outcomes from DCOR & RINDOutcome Suitable for model?
All-cause mortality Yes, but modelled to specify cause
CV mortality Yes, see above
Hospitalisations Only for costing purposes
Time to 1st hospitalisation No – only use overall rate
Medicare costs No, not representative of ‘real world’
Non-fatal CV events Yes, for quality of life and costing
Non-fatal other events Yes, for quality of life and costing
Change in calcification Not as main outcome (use as marker)
Discussion Point – Outcomes
Currently no utility data for patients with ESRD and adverse events (i.e. myocardial infarction)
Options: Elicit utility scores
Ideal, but insufficient time Obtain utility scores from literature
Search already undertaken Additional search from York, but no positive findings
Based on assumptions i.e. multiplicative (or additive) effect of AEs + ESRD, with
extensive discussion No use of utility (i.e. use life years only)
Discussion of likely impact (i.e. overestimation of benefits)
Discussion Point - Scenarios
Subgroup analysis Incident / prevalent patients Vintage Age Pre-end stage renal disease
Time horizon Lifetime (captures long-term benefits) Five-year analysis (to address issues relating to
lack of long-term data)
Discussion Point - Costing Should we include the cost of dialysis?
This will apply to both treatment arms (i.e. calcium binders and sevelamer)
However, increased life expectancy will be associated with increased costs
Are ‘background costs’ important when considering the cost-effectiveness of sevelamer?
NICE tend to account for all costs We should accommodate an alternative analysis
which includes dialysis costs in order to anticipate the Assessment Group’s approach.
Summary Sevelamer differs from cinacalcet submission
Improved ICER ‘Treatment versus treatment’ analysis, rather than ‘treatment
versus do nothing’
Are DCOR and/or RIND applicable to the UK setting? Approach towards cost-utility analysis Time horizon Subgroup analysis Inclusion of dialysis costs
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006
Workshop Two: CEA Critique
Great Fosters, UK28th -29th June 2006
Group A: Orangery Group B: Mowbray
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Renagel Health Economics Advisory Board
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NICE Discussion
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Renagel Health Economics Advisory Board
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Assessment and Recommendations:Presenting the Evidence to Health
Authorities Country by Country
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Renagel Health Economics Advisory Board
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Meeting Wrap-up
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David Goldsmith
Renagel Health Economics Advisory Board
Great Fosters, UK28th -29th June 2006