Helical/Spiral CT. 2-4 slice 8-16 slice 16-32 slice 32-64 slice Helical/Spiral CT.

Helical/Spiral CT

2-4 slice

8-16 slice

16-32 slice

32-64 slice

Helical/Spiral CT

Arterial Calcification on Plain X-Rays

http://s4.tcs.tulane.edu:2278/cgi/content/full/16/8/978/F1

Arterial Calcification Increases Mortality Risk

‡Carotid artery, abdominal aorta, iliofemoral axis, and legs P<0.0001 for each increase in number of arteries calcified

n=110

1

Follow-up (months)

0

0.25

0.5

0.75

0 20 40 60 80

Pro

bab

ility

of

surv

ival

0 arteries‡ calcified

1 artery calcified

2 arteries calcified



73% mortalityin patients with4 arterial sites

calcified

Blacher J, Guerin AP, Pannier B et al. Hypertension 2001;38:938-942

Other Types of Calcification Predict Risk in CKD-5

Wang A, JASN 2003

Valve Calcification Predicts All-Cause Mortality and Cardiovascular Mortality in Peritoneal

Dialysis Patients

Wang AYM et al. JASN 2003

Follow-up time (months)

363024181260

Cumu

lative

Sur

vival

(%)

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Valves calcifed

Both Mitral and

Aortic

Either Mitral or

Aortic

Neither

P<0.0005

Follow-up time (months)

363024181260

Cum

ulat

ive

Sur

viva

l (%

)

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Valves Calcified

Both Mitral and

Aortic

Either Mitral or

Aortic

Neither

P<0.0005

All-Cause Mortality Cardiovascular Mortality

How Do these Methods Correlate?

Abdominal Aorta X-ray Score

ROC characteristics for a + abdominal X-ray score predicting a CACS> 30

Sensitivity= 0.74

Specificity= 0.77

L1

L2

L3

L4

Bellasi A. et al, KI 2006

Impacting Outcome in CKD

Sevelamer attenuates the progression of coronary artery and aorta calcification in

hemodialysis patients

Chertow GM, Burke SK, Raggi P, and the Treat to Goal Working Group

Kidney Int Vol 62; 2002

Treat-to-Goal Study Study Design

BL EBCT

Titrate dose:P=3.0-5.0 mg/dLCa <10.5 mg/dL

26 wk EBCT

Titrate dose:P=3.0-5.0 mg/dLCa < 10 mg/dL

PTH 150-300 pg/mL

Vitamin D if PTH >300 pg/mLIf P >5.5 mg/dL

2 weeks 12 weeks 40 weeks

Calcium binder Extended treatmentWashout

Extended treatmentSevelamerWashout

52 wk EBCT

Chertow GM et al. Kidney Int 2002;62:245-252

Randomize

Treat-to-Goal StudyBaseline Demographics

Smoker

Diabetes

BMI (kg/m2)

Sex (% male)

Time on dialysis (years)

Age (years)

8%

33%

26 ± 5

66%

2.9

56 ± 16

Calcium

3%

32%

26 ± 5

64%

3.6

57 ± 14

Sevelamer

Race (% white) 66% 71%


Mea

n s

eru

m p

ho

sph

oru

s (m

g/d

L)

Treatment (weeks)

-3 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 16 20 24 28 32 36 40 44 48 524.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0Sevelamer (S): 6.5 g/day (~8 800 mg tablets) Calcium acetate (C): 4.6 g/day (~7 667 mg tablets)

S=5.1 C=5.1

Treat-to-Goal StudySerum Phosphorus


Treat-to-Goal StudySerum Calcium

Study (weeks)

-2 0 3 6 9 12 16 20 24 28 32 36 40 44 48 52

10.5

10.0

9.5

9.0

8.5

S=9.50C=9.70

S = 9.40C = 9.30

Sevelamer Calcium


Mea

n s

eru

m c

alci

um

(m

g/d

L)

Serum Ca x P Product

Study Week

-2 0 3 6 9 12 16 20 24 28 32 36 40 44 48 52

Ser

um C

alci

um x

Pho

spho

rus

Pro

duct

(m

mol

2 /L

2 )

3.5

4.0

4.5

5.0

5.5

6.0

6.5

S=5.72C=5.59

S=3.88C=4.00

Calcium Sevelamer

Treat-to-Goal StudyCoronary Artery and Aortic Calcification

CalciumSevelamer

Coronary artery Aorta

*Within treatment P<0.0001; between treatment groups P=0.02


0

6

14*

25*

0

5

10

15

20

25

30

Week 26 Week 52

Med

ian

% c

han

ge

1

5

24*

28*

0

5

10

15

20

25

30

35

Week 26 Week 52

Me

dia

n %

ch

an

ge

Between group: P=0.03 (coronary), P=0.01 (aorta)

Sevelamer Calcium

Med

ian

ch

ang

e (%

)

-7%

0

10

20

30

40

60

70

90

20%

83%

66%

-10

-5

50

80

Coronary artery Aorta

P=NS

P=NS

P<0.0001

P<0.0001

Treat-to-Goal Study: 2-Year European Data Coronary Artery and Aortic Calcification

Asmus HG et al. NDT 2005; 20:1653-1661

“RIND trial”

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 versus calcium containing phosphate binders on the development and progression of coronary artery calcification.

Block G et al Kidney International, Vol68(4): 1815-1824 (2005)

Materials and methods

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.


Patients New to Dialysis and Established Patients

Prevalence of Coronary Calcification in CKD

*Russo D et al Am J Kidney Dis 2004;44:1024-1030 (CrCl =33 ml/min)**Spiegel D et al. Hemod Internat 2004: 8:265*** Chertow GM et al. Kidney Int 2002;62:245-252

40%*

57%**

83%***

0%

20%

40%

60%

80%

100%

Russo et al RIND TTG

Results: medication P-binders use:

– Of the 55 patients in the calcium arm, 38 received calcium carbonate only, 3 received calcium acetate only, and 14 received both medications during the 18-month study period.

– The average dose of Sevelamer was 8 g/day (10 pills), and the average dose of calcium was 5.75 g of CaCO3 or 9.2 g of Ca-acetate

Vitamin D use: slightly higher use in the Sevelamer group, but not statistically significant. Average doses were similar in both groups.

Statins: There were no statistically significant differences in the use of statins between the two groups.


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

Ser

um

ph

osp

ho

rus

Renagel Calcium

Block, GA et al. Kidney Int 2005; 68:1815-1824

average dose 8 g/dayaverage dose elemental Ca 2.3 g/day

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

Ser

um

cal

ciu

m (

alb

.co

rrec

ted

)

Renagel Calcium

Block, GA et al. Kidney Int 2005; 68:1815-1824

Results: Coronary Calcification

0

20

40

60

80

100

120

140

Sevelamer Ca Salts

SevelamerCa Salts

P<0.002


11x greater increase

Results: Median Coronary Artery Calcium Score

0

50

100

150

200

250

300

350

Baseline 6 months 12 months 18 months

Me

dia

n C

AC

S

Sevelamer Calcium

N=45

N=54N=55

N=51

N=53

N=45

N=47

N=40

N=45


Median Change in Total Coronary Artery Calcium Score by Diabetic Status-RIND

Sev

elam

er

Cal

cium

Sev

elam

er

Cal

cium

020406080

100120140160180

6 months

12 months

18 months

Diabetes

Med

ian

Ch

ang

e in

T

ota

l CA

CS

No Diabetes

PTH=293

PTH=229

P=0.038

P=0.015

Galassi A et al NDT 2006

Russo D, Kid Int, Advance Online, 5 September 2007

Progression of coronary artery calcification in predialysis patients with CaCO3 or Sevelamer

800P =0.001

P =0.001 NS

Initial

Final750

650

550

450

350

250

150

700

600

500

400

300

200

10050

0

Controls(n =29)

Sevelamer(n =27)

Calciumcarbonate(n =28)

TC

S

Figure 2: Initial (white bars) and final (dark bars) absolute TCS incontrols (n = 29) and in patients assigned to calcium carbonate(n = 28) and sevelamer (n =27). Numbers are mean and s.e.

Russo D, Kid Int, Advance Online, 5 September 2007

Annual progression of coronary artery calcification in predialysis patients

Controls(n=29)

Sevelamer(n=27)

Calciumcarbonate

(n=28)

TC

S

020406080

100120140160180200220240260280

320300

Figure 3: Annualized progression of TCS in controls (n = 29) and in patients assigned to calcium carbonate (n = 28) and sevelamer (n = 27).Numbers are mean and s.e.

RIND mortality

Baseline Coronary Artery ScoreIs a Strong Predictor of Mortality

0

20

40

60

80

100

Per

cen

t S

urv

ival

0

20

40

60

80

100

Per

cen

t S

urv

ival

Days

0 365 730 1095 1460 1825 2190

n=129

P=0.0035

Zero

<400

>400

Block GA et al. KI 2007

Increased Mortality in Patients Randomized to Calcium vs Sevelamer

0

20

40

60

80

100

Per

cen

t S

urv

ival

Days

0 365 730 1095 1460 1825 2190

n=129

P=0.0214

Sevelamer

Calcium

Cox Proportional Hazard Regression Model

Age

Race

Gender

Diabetes

Baseline CCS

Calcium vs. Sevelamer p=0.02 (HR 2.2)

Block GA et al. KI 2007

The Dialysis Clinical Outcomes Revisited (DCOR) Trial

Suki WN et al. Effects of Sevelamer and Calcium-Based Phosphate Binders on Mortality in Hemodialysis Patients

Kidney Int 2007;online Aug 29th

Study Design Primary study endpoint

– all-cause mortality

Secondary study endpoints

– cause-specific mortality (cardiovascular, infection, and other causes), and

– all-cause hospitalizations

Treatment interactions with each of the pre-defined prognostic factors were assessed: race, age (<65 or ≥65 years), sex, diabetes, primary cause of ESRD, and dialysis vintage

– a statistically significant interaction was required as a gating step prior to strata-specific subset analysis

Patient Disposition

*Did not discontinue from study prior to death or study cessation. In addition, 11 sevelamer patients and 18 calcium patients who discontinued early died during the 90-day follow-up period and were included in the mortality analyses (sevelamer, N=562; calcium, N=535).

RandomizedN = 2103

SevelamerN = 1053

Calcium-based binder N = 1050

Terminated Early (N=533)• Consent withdrawn (n=83)• Investigator decision (n=151)• Lost to follow-up (n=99)• Adverse event (n=50)• Renal transplant (n=46)• Changed dialysis modality (n=26)• Clinical site closure (n=19)• Other (n=70)

Completed study*N = 517

Terminated Early (N=502)• Consent withdrawn (n=69)• Investigator decision (n=94)• Lost to follow-up (n=108)• Adverse event (n=81)• Renal transplant (n=59)• Changed dialysis modality (n=22)• Clinical site closure (n=22)• Other (n=47)

Completed study*N = 551

All-Cause Mortality Overall Study Population

Time (Years)

Cu

mu

lati

ve I

nci

de

nce

of

All

-Cau

se M

ort

alit

y

CalciumSevelamer

1050 640 430 161 1053 656 449 196

No. at Risk

1 2 3 40

0.0

0.1

0.2

0.3

0.4

0.5

0.6

SevelamerCalcium

p = 0.40

HR = 0.93 (0.79 - 1.10)

For patients on treatment for 2 years, a difference between groups appears to emerge

(time-treatment interaction, p = 0.02)

All-Cause Mortality

0 1 2 3 40

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Time (Years)

Cu

mu

lati

ve I

nci

de

nce

of

All

-Cau

se M

ort

alit

y

p = 0.02

HR = 0.77 (0.61- 0.96)

Patients 65 Years

Time (Years)

1 2 3 400

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

SevelamerCalcium

p = 0.21

HR = 1.18 (0.91- 1.53)

Patients <65 Years

SevelamerCalcium

CalciumSevelamer

472 274 185 62 455 275 196 97

No. at Risk578 366 245 99 598 381 253 99

Multiple hospitalizations

1.7

1.9

1

1.5

2

Mu

ltip

le h

os

pit

aliz

ati

on

ra

te

(/p

ati

en

t-y

ea

r)Multiple hospitalizations

1.7

1.9

1

1.5

2

Mu

ltip

le h

os

pit

aliz

ati

on

ra

te

(/p

ati

en

t-y

ea

r)

A Comparison of Sevelamer and Calcium-Based Phosphate Binders on Hospitalization in Hemodialysis: Secondary

Analysis of DCOR Using Claims Data

Sevelamer Calcium

Unadjusted RR (referent: calcium) 0.90, P=0.03Adjusted RR* (referent: calcium) 0.89, P=0.02*Adjusted for demographic variables and prestudy cardiovascular comorbidity.

St. Peter W, Liu J, Weinhandl E, et al. AJKD 2008;51:445-454

Hospital Days

12.3

13.9

10

12

14

Ra

te f

or

ho

sp

ita

l da

ys

(/

pa

tie

nt-

ye

ar)

Hospital Days

12.3

13.9

10

12

14

Ra

te f

or

ho

sp

ita

l da

ys

(/

pa

tie

nt-

ye

ar)

Sevelamer Calcium

Unadjusted RR (referent: calcium) 0.88, P=0.05Adjusted RR* (referent: calcium) 0.88, P=0.03*Adjusted for demographic variables and prestudy cardiovascular comorbidity.

St. Peter W, Liu J, Weinhandl E, et al. AJKD 2008;51:445-454

A Comparison of Sevelamer and Calcium-Based Phosphate Binders on Hospitalization in Hemodialysis: Secondary

Analysis of DCOR Using Claims Data

What happened to the BONE?

Treat-to-Goal StudySerum Intact Parathyroid Hormone

Study (weeks)-2 0 12 16 20 24 28 32 36 40 44 48 52

0

50

100

150

200

250

300

350

400

Sevelamer Calcium

PTH below targetS=30%C=57%P=0.001


Med

ian

ser

um

iP

TH

(p

g/d

L)

Time 0 1 & 2 Years f/u

Change in vertebral bone density

-8

-6

-4

-2

0

2

4

6

Sevelamer Calcium saltsTrabecularCortical

*

**P<0.05

%

ch

ang

e (h

ou

nsf

ield

un

its)

5%

2%

-7%

-2%

Raggi P. J Bone Min Res 2005;20:764-772

Total Hip Bone Mass Predicts Survival in Patients with CKD Stage 5

Survival (d)Survival (d)

14001400120012001000100080080060060040040020020000

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

NormalNormal

Osteopenia (T-score -1.0 – 2.5 SD)Osteopenia (T-score -1.0 – 2.5 SD)

Osteoporosis(T-score >-2.5 SD)Osteoporosis(T-score >-2.5 SD)

N=88P=0.03N=88P=0.03

Taal et al. Kidney Int. 2003;63: 1116-1120Taal et al. Kidney Int. 2003;63: 1116-1120

Summary

CVC is highly prevalent in CKD 5 CVC is linked with a poor prognosis in CKD 5 Sevelamer stopped progression of CVC in maintenance

HD pts (2002) Sevelamer inhibited progression of CVC in new

hemodialysis pts (2005) Sevelamer inhibited progression of CVC in pre-dialysis pts

(2007) Calcium salts were associated with reduced and

sevelamer with increased vertebral trabecular bone density (2005)

Renvela: New sevelamer “without” HCl and GI symptoms RIND: Sevelamer reduced mortality [HR: 2.2] (2007) DCOR: Pts >65 y/o treated w/ Sevelamer had fewer deaths,

fewer hospitalizations, lower overall cost of care (2008)

Wash-out up to 6 weeks

Sevelamer +/- Atorvastatin (N= 100 patients)

Ca Acetate + Atorvastatin (N= 103 patients)

EBCT Baseline EBCTWeek 26

1:1 randomization

Discontinuation of: all P-binders Ca supplements lipid-lowering agents vit D analogues

Randomized if: Serum P > 5.5 mg/dl LDL-C > 80 mg/dl Baseline EBCT score 30-

7000

P-binder: dose titration to achieve level of 3.5-5.5 mg/dl PTH target 150-300 pg/ml Dialysate Ca level maintained at 2.5 mEq/L throughout study

period

EBCTWeek 52

CARE-2 Study Design

Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008

Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Kidney Int. 2002;62:245-252.

0%

6%

14%

25%

0%

5%

10%

15%

20%

25%

30%

6 months 12 months

Med

ian

% C

han

ge

in C

AC

Sevelamer Calcium

*Within treatment P<0.001

*

*

Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008; Advance On Line

n = sev 100 80 68 n = ca 103 71 58

*Significant within treatment

14%

30%

20%

29%

0%

5%

10%

15%

20%

25%

30%

35%

6 months 12 monthsM

edia

n %

Ch

ang

e in

CA

C

Sevelamer Calcium Acetate

CARE 2

**

*

*

Treat to Goal

Change in Coronary Artery Calcium Score

100

150

200

250

300

350

400

450

500

550

0 30 60 90 120

150

180

210

240

270

300

330

360

100

150

200

250

300

350

400

450

500

550

0 30 60 90 120150180210240270300330360

1. Chertow GM et al. Kidney Int. 2002;62:245-252;2. Qunibi W et al. Am J Kidney Dis. 2008; 51:952-965.

Treat to Goal CARE-2

Lo

g M

ean

iPT

H (

pg

/mL

)

Study day Study day

PTH Levels in TTG and CARE-2

SevelCalcium

Observed increase: 2.3%/y

Question 2

The administration of non-calcium-based phosphate binders results in slowing of cardiovascular calcification only in de novo dialysis patients

1. True

2. False

Question 2

The administration of non-calcium-based phosphate binders results in slowing of cardiovascular calcification only in de novo dialysis patients

1. True

2. False - CORRECT

Question 4

The multivariable adjusted mortality with sevelamer treatement in RIND was:

1. 3.1-fold higher than with calcium-based binders

2. 4.7-fold lower than with calcium-based binders

3. Not significantly different compared with calcium-based binders

4. 2.2-fold lower than calcium-based binders

Question 4

The multivariable adjusted mortality with sevelamer treatement in RIND was:

1. 3.1-fold higher than with calcium-based binders

2. 4.7-fold lower than with calcium-based binders

3. Not significantly different compared with calcium-based binders

4. 2.2-fold lower than calcium-based binders - CORRECT

Question 5

In the DCOR study, the progression of vascular calcification among calcium salts and sevelamer-treated patients was the same

1. True

2. False

Question 5

In the DCOR study, the progression of vascular calcification among calcium salts-treated and sevelamer-treated patients was the same

1. True

2. False - CORRECT

Question 6

In DCOR, the survival of patients above and below age 65 was a pre-specified end-point at the time of study design

1. True

2. False

Question 6

In DCOR, the survival of patients above and below age 65 was a pre-specified end-point at the time of study design

1. True - CORRECT

2. False

Question 7

At the conclusion of this meeting:

1. I know much more about the current issues regarding dialysis patients

2. I am EXTREMELY BORED with dialysis talks

3. I am going to the pharmacy IMMEDIATELY to buy Sevelamer for my own use!

4. I am going to leave my job and get a new one with Genzyme VenCAC

5. ……I want to be like RAGGI when I grow up!

P Evenepoel, Kidney International (2007) 71, 376–379.

The Pleiotrophic Activites of SevelamerThe Pleiotrophic Activites of Sevelamer

Helical/Spiral CT. 2-4 slice 8-16 slice 16-32 slice 32-64 slice Helical/Spiral CT.

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