CSM-1Patients With and Without ObesityLSM Difference and 95% CI in BP (230, 231 Pooled)†

-8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8

Diastolic BP

Overall (N = 1,191)

Obese (n = 650)

Not obese (n = 537)

Systolic BP

Overall (N = 1,191)

Obese (n = 650)

Not obese (n = 537)

Trough change from baseline at Wk 8, ITT

Favors CC Favors losartan

14

CC = Candesartan cilexetil.Obese = BMI ≥ 30 kg/m2.†Post hoc.ITT population.

CSM-2

Dose Related BP ReductionMean Change in BP From Baseline at 8 Weeks

-15

-10

-5

0

Diastolic Systolic

Mea

n c

han

ge,

mm

Hg

Placebo (n = 53) CC 8 mg (n = 50)

CC 16 mg (n = 51) CC 32 mg (n = 47)

Measured 24 hr postdoseCC = Candesartan cilexetil.*p < 0.001 vs placebo (per protocol population). Note: p < 0.001 for dose response over thedose range studied, 2 mg to 32 mg, for DBP and SBP.

Adapted from Reif M, et al. Am J Cardiol. 1998;82:961-965.

* *

*

**

*

14

CSM-3Comparison of Antihypertensive Efficacy of Candesartan Cilexetil and Losartan Study Design (175)

1

Gradman AH, et al. Heart Disease. 1999;1:52-57.

CS

R 1

75

Fig

1

100 mg100 mg

50 mg50 mg

Placebo run-inPlacebo run-in

32 mg32 mg

16 mg16 mg

0 4 weeks 8 weeks

Losartan

Candesartan cilexetil

RRAANNDDOOMMIIZZEEDD

Randomized, double-blind, multicenter, titration-to-effect, parallel-group design

CSM-4Least Squares Mean Change From Baseline to Week 8: Once-daily vs Twice-daily Candesartan Cilexetil (116)

-16

-14

-12

-10

-8

-6

-4

-2

0

CC 16 mg QD CC 8 mg BID Placebo

Me

an

ch

an

ge

fro

m b

as

elin

e, m

m H

g

Trough diastolic BP

Trough systolic BP

(n = 90) (n = 93) (n = 91)

*p < 0.001 versus placebo for each treatment.Zuschke C et al. Clin Ther. 1999; 21:464-474.

*

**

*p = NS

p = NS

15

CSM-5

Mean Change in Trough Diastolic Blood Pressure from Baseline to Week 4 (Weber)

-12

-10

-8

-6

-4

-2

0

2

Placebo (n = 30)

Losartan 50 mgQD (n = 29)

Losartan 100mg QD (n = 28)

Losartan 50 mgBID (n = 30)

*p < 0.05 vs placebo** p < 0.01 vs placebo

100.3 100.0 101.1 101.4BaselineDBP, mm Hg

Weber MA, et al. Arch Intern Med. 1995;155:405-411.

17

*

****m

m H

g

CSM-6Patients With and Without DiabetesLSM Difference and 95% CI in BP (230, 231 Pooled)†

-8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8

Diastolic BP

Overall (N = 1,191)

Diabetes (n = 107)

No diabetes (n = 1,084)

Systolic BP

Overall (N = 1,191)

Diabetes (n = 107)

No diabetes (n = 1,084)

Trough change from baseline at Wk 8, ITTFavors CC Favors losartan

14

†Post hoc.ITT population. CC = Candesartan cilexetil.

CSM-7

Subpopulations Trough Diastolic Blood Pressure (230, 231)

Population N N N N

Overall 284 (–10.4) 280 (–9.0) 321 (–11.0) 306 (–8.9)

Black 57 (–6.4) 52 (–7.7) 57 (–8.2) 47 (–6.6)

Non-Black 227 (–11.4) 228 (–9.3) 264 (–11.6) 259 (–9.4)

Age ≥ 65 yr 58 (–8.7) 50 (–8.7) 52 (–11.1) 47 (–8.1)

Age < 65 yr 226 (–10.9) 230 (–9.1) 269 (–11.0) 259 (–9.1)

Female 118 (–11.1) 121 (–9.8) 137 (–11.3) 127 (–9.9)

Male 166 (–9.9) 159 (–8.4) 184 (–10.9) 179 (–8.3)

CC = Candesartan cilexetil.ITT population.

CS

R 2

30

, 2

31

Ta

ble

26

C

mm Hg

Study 230 Study 231

CC Losartan CC Losartan

CSM-8Mean Change From Baseline to Week 8 in Diastolic Ambulatory Blood Pressure (CHAMP)

Lacourcière Y & Asmar R for the Candesartan/Losartan Study Investigators. Lacourcière Y & Asmar R for the Candesartan/Losartan Study Investigators. Am J Hypertens.Am J Hypertens. 1999;12:1181-1187.1999;12:1181-1187.

00

––22

––44

––66

––88

––1010

––1212

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828 3030 3232 3434 3636

Time after dose, hrTime after dose, hr

2

Candesartan cilexetil 16 mg (n = 106)Losartan 100 mg(n = 100)

Mea

n C

han

ge

in D

BP

, mm

Hg

Mea

n C

han

ge

in D

BP

, mm

Hg

CSM-9Mean Change From Baseline to Week 8 in Systolic Ambulatory Blood Pressure (CHAMP )

Lacourcière Y & Asmar R for the Candesartan/Losartan Study Investigators. Lacourcière Y & Asmar R for the Candesartan/Losartan Study Investigators. Am J Hypertens.Am J Hypertens. 1999;12:1181-1187.1999;12:1181-1187.

0

–2

–4

–6

–8

–10

–12

–14

–16

–18

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Candesartan cilexetil 16 mg (n = 106)Losartan 100 mg(n = 100)

Time after dose, hr

Mea

n C

han

ge

in S

BP

, mm

Hg

Mea

n C

han

ge

in S

BP

, mm

Hg

2

CSM-10Change From Baseline for Serum Chemistry and Hematology Parameters in Randomized Patients

Study 230 Study 231

Parameter CC Losartan CC Losartan

ALAT, U/L 1.7 1.1 1.4 1.8

Alkaline phos, U/L 0.4 3.1 0.5 2.3

ASAT, U/L 1.1 –0.7 –0.7 0.1

Bilirubin total, mg/dL 0.0 0.0 0.0 0.0

Creatinine, mg/dL 0.0 0.0 0.0 0.0

Potassium, mEq/L 0.0 0.0 0.1 0.1

Urea nitrogen, mg/dL 0.8 0.8 0.8 0.5

Uric acid, mg/dL –0.1 –0.6 0.0 –0.5

HCT, % –0.5 –0.3 –0.2 –0.2

Hb, g/dL –0.2 –0.1 –0.1 –0.1

WBC, 103/µL –0.1 0.1 0.1 0.1

1C

SR

23

0,

23

1 T

ab

le 3

2

CC = Candesartan cilexetil.Safety population.

CSM-11

Patient Compliance† (230)

Compliant, n (%)

Treatment < 90% ≥ 90% Total, N

Candesartan cilexetil 28 (9) 279 (91) 307 (100)

Losartan 17 (6) 287 (94) 304 (100)

Total 45 (7) 566 (93) 611 (100)

7

†Based on tablet counts.

CSM-12

BP Determination Methods (230, 231)

Patients: sitting for 5 minutes Sphygmomanometer: Hg column, appropriate cuff

size at heart level, right arm Readings: Systolic = Korotkoff I

Diastolic = Korotkoff V Determination

• Mean of 3 sequential readings ≥ 2 minutes apart with ≤ 5 mm Hg highest to lowest value

Qualifying blood pressure: diastolic 95 to 114 mm Hg at Wk 3 and 4 (or 4 and 5) of placebo run-in period

CSM-13

Controlled Patients and Responders at Week 8 (Pooled)

51%

36%

48%

58%

45%

31%

46%51%

0

20

40

60

80

Controlled DBP Controlled DBP &SBP

Controlled SBP Responder

Pe

rce

nt

Candesartan cilexetil Losartan

N = 639 N = 625 N = 639 N = 625 N = 639 N = 625 N = 639 N = 625

Control DBP: DBP < 90 mm Hg; Control: SBP < 140 mm Hg; Control DBP and SBP: DBP < 90 mm Hg and SBP < 140 mm Hg; Responder: DBP < 90 mm Hg or DBP ≥ 10 mm Hg decrease.

19

CSM-14

Regulatory Precedent ZESTRIL®/Prinivil® Comparative Studies

Lisinopril vs HCTZ vs lisinopril + HCTZ Multicenter, randomized, parallel, double-blind,

titration-to-effect, 24 wk with extension 390 patients with mild to moderate HTN

(DBP 90 to 120 mm Hg) Lisinopril 20 to 80 mg, HCTZ 12.5 to 50 mg or lisinopril

20 mg + HCTZ 12.5 to 80 mg + 50 mg Primary endpoint: mean reduction in diastolic BP Significant reductions in systolic and diastolic BP at Wk

12 and 24: HCTZ + lisinopril (–18.2 mm Hg) > lisinopril (–12.5 mm Hg) > HCTZ (–6.8 mm Hg) (p 0.01)