# Presentation: 926946

## Comparison of the Antihypertensive Efficacy of Candesartan Cilexetil and Losartan

**Vasilios Papademetriou, MD, DSc, FACC**
**Professor of Medicine ****Georgetown University **
**Director of Hypertension and Cardiovascular Research****VA Medical Center, Washington, DC**

## The Renin-Angiotensin System

**ACE = Angiotensin-converting enzyme; ARB = Angiotensin receptor blocker; **
**CAGE = Chymase-angiotensin generating enzyme.**
**Adapted from Hollenberg 1998.**

## Initial Comparative Studies in Hypertensive Patients

**Two randomized, double-blind, multicenter, controlled, parallel-group, 8-wk studies in patients with a mean sitting DBP of 95 to 114 mm Hg**

**SH-AHM-0001 (n = 337)**
**Candesartan cilexetil**
**8 mg QD**
**Candesartan cilexetil**
**16 mg QD**
**Losartan 50 mg QD**
**Placebo QD**

**Study 175 (n = 332)**
**Candesartan cilexetil 16 mg titrated as needed****†**** to 32 mg QD**
**Losartan 50 mg titrated as needed****†**** to 100 mg QD**

**†****At 4 wk if mean sitting DBP ≥ 90 mm Hg.**

## Change in Trough Diastolic Blood Pressure at Wk 8

**∆ –****3.7**
**95% CI: (–6.7, –0.8)**
***p***** = 0.013**

**∆ –****2.2**
**95% CI: (–3.9, –0.4)**
***p***** = 0.016**

**†****Placebo-corrected.**
**Anderson et al. *****Blood Pressure*****. 1998;7:53-59.**
**Gradman et al. *****Heart Disease*****. 1999;1:52-57.**

**16 mg**

**50 mg**

**16 to **
**32 mg**

**50 to**
**100 mg**

**†**

**†**

## CLAIM Program 

**Evaluate antihypertensive efficacy of candesartan cilexetil in comparison with ****losartan in hypertensive patients**
**Replicated in 2 studies (230 and 231)**
**Maximum recommended daily dose administered once-daily, in the approved label for both drugs**
**Forced-titration design**

**C**

## Design of Studies 230 and 231

**Losartan**

**50 mg**

**100 mg**

**Design of Studies 230 and 231**

**1**

**†****Randomization visit (placebo run-in Wk 4 or optional placebo run-in Wk 5).**

**Visit**

**0**

**1**

**2**

**3**

**Placebo**

**Run-in wk**

**4 (5)**

- CSR 230, 231 Fig 1

**0****†**

**1**

**2**

**4**

**8**

**2 wk**

**48 hr**

**R**
**A**
**N**
**DO**
**M**
**I**
**Z**
**E**
**D**

**Double-blind wk**

**16 mg**

**32 mg**

**Candesartan cilexetil**

**Follow-up**

**Randomized, double-blind, multicenter, forced-titration, ****parallel-group design**

## Inclusion Criteria (230, 231)

**Age 18 to 80 yr, male, or female without childbearing potential or using appropriate birth control measures**
**Essential hypertension**
**Mean DBP 95 to 114 mm Hg on 2 consecutive visits at the end of placebo run-in period**

**2**

- CSR 230, 231 Section 9.3.1

## Key Exclusion Criteria (230, 231)

**Blood pressure ≥ 180 mm Hg systolic **
**Myocardial infarction, coronary bypass, stroke, ****or transient ischemic attack within 6 months **
**Coronary angioplasty within 3 months **
**Angina requiring more than short-acting nitrates**
**Hemodynamically significant valvular disease**
**Other prescription treatments for blood pressure **
**Persistent ASAT or ALAT > 3 times ULN**
**Serum creatinine > 2.0 mg/dL**

**2**

- CSR 230, 231 Section 9.3.2

**ASAT = Aspartate aminotransferase; ALAT = Alanine aminotransferase;**
**ULN = Upper limit of normal.**

## Efficacy Endpoints (230, 231)

**Primary**
**Change from baseline to Wk 8 in trough sitting diastolic blood pressure (DBP)**
**Secondary**
**Change from baseline to Wk 8 in trough sitting systolic blood pressure (SBP)**
**Change from baseline in peak DBP and SBP **
**Trough to peak ratio for change from baseline in DBP**
**Proportions of patients “controlled” and “responders” **
**Change from baseline to 48 hr postdose in ****DBP and SBP at Wk 8**

**C**

## Definitions (Per Protocol)

**	****Trough****	****(Drug effect) 24 ± 3 hr postdose**
**	****Peak****	****(Drug effect) 6 ± 2.5 hr postdose**
**	****Controlled****	****Trough sitting DBP < 90 mm Hg**
**	****Responders****	****Trough sitting DBP < 90 mm Hg or ****≥ 10-mm Hg decrease from baseline**

## Statistical Analysis (230, 231)

**Analysis of covariance (ANCOVA) for change**
**from baseline to Wk 8 in trough DBP**
**Intent-to-treat (ITT) population/LOCF analysis**
**ANCOVA model included treatment, center, and center-by-treatment interaction; and baseline DBP as covariate**
**Differences between treatments presented as least squares means (LSM)**

**1**

## Sample Size Calculation (230, 231)

**Detect 2 mm Hg difference between treatments in DBP (SD = 7.5 mm Hg)**
****** ****= 0.05 (2-tailed test)**
**Power = 95% **
**Planned to randomize 735 patients per study**
**Actual enrolled 613 patients (Study 230); ****655 patients (Study 231)**

- Briefing Book, Table 1

**C**

## Disposition of Patients (230)

**Disposition of Patients (230)**

**Screened****926**

**Randomized****613**

**Losartan****304**

**Discontinued study****39 (12.7%)**

**Completed study****268 (87.3%)**

**Completed study****267 (87.8%)**

**2**

**Lost to follow-up****5 (1.6%)**
**Lack of response****8 (2.6%)**
**Adverse event****11 (3.6%)**
**Consent withdrawn****10 (3.3%)**
**Sponsor/investigator decision****5 (1.6%)**

**Lost to follow-up****4 (1.3%)**
**Lack of response****13 (4.3%)**
**Adverse event****6 (2.0%)**
**Consent withdrawn****8 (2.6%)**
**Sponsor/investigator decision****6 (2.0%)**

**CES-**

**Discontinued study****37 (12.2%)**

**Candesartan cilexetil****309**

**Postbaseline contact**
**307****†**

**Postbaseline contact****304**

**†****2 patients discontinued without postbaseline contact.**

## Disposition of Patients (231)

**Disposition of Patients (231)**

**Screened****921**

**Randomized****655**

**Losartan****323**

**Discontinued study****15 (4.5%)**

**Completed study****317 (95.5%)**

**Completed study****302 (93.8%)**

**2**

**Lost to follow-up****2 (0.6%)**
**Lack of response****2 (0.6%)**
**Adverse event****6 (1.8%)**
**Consent withdrawn****2 (0.6%)**
**Sponsor/investigator decision****3 (0.9%)**

**Lost to follow-up****3 (0.9%)**
**Lack of response****5 (1.6%)**
**Adverse event****5 (1.6%)**
**Consent withdrawn****3 (0.9%)**
**Sponsor/investigator decision****4 (1.2%)**

**CES-**

**Discontinued study****20 (6.2%)**

**Candesartan cilexetil****332**

**Postbaseline contact****332**

**Postbaseline contact****322****†**

**†****1 patient discontinued without postbaseline contact.**

## Baseline Demographics

**	****                       ****Study 230****	****	****                        Study 231**
**	****CC****	****Losartan ****	****CC****	****Losartan****	****n = 307****	****n = 304****	****n = 332****	****n = 322**

**Age, yr (SD) ****	****56****	****(10)****	****55****	****(11) ****	****54****	****(11)****	****54****	****(10)**
**	****< 65, n (%)****	****245****	****(80)****	****248****	****(82)****	****278****	****(84)****	****273****	****(85)**
**	****≥ ****65, n (%)****	****62****	****(20)****	****56****	****(18)****	****54****	****(16)****	****49****	****(15)**
**Mean weight, lb (SD)****	****205****	****(44)****	****201****	****(41) ****	****206****	****(47)****	****203****	****(42)**
**Mean duration of****hypertension, yr (SD) ****	****11****	****(9)****	****10****	****(10) ****	****10****	****(9)****	****10****	****(9) **
**Sex, male:female, %****	****58:****	****42****	****59:****	****41****	****58:****	****42****	****58:****	****42**
**Race, n (%)**
**	****Non-Black****	****245****	****(80)****	****245****	****(81)****	****273****	****(82)****	****268****	****(83)**
**	****Black****	****62****	****(20)****	****59****	****(19)****	****59****	****(18)****	****54****	****(17)**

**CC = Candesartan cilexetil.**
**ITT population.**

**1**

- CSR 230, 231 Table 4

## Baseline Blood Pressures, Mean (SD) mm Hg

**	****                       ****Study 230****	****	****                     Study 231**
**	****CC****	****Losartan ****	****CC****	****Losartan ****	****n = 307****	****n = 303****	****n = 332****	****n = 322**

**Trough DBP ****	****100.4****	****(4.3)****	****100.2****	****(4.3)****	****100.1****	****(3.9)****	****99.9****	****(4.2) **
**Trough SBP ****	****153.6****	****(11.7)****	****152.2****	****(12.3)****	****152.6****	****(12.3)****	****152.0****	****(12.6)**

**1**

- Briefing Book, Table 1

**CC = Candesartan cilexetil.**
**ITT population.**

## Primary EndpointLSM Change in Trough Diastolic Blood Pressure at Wk 8

**Primary Endpoint****LSM Change in Trough Diastolic Blood Pressure at Wk 8**

**3**

**Δ –1.5**
**(95% CI: –2.9, –0.06)**
***p***** = 0.0411**

**Δ –2.2**
**(95% CI: –3.4, –1.0)**
***p***** = 0.0005**

- CSR 230, 231 Tables 5

**N = ****	****306****	****303****	****332****	****322**

## Primary and Secondary EndpointsChange in Blood Pressure (230)

**Primary and Secondary Endpoints****Change in Blood Pressure (230)**

**Δ –1.5**
***p***** = 0.0411**

**Δ –3.4**
***p***** = 0.0050**

**Δ**** ****–3.4**
***p***** < 0.0001**

**Δ –3.5**
***p***** = 0.0032**

**Δ –2.8**
***p***** = 0.0002**

**Δ – 4.6**
***p***** = 0.0003**

**Trough**

**Peak**

**48 hr**

- CSR 230, 231 Tables 5, 19

**C**

**†****Primary endpoint.**

## Primary and Secondary EndpointsChange in Blood Pressure (231)

**Primary and Secondary Endpoints****Change in Blood Pressure (231)**

**Trough**

**Peak**

**48-hr**

**Δ –2.2**
***p***** = 0.0005**

**Δ –3.5**
***p***** = 0.0007**

**Δ –1.5**
***p***** = 0.0375**

**Δ –2.6**
***p***** = 0.0170**

**Δ – 4.3**
***p***** < 0.0001**

**Δ –5.9**
***p***** < 0 .0001**

- CSR 230, 231 Tables 5, 19

**C**

**†****Primary endpoint.**

## Mean Trough Diastolic Blood Pressure by Visit

**C**

**	****	****1****	****2****	****4****	****8**

**	****	****1****	****2****	****4****	****8**

**Mean for DBP, mm Hg**

**Visit, wk from randomization**

**Study 230**

**Study 231**

**ITT population.**

## Mean Trough Systolic Blood Pressure by Visit

**C**

**	****	****1****	****2****	****4****	****8**

**	****	****1****	****2****	****4****	****8**

**Mean for SBP, mm Hg**

**Visit, wk from randomization**

**Study 230**

**Study 231**

**ITT population.**

## Trough to Peak Ratios† at Wk 8 for Changes in Diastolic Blood Pressure

**Treatment ****	****Study 230****	****Study 231**
**Candesartan ****cilexetil****	****0.855****	****0.958**
**Losartan****	****0.915****	****0.877****	**

**1**

**ITT population.**

- CSR 230, 231 Table 18

**†****Ratio = **

****** ****in trough DBP from baseline**
****** ****in peak DBP from baseline **

## Controlled Patients and Responders at Wk 8

**Controlled = DBP < 90 mm Hg; Responder = DBP < 90 mm Hg or decrease from baseline ≥ 10 mm Hg; ITT/LOCF population.**

**N =****	****306****	****303****	****306****	****303****	****332****	****322****	****332****	****322**

***p***** = 0.291**

***p***** = 0.103**

***p***** = 0.023**

***p***** = 0.033**

**Study 230**

**Study 231**

**Controlled**

**Responders**

**Controlled**

**Responders**

## SubpopulationsLeast Squares Mean Difference and 95% CI in Diastolic Blood Pressure 

**Non-Black**

**Black**

**Female**

**Male**

**Age < 65 yr**

**Trough change from baseline Wk 8, ITT **

**Age ≥ 65 yr**

**C**

**†****Post hoc; ITT = Intent-to-treat population; CC = Candesartan cilexetil.**

**Favors:**

**Overall**

**-6**

**-4**

**-2**

**0**

**2**

**4**

**6**

**CC**

**Losartan**

**Studies 230/231 pooled****†**

**CC**

**Losartan**

**-6**

**-4**

**-2**

**0**

**2**

**4**

**6**

**Study 230**

**-6**

**-4**

**-2**

**0**

**2**

**4**

**6**

**CC**

**Losartan**

**Study 231**

**N = 564**

**n = 456**

**n = 108**

**n = 325**

**n = 239**

**n = 109**

**n = 455**

**N = 627**

**n = 528**

**n = 363**

**n = 264**

**n = 523**

**n = 104**

**n = 99**

**N = 1,191**

**n = 984**

**n = 688**

**n = 503**

**n = 978**

**n = 213**

**n = 207**

## SubpopulationsLeast Squares Mean Difference and 95% CI in Systolic Blood Pressure 

**Non-Black**

**Black**

**Female**

**Male**

**Age < 65 yr**

**Trough change from baseline Wk 8, ITT **

**Age ≥ 65 yr**

**C**

**†****Post hoc; ITT = Intent-to-treat population; CC = Candesartan cilexetil.**

**Favors:**

**Overall**

**CC**

**Losartan**

**-6**

**-4**

**-2**

**0**

**Study 230**

**-8**

**-10**

**2**

**4**

**6**

**8**

**10**

**CC**

**Losartan**

**Study 231**

**-6**

**-4**

**-2**

**0**

**-8**

**-10**

**2**

**4**

**6**

**8**

**10**

**N = 564**

**n = 456**

**n = 108**

**n = 325**

**n = 239**

**n = 109**

**n = 455**

**N = 627**

**n = 528**

**n = 363**

**n = 264**

**n = 523**

**n = 104**

**n = 99**

**N = 1,191**

**n = 984**

**n = 688**

**n = 503**

**n = 978**

**n = 213**

**n = 207**

## Summary of Adverse Events—CLAIM Program (230, 231)

**	****	****                           ****Patients, n (%)**
**	****                                                       ****Study 230****†****                       Study 231****†****	**
**	****CC****	****Losartan****	****CC****	****Losartan****	****	****n = 307****	****n = 304****	****n = 332****	****n = 322****	**
**≥ ****1 AE****	**** 140  (46)****	****136 (45)****	****154 (46)****	****147 (46)****	**
**Serious AEs****	****  4****††**** (1)****	****  2 (1)****	****  3 (1)****	****    1 (< 1)****	**
**Discontinued****	**** 11  (4)****	****  6 (2)****	****  6 (2)****	****  5 (2)****	**** ****due to AE**

- Briefing Book, Tables 12, 13, 14

**C**

**CC = Candesartan cilexetil**
**†****No deaths were reported.**
**††****2 SAEs occurred during the 2-wk safety follow-up at the end of the study.**

## Adverse Events in ≥ 2% of Patients

**	****                       ****Study 230****	****                          Study 231****	****	****                   Pooled****†**
**	****CC****	****Losartan ****	****CC****	****Losartan ****	****CC****	****Losartan****	****n = 307****	****n = 304****	****n = 332****	****n = 322****	****n = 639****	****n = 626**

**Any AE****	****140****	****(****45.6****)****	****136****	****(****44.7****)****	****154****	****(****46.4****)****	****147****	****(****45.7****)****	****294****	****(****46.0****)****	****283****	****(****45.2****)**
**Headache****	****22****	****(****7.2****)****	****18****	****(****5.9****)****	****15****	****(****4.5****)****	****17****	****(****5.3****)****	****37****	****(****5.8****)****	****35****	****(****5.6****)**
**Dizziness****	****11****	****(****3.6****)****	****4****	****(****1.3****)****	****17****	****(****5.1****)****	****8****	****(****2.5****)****	****28****	****(****4.4****)****	****12****	****(****1.9****)**
**Fatigue****	****5****	****(****1.6****)****	****11****	****(****3.6****)****	****6****	****(****1.8****)****	****4****	****(****1.2****)****	****11****	****(****1.7****)****	****15****	****(****2.4****)**
**Respiratory**** i****nfections****	****12****	****(****3.9****)****	****24****	****(****7.9****)****	****30****	****(****9.0****)****	****32****	****(****9.9****)****	****42****	****(****6.6****)****	****56****	****(****8.9****)**
**Sinusitis****	****12****	****(****3.9****)****	****7****	****(****2.3****)****	****15****	****(****4.5****)****	****7****	****(****2.2****)****	****27****	****(****4.2****)****	****14****	****(****2.2****)**
**Rhinitis****	****2****	****(****0.7****)****	****11****	****(****3.6****)****	****10****	****(****3.0****)****	****9****	****(****2.8****)****	****12****	****(****1.9****)****	****20****	****(****3.2****)**
**Pharyngitis****	****5****	****(****1.6****)****	****4****	****(****1.3****)****	****4****	****(****1.2****)****	****12****	****(****3.7****)****	****9****	****(****1.4****)****	****16****	****(****2.6****)**
**Back pain****	****6****	****(****2.0****)****	****6****	****(****2.0****)****	****7****	****(****2.1****)****	****11****	****(****3.4****)****	****13****	****(****2.0****)****	****17****	****(****2.7****)**
**Edema peripheral****	****6****	****(****2.0****)****	****10****	****(****3.3****)****	****4****	****(****1.2****)****	****7****	****(****2.2****)****	****10****	****(****1.6****)****	****17****	****(****2.7****)**

**Patients, n (%)**

**1**

- Briefing Book, Table 12

**CC = Candesartan cilexetil.**
**†****ISS analysis for sNDA.**

## Efficacy Data for 2 CLAIM Trials (230, 231)

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**C**

**Favors CC**

**Favors losartan**

**Trough DBP at Wk 8****† ****(N = 609)**

**Trough SBP at Wk 8 (N = 609)**

**Peak DBP at Wk 8 (N = 540)**

**Peak SBP at Wk 8 (N = 540)**

**230**

**ITT/LOCF population for trough BP; ITT population for peak BP.**
**†****N = Primary endpoint.**

**Study**

**Trough DBP at Wk 8****† ****(N = 654)**

**231**

**Trough SBP at Wk 8 (N = 654)**

**Peak DBP at Wk 8 (N = 606)**

**Peak SBP at Wk 8 (N = 606)**

## Primary Efficacy Endpoint Data for 4 Comparative Hypertension Trials (230, 231, 175, 0001)

**-8**

**-7**

**-6**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**C**

**Favors CC**

**Favors losartan**

**Trough DBP at Wk 8**

**230**
**(N = 609)**

**Study**

**175**
**(N = 329)**

**Trough DBP at Wk 8**

**Trough DBP at Wk 8**

**231**
**(N = 654)**

**ITT/LOCF population.**
**†****CC 16 mg QD vs losartan 50 mg QD.**

**0001**
**(N = 167)****†**

**Trough DBP at Wk 8**

## Summary—CLAIM Program (230, 231)

**These 2 adequate and well-controlled studies provide substantial evidence that candesartan cilexetil provides greater blood pressure reduction compared with losartan at the maximum recommended doses administered once daily**
**Candesartan cilexetil 32 mg once daily consistently lowered trough, peak, and 48-hr postdose DBP and SBP more effectively than losartan 100 mg ****once daily**
**Both drugs were well tolerated and demonstrated a tolerability and safety profile consistent with current prescribing information**

## Conclusion

**The greater blood pressure-lowering effect of candesartan cilexetil compared with losartan in the CLAIM program is also consistent with other clinical studies **
**This information is clinically relevant and important for prescribing healthcare professionals**