The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure

Bakris GL, Sica D, Weber M, White WB, Roberts A, Perez AP, Cao C, Kupfer S
J Clin Hypertens. 2011;13:81-88

Prescribing information can be obtained from your Takeda representative

EU/AZI-010002 Date of preparation: 01/11/2011

Disclosures

Grants, Consultancy and Speaker honoraria received by Takeda Pharma

EU/AZI-010002

Hypertension has been identified as the leading risk factor for mortality worldwide1
Hypertension affects approximately 44% of people aged 35-64 years and remains poorly controlled3

For every 20mmHg increase in clinical SBP or 10mmHg clinical DBP, the risk of vascular mortality doubles4 Cardiovascular disease costs Europe an estimated 169 billion each year2, with hypertension a major modifiable risk factor Modest reductions in SBP can substantially reduce morbidity and mortality of vascular events5
% Reduction in mortality Reduction in SBP (mmHg) Stroke CHD Total

2
3

-6
-8

-4
-5

-3
-4

-14

-9

-7

SBP = systolic blood pressure; DBP=diastolic blood pressure; CHD=coronary heart disease
1. Ezzati et al. Lancet. 2002;360:134760. 2. Leal J, et al. Eur Heart J 2006;27:1610-19. 3. Wolf-Maier K, et al. JAMA 2003;289:2363-2369. 4. Lewington S, et al. Lancet. 2002;360:19031913. 5. Whelton PK, et al. JAMA 2002;288:1882-1888.

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Azilsartan medoxomil: a new-generation ARB for the treatment of essential hypertension

ARBs are effective in reducing BP and are better tolerated than other classes of antihypertensive1

O O H 3C O OOC N OCH2CH3

N O

NH
O

Azilsartan medoxomil (AZL-M): 2

Prodrug, rapidly hydrolysed to azilsartan a highly selective angiotensin receptor blocker
Once-daily dosing
HOOC

N TAK-491 MW=606.62
Hydrolysis

Estimated bioavailability 60%

N OCH2CH3 N

NH O

Elimination half-life 12 hours

TAK-536 MW=456.46

1. Veronesi M, et al. Vasc Health Risk Manag 2007;3:999-1005 2. Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Study design and treatments

AZL-M 20 mg (n=283)

Washout

AZL-M 40 mg (n=283)

Single-blind placebo run-in phase

AZL-M 80 mg (n=285)

OLM-M 40 mg (n=282)

PLACEBO (n=142)

Screening

Baseline ABPM and randomisation (N=1,275)

ABPM at final visit

1 week

2 weeks

6 weeks

AZL-M = azilsartan medoxomil, OLM-M = olmesartan medoxomil Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Inclusion and exclusion criteria

Inclusion criteria:
Age 18 years Primary hypertension
Clinic SBP 150180 mmHg 24-hour mean SBP 130170 mmHg

Key exclusion criteria:

Sitting clinic DBP >114 mmHg History of major CV events

Cardiac conduction defects

Secondary hypertension

Severe renal impairment or known/suspected renal artery stenosis Type 1 or poorly controlled type 2 diabetes
Significant hepatic abnormalities Hyperkalaemia

CVD = cardiovascular disease, SBP = systolic blood pressure, DBP = diastolic blood pressure
Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

EU/AZI-010002

Study endpoints
Primary endpoint:
Mean change in 24-hour mean SBP (by ABPM) at 6 weeks

Safety endpoints:

Adverse events
Laboratory tests

Key secondary endpoints:

Mean change in trough sitting clinic SBP at 6 weeks

ECG
Vital signs

Other:
Mean change in 24-hour DBP by ABPM Mean change in trough sitting clinic DBP Day-time mean (6 am10 pm), night-time mean (12 am6 am), mean at 0-12 hours after dosing, mean trough (22 24 hours after dosing) SBP and DBP

Proportion of responders*

*Response defined as clinic SBP <140 mmHg and/or reduction 20 mmHg from baseline Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Statistical analysis
Changes in 24-hour mean SBP and clinic SBP were analysed by a step-wise testing procedure (ANCOVA)
if the treatments failed to meet significance at one step, then analysis of the remaining steps became invalid

Step 1: AZL-M 80 mg vs placebo

Step 2: AZL-M 40 mg vs placebo

Step 3: AZL-M 20 mg vs placebo

Step 6: AZL-M 80 mg vs OLM-M

Superiority analysis

Step 4: AZL-M 80 mg vs OLM-M

Non-inferiority (1.5 mmHg margin)

Step 7: AZL-M 40 mg vs OLM-M

Superiority analysis

Step 5: AZL-M 40 mg vs OLM-M

Non-inferiority (1.5 mmHg margin)

Step 8: AZL-M 20 mg vs OLM-M

Non-inferiority (1.5 mmHg margin)

Step 9: AZL-M 20 mg vs OLM-M

Superiority analysis

Other secondary variables used similar ANCOVA model without step-wise testing

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Patient demographics were similar across treatment groups

Placebo n Mean age (SD), years 142 59.4 (10.5) AZL-M 20 mg 283 57.1 (11.0) AZL-M 40 mg 283 57.4 (9.6) AZL-M 80 mg 285 58.1 (11.6) OLM-M 40 mg 282 58.9 (11.6)

Mean weight (SD), kg

Mean BMI (SD), kg/m2 Gender, n (%) Male Female

83.4 (19.0)
30.0 (4.9)

84.2 (21.5)
30.4 (5.7)

84.6 (20.4)
30.6 (5.9)

83.5 (19.6)
30.0 (5.5)

82.9 (19.6)
29.8 (5.3)

76 (53.5) 66 (46.5)

133 (47.0) 150 (53.0)

142 (50.2) 141 (49.8)

149 (52.3) 136 (47.7)

140 (49.6) 142 (50.4)

Ethnicity, n (%)*
Caucasian Black/African-American American Indian/Alaska Native 103 (72.5) 16 (11.3) 29 (20.4) 202 (71.4) 32 (11.3) 51 (18.0) 205 (72.4) 31 (11.0) 49 (17.3) 209 (73.3) 31 (10.9) 52 (18.2) 209 (74.1) 31 (11.0) 50 (17.7)

* Rest Asian or multiracial; patients may have chosen more than one category for race

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Baseline blood pressure was similar across treatment groups

OLM-M 40 mg 282 146.3 (9.8) 87.5 (9.8) 282 159.2 (12.1) 91.4 (10.7)

Placebo 24-hour mean BP, mmHg/n SBP (SD) DBP (SD) Clinic BP, mmHg/n SBP (SD) DBP (SD) 142 146.0 (12.5) 87.2 (9.4) 142 158.7 (11.4) 91.3 (10.4)

AZL-M 20 mg 282 145.6 (9.7) 87.6 (9.2) 283 158.7 (11.6) 92.4 (10.4)

AZL-M 40 mg 281 146.2 (10.2) 88.0 (9.2) 281 158.5 (12.2) 92.2 (11.2)

AZL-M 80 mg 282 146.3 (9.9) 87.7 (8.8) 284 159.4 (12.0) 92.1 (10.3)

TPEU Data on file EU/AZI-010024

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Significantly greater reduction in 24-hour mean SBP at Week 6 with AZL-M 80 mg vs OLM-M 40 mg

Placebo

AZL-M 20mg
Baseline: 146.3 mmHg N=120

AZL-M 40mg

AZL-M 80mg

OLM-M 40mg

2 -2

-1.4

Baseline: 145.4 mmHg N=241

Baseline: 146.0 mmHg N=244

Baseline: 146.2 mmHg N=243

Baseline: 146.5 mmHg N=250

-6
-10

-14
-18
*p<0.001 vs placebo

-12.2* -13.5* -14.6*

-12.6*

p=0.038 vs OLM-M

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Greater numerical reduction in trough clinic SBP at Week 6 with AZL-M 80 mg vs OLM-M 40 mg

Placebo

AZL-M 20mg
Baseline: 158.7mmHg N=140

AZL-M 40mg

AZL-M 80mg

OLM-M 40mg

0
-4 -8 -12 -16

-2.1

Baseline: 158.5mmHg N=274

Baseline: 158.5mmHg N=276

Baseline: 159.4mmHg N=279

Baseline: 159.2mHg N=280

-14.3*

-14.5* -17.6*

-14.9*

-20

p=0.043 (NS) vs OLM-M

*p<0.001 vs placebo; Superiority of AZL-N 80 mg vs OLM-M 40 mg could not be claimed because prior step in sequential testing was not statistically significant.
Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Reductions in ambulatory SBP were sustained throughout the 24-hour monitoring period
5

Change in SBP (mm Hg) by ABPM

0 -5 -10 -15 -20

0 6 12 Hour after dosing 18 24 Placebo AZL-M 20 mg AZL-M 40 mg AZL-M 80 mg OLM-M 40 mg

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Efficacy results: mean change in diastolic BP at week 6

24 hr mean DBP
Placebo AZL-M 80 mg
N=142

Trough clinic DBP

Placebo AZL-M 80 mg AZL-M 20 mg OLM-M 40mg AZL-M 40 mg

AZL-M 20 mg OLM-M 40mg

N=283 N=281

AZL-M 40 mg

N=284 N=282

2 0.2
N=283 N=281 N=284 N=282 N=142

-0.7

-2
-2

-6

-6
-7.5* -8.4* -8.6* -7.7* -6.8* -6.9* -8.4* -6.9*

-10

*P<0.001 vs placebo

-10
P=0.172 vs OLM-M

*P<0.001 vs placebo

P=0.044 vs OLM-M

TPEU Data on file EU/AZI-010025 Adapted from Bakris G L, et al. J Clin Hypertens 2011; 13:81-88

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Response rate was similar between treatments

AZL-M 20mg AZL-M 40mg AZL-M 80mg
56.6

OLM 40mg
53.2
N=282

60

Responders* (%)

50
40 30

47.8
N=283

50.4
N=281

N=284

20
10 0

*Reduction in clinic SBP to <140 mmHg and/or 20 mmHg decrease from baseline

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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AZL-M has a similar tolerability to OLM-M

Placebo (n=142)

AZL-M 20 mg (n=283) 109 (38.5)

11 (3.9) 8 (2.8) 1 (0.4)*

AZL-M 40 mg (n=281) 101 (35.9)

3 (1.1) 0 0

AZL-M 80 mg (n=284) 117 (41.2)

6 (2.1) 1 (0.4) 0

OLM-M 40 mg (n=282) 107 (37.9)

4 (1.4) 2 (0.7) 0

Any AE, N (%)

AE leading to discontinuation, N (%) Serious AEs, N (%) Death, N (%) Most common AEs, N (%) Headache Dyslipidaemia Dizziness

51 (35.9)
6 (4.2) 3 (2.1) 0

10 (7.0) 3 (2.1) 4 (2.8)

13 (4.6) 10 (3.5) 8 (2.8)

9 (3.2) 11 (3.9) 6 (2.1)

16 (5.6) 16 (5.6) 8 (2.8)

9 (3.2) 10 (3.5) 10 (3.5)

* Due to gastrointestinal haemorrhage and shock. Not related to treatment

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Study summary
Efficacy (at Week 6)
AZL-M 80 mg lowered 24-hour mean SBP to a significantly greater extent than OLM-M 40 mg (-14.6 mmHg vs -12.6 mmHg; p=0.038) AZL-M 40 mg was non-inferior to OLM-M 40 mg

Safety (at Week 6)

AZL-M had a similar safety and tolerability profile to placebo and OLM-M (most common AEs: headache, dyslipidaemia, dizziness)

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

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Implications for hypertension management

An important aspect of this trial is the use of ABPM to establish the primary end point. ABPM provides more reliable predictive data on cardiovascular outcomes than conventional office readings1 ...Data from this study suggest that AZL-M 80 mg is more effective in reducing SBP than the highest approved dose of OLM-M, which is considered to be more effective than others in the ARB class2,3

1. Bakris GL, et al. J Clin Hypertens 2011;13:81-88. 2. Zannad F, et al. Fundam Clin Pharmacol 2007;21:181-190. 3. Oparil S, et al. J Clin Hypertens 2001;3:283-291.

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This study was funded by Takeda Global Research and Development

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