1. Treatment Inertia
1

2. Are you guilty of
Treatment Inertia
in the
Management of
Hypertension
2

3. Hypertension awareness, treatment and
control: US 1976 to 2004
ACEIs
introduced
Adults (%)
73%
51%
55%
ARBs
introduced
71%
68%
70%
54%
59%
60%
34%
33%
31%
29%
27%
10%
JNC IV
JNC V
JNC VI
NHANES II NHANES III NHANES III NHANES
1976–1980 (Phase 1) (Phase 2) 1999–2000
1988–1991 1991–1994
76%
65%
37%
Awareness
Treatment
Control
JNC VII
NHANES
NHANES
2001–2002 2003–2004
Burt et al. Hypertension 1995;25:305–13; The Sixth Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure. Arch Int Med 1997;157:2413–46;
Hajjar & Kotchen. JAMA 2003;290(2):199–206; Chobanian et al. Hypertension 2003;42(6):1206–52;
Ong et al. Hypertension 2007;49(1):69–75

4. Hypertensives on Treatment
5 out of 10 Treated Hypertensive Patients
are not at Goal BP
Controlled
53%
Uncontrolled
47%
69% of hypertensive Americans are aware of their disease
58% of hypertensive Americans are receiving treatment for their disease
Hajjar I, Kotchen TA. JAMA. 2003;290:199-206.
Burt et al. Hypertention. 1995;25:305-313; Hyman et al. N Engl J Med. 2001;345:479-486; .

5. Increasing Awareness and Treatment of
Hypertension in Canada
Adults with hypertension (%)
Percentage of adults with hypertension who are aware,
treated and controlled
100
86%
82%
60
Treated
66%
80
Aware
Controlled
56%
40
34%
20
13%
0
1992
Leenen et al. CMAJ 2008;178:1441-9; Joffres et al. Am J Hypertens 2001;14:1099-105
2006
7

6. Increasing Rates of Treatment and
Control of Hypertension in Canada
1992
2006
Canadian Heart Health
Survey: Canada
Ontario Survey on the Prevention
and Control of Hypertension
21%
13%
15%
22%
66%
6%
14%
43%
Treated and controlled
Treated and not controlled
Aware, untreated
Unaware, untreated
Joffres et al. Am J Hypertens 2001;14:1099-105; Leenen et al. CMAJ 2008;178:1441-9
Treated and controlled
Treated and not controlled
Aware, untreated
Unaware, untreated
8

7. Worldwide blood pressure control in
treated hypertensive patients
Canada
66.0
USA
63.1
Mexico
21.8
Turkey
19.8
Germany
33.6
England
29.2
Greece
49.5
Japan
55.7
China
28.8
Spain
38.8
Taiwan
18.0
Egypt
33.5
South
Africa
47.6
Italy
37.5
Updated from Kearney et al. J Hypertens 2004;22:11–9

8. Treatment Inertia: Definition
Failure to initiate, intensify or change therapy in patients with
uncontrolled BP
• >140/90 mm Hg
• or >130/80 mm Hg in patients with diabetes, renal or coronary heart disease
Situations in which patients return for visits having taken their
medication but have not had therapy changed despite higher
than guideline recommended BP levels
Moser. J Clin Hypertens 2009;11:1-4
10

9. Percentage of Patients Achieving
Adequate Blood Pressure Control
On or below
Target DBP
37%
Over target DBP
63%
● Target BP set by
physician
● Study includes
● 11, 613 patients from
France, Germany,
Italy, Spain, and
United Kingdom
Taylor Nielson Healthcare, Epson, Surry, England-Cardiomonitor 2007

10. Action Taken In Those Patients
Not At Their Target BP
Dose Titration
Alternative Drug
Additional Drug
18%
82%
No Action Taken

11. Therapeutic Inertia: Action Taken In Patients
Not At Target BP
Proportion of patients not meeting targets and medication changes in
DIOVANTAGE 4 observational study across Canada (n=34,033)
Total patients
59%
Achieved
target
41%
Did not
achieve target
Treatment recommendation in
patients not meeting targets
55.1%
44.9%
change of
medication
Medication
change
NO
• Over half of the 41% of patients not achieving BP targets did not
receive any modification of their current therapy after 3 months
Tardif et al. Can J Clin Pharmacol 2008;15:e177-87
13

12. Barriers to Effective Management
of Uncontrolled Hypertension
• Lack of concern for higher than ideal but ‘not very high’ BPs
• Complexity of prescribing or monitoring drug regimens
• Practice patterns
• Lack of physician-patient rapport
• Failure to communicate the importance of continuing therapy
• Lack of ongoing attention to asymptomatic diseases (HTN) in patients
with symptomatic comorbidities
• Concern regarding adverse effects
Moser. J Clin Hypertens 2009;11:1-4
14

13. UKPDS mean blood pressures
Baseline
(mmHg)
Mean BP over
9 years
(mmHg)
Less tight control
160/94
154/87
Tight control
161/94
144/82
Difference
1/0
10/5
p-value
n.s.
p<0.0001
UKPDS(38). BMJ 1998;17:703–13

14. UKPDS: Significant Benefits with Tight vs. Less
Tight BP Control in Patients with Diabetes
Relative risk reduction with tight vs. less tight
BP control (10/5 mm Hg) (n=1148)
Diabetesrelated death
All cause
mortality
MI
Stroke
Microalbuminuria
P=0.019
P=0.17
P=0.13
P=0.013
P=0.009
0
Patients (%)
-10
-20
-18%
-21%
-30
-29%
-32%
-40
-44%
-50
UKPDS 38. BMJ 1998;317:703-13
16

15. Primary End Point: Nonfatal MI
and Fatal CHD
Atorvastatin 10 mg
Number of events
100
Placebo
Number of events
154
36%
reduction
HR = 0.64 (0.50-0.83)
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
p=0.0005

16. Steno-2 Study: Significant Benefits with
Intensive Treatment in Patients with Diabetes
Macro and microvascular complications in type 2 diabetes
BP
(mmHg)
Usual
treatment
Intensive
treatment
SBP initial
149 ± 19
146 ± 20
SBP final
146
132
Reduction
-3 ± 3
-14 ± 2
DBP initial
86 ± 11
85 ± 10
DBP final
78
73
Reduction
-8 ± 2
-12 ± 2
Intensive Usual
better better
STENO-2 (n=160); age 55.1 years;
follow-up 7.8 years
Gaede et al. N Engl J Med 2003;348:383-93
Cardiovascular
events
RR=0.47
P=0.008
Nephropathy
RR=0.39
P=0.003
Retinopathy
RR=0.42
P=0.02
Autonomic
neuropathy
RR=0.37
P=0.002
0
0.25
0.50
0.75
1
RR (95% CI)
18

17. PROGRESS Study
Lowering of BP and Secondary Prevention of Stroke
Stroke
Prevention
Treat Placebo Favours Favours RR (CI 95%)
(n= 2051) (n= 3054) treat placebo reduction
150
Combination
157
Monotherapy
163
Hypertensive
Non-Hypertensive144
307
Total
255
165
235
185
420
BP reduction vs placebo:
Monotherapy: 4.9/2.8 mmHg
Combination: 12.3/5.0 mmHg
43% (30 - 54)
5% (-19 - 23)
32% (17 - 44)
27% (8 - 42)
28% (17 - 38)
0.5
1.0
2.0
PROGRESS. Lancet 2001; 358: 1033-1041

18. Failure of the Stepped Care
Approach
4 JNC Reports
Between 1988
and 2000
11/09/13
Control Rate in the USA
BP goal 140/90 mm HG
34%
Control Rate (%)
Why Has the
Stepped Care
Approach to the
Management of
Hypertension
Failed?
29%
NHANES
1988-91
27%
NHANES
1991-94
NHANES
1991-2000
20

19. Physician Considerations in the
Selection of Anti-hypertensive Agents
1
Efficacy
2
Side
Effects
3
Outcome
Studies
Neutel 2005

20. The New Therapeutic Window in
Hypertension
100
ideal
Ideal
Efficacy
80
80
60
60
Traditional
40
20
40
Efficacy
Side Effects
0
20
0
Dose
Man Int Veld AJ, Journal of Hypertens 1997;15 (suppl 7): S27-S33
Freedom from side effects
100

21. Titration vs. Combination
Frishman WH et al,Arch Intern Med 1994;154, 1461-1468

22. Efficacy: Up-titration vs Combination
Change in SBP (mm Hg)
T40 T80
T40
T40 HCT12.5 V80 V160
V80
V80 HCT12.5 Ol20 Ol40
O20
Ol20 HCT12.5

23. Adverse Events
Placebo
Bisoprolol/HCTZ
2.5-10mg
N
BP Reduction (mmHg)
144
2.9/3.9
221
15.8/12.6
Adverse Event (%)
Bradycardia
Peripheral Ischemia
Bronchospasm
Cough
Fatigue
Dizziness
Headache
Insomnia
Somnolence
Loss of Libido
Impotence
0.7
0.9
0.0
0.7
1.7
1.8
2.7
2.0
0.7
1.2
0.7
0.9
0.4
0.0
1.5
3.0
3.2
0.4
1.2
0.9
0.4
1.1

24. Tolerability of ARB Combination Therapy
and Components
40
35
34.1
Placebo (n=44)
30
HCTZ monotherapy (n=123)
25
ARB monotherapy (n=126)
Patients
20
(%)
15
10
ARB/HCTZ (n=390)
14.6
10.5
8.7
9.5
6.8 6.5
5
5.6
6.9
4.8
4.5
2.4
4.5 4.1
4.1
2.3
1.6 2.3
0
Headache
Dizziness
Fatigue
Cough
3.8
0
Discontinuations
due to adverse
events

25. Advantages of Combination Therapy
120
Ideal
100
Percent
80
60
40
Freedom from side effects
Efficacy
20
0
Dose
Neutel. Nephrol Dial Transplant 2006;21:1469-73.
27

26. Hypertension awareness, treatment and
control: US 1976 to 2004
ACEIs
introduced
Adults (%)
73%
51%
55%
ARBs
introduced
71%
68%
70%
54%
59%
60%
34%
33%
31%
29%
27%
10%
JNC IV
JNC V
JNC VI
NHANES II NHANES III NHANES III NHANES
1976–1980 (Phase 1) (Phase 2) 1999–2000
1988–1991 1991–1994
76%
65%
37%
Awareness
Treatment
Control
JNC VII
NHANES
NHANES
2001–2002 2003–2004
Burt et al. Hypertension 1995;25:305–13; The Sixth Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure. Arch Int Med 1997;157:2413–46;
Hajjar & Kotchen. JAMA 2003;290(2):199–206; Chobanian et al. Hypertension 2003;42(6):1206–52;
Ong et al. Hypertension 2007;49(1):69–75

27. Prevalence of controlled BP in CONVINCE
Fraction with controlled BP (%)
SBP ≤140 mmHg
DBP ≤90 mmHg
100
94
85
80
90
91
90
84
71
60
SBP ≤140 mmHg
and DBP ≤90 mmHg
70
68
66
67
66
52
40
23
20
0
20
Baseline
EOT
12 months 24 months 36 months
(n=16,469) (n=15,314) (n=13,853) (n=6364)
(n=773)
Duration of study treatment
Black et al. Am J Hypertens 2000;13(part 2):61A

28. BP control in ALLHAT participants:
Percentage meeting goal by year of follow-up
SBP <140 mmHg
DBP <90 mmHg
Patients meeting goal (%)
BP <140/90 mmHg
Mean BP
145/83
140/81
138/79
137/78
136/77
135/76
135/75
No drugs
-
1.3
1.4
1.6
1.7
1.8
2.0
Cushman et al. J Clin Hypertens 2002;4:393–404

29. Steno-2 Study: Significant Benefits with
Intensive Treatment in Patients with Diabetes
Macro and microvascular complications in type 2 diabetes
BP
(mmHg)
Usual
treatment
Intensive
treatment
SBP initial
149 ± 19
146 ± 20
SBP final
146
132
Reduction
-3 ± 3
-14 ± 2
DBP initial
86 ± 11
85 ± 10
DBP final
78
73
Reduction
-8 ± 2
-12 ± 2
Intensive Usual
better better
STENO-2 (n=160); age 55.1 years;
follow-up 7.8 years
Gaede et al. N Engl J Med 2003;348:383-93
Cardiovascular
events
RR=0.47
P=0.008
Nephropathy
RR=0.39
P=0.003
Retinopathy
RR=0.42
P=0.02
Autonomic
neuropathy
RR=0.37
P=0.002
0
0.25
0.50
0.75
1
RR (95% CI)
31

30. Management Principle
Study protocol requires
you to follow a prescribed
drug algorithm

31. Opportunities for accepting inadequate
BP control
Patient
Persistent attempts at
nonpharmacologic dx
Cost
Perception that drug is not
working
Education (HTN is curable)
Concerns over
polypharmacy
Side effects
Change in lifestyle
Missed visits
Diagnosis
Physician
Confirming diagnosis
Inappropriate
nonpharmacologic Rx
Formulary guidelines
Patient pressure
Reluctance to
titrate or add drug
Cost
Uneducated
on BP goal
Change in HMO plan
Home BP measurements
BP Control
Concern
over AEs
Concern
over
metabolic
effects
Patient
Pressure

32. SBP control in three large trials
CONVINCE @ 12 mo
71
(n=13,853)
ALLHAT @ 12 mo
53*
(n=14,722)
LIFE @ 12 mo
(n=9,194)
0
10
20
26†
30
40
50
60
70
80
Subjects with SBP <140 mmHg (%)
*Cushman et al. Am J Hypertens 1998;11(part 2):17A
†Dahlöf et al. Am J Hypertens 1999;12(part 2):142A

33. Management Principle
A well established blood pressure
goal results in clinicians being
more aggressive in their
management of BP

34. Goal Rates
Drug Algorithm
+
BP Goal
Neutel, Smith, Weber, Wang, Masonson. J Clin Hypertens 2004;6:168–74

35. Management Principle
Combination
always more effective than
Titration

36. Treatment algorithm
OLM 40mg/day
+ HCTZ 25mg/day
+ AMLO 10mg/day
Target BP:
<130/85 mmHg
<140/90 mmHg
OLM 40mg/day
+ HCTZ 25mg/day
+ AMLO 5mg/day
OLM 40mg/day
+ HCTZ 25mg/day
n=201
OLM 40mg/day
+ HCTZ 12.5mg/day
OLM 40mg/day
OLM 20mg/day
Step 1
week 4
Step 2
week 8
Step 3
week 12
OLM: olmesartan; HCTZ: hydrochlorothiazide;
AMLO: amlodipine
Step 4
week 16
Step 5
week 20
Step 6
week 24
Neutel et al. J Clin Hypertens 2004;6:168–74

37. Olmesartan: ARB/receptor interactions
HO
O
N
O
VI
III
V
IV
N
Binding
Sites
N
N
AT1 Receptor
(transmembrane regions 3–6)
N
N
Olmesartan
Yanagisawa et al. J Med Chem 1996;39:323–38

38. Proportion of Patients Achieving
Treatment Goal with Various ARBs
Proportion of patients achieving BP goal (<140/90 mmHg),
retrospective analysis of RCT (n=588)
60
Patients (%)
50
*p<0.01
vs. olmesartan
40
32.4
30
25.9
20
16.1*
14.5*
Losartan 50 mg
Valsartan 80 mg
10
0
Olmesartan 20 mg
Irbesartan 150 mg
Oparil et al. Am J Hypertens 2005;18:287-94; Oparil et al. J Clin Hypertens 2001;3:283-91, 318
40

39. Treat to goal study: Baseline demographics
for efficacy cohort (n=197)
Age (years)
53
Gender (% male)
65
Race (%)
- Caucasian
74
- Black
16
- Asian
2
- Hispanic
7
Mean SBP (mmHg)
161.2
Mean DBP (mmHg)
96.6
Neutel et al. J Clin Hypertens 2004;6:168–74

40. Hypertension management with an
olmesartan-based algorithm
Week 8
Week 16
Week 24
Patients achieving
BP goal (%)
100
83.2
80
69.3
58.7
60
40
35.2
20
≤130/
85
≤140/
90
≤130/
85
≤140/
90
≤130/
85
≤140/
90
DBP
SBP
DBP
SBP
DBP
SBP
0
Change in BP
(mmHg)
87.7
N=198
93.3
-10
-20
BP goal
-10.7
-17.7
-30
-16.1
-18.2
-29.3
-33.7
-40
OLM + HCTZ + AML
OLM + HCTZ
OLM
Neutel et al. J Clin Hypertens 2004;6:168–74

41. Baseline characteristics
Stage 1
(n=85)
Age (years)
Stage 2
(n=113)
49.4 (28–80)
55.3 (35–80)
69.4
61.9
- Caucasian
70.6
76.1
- Black
18.8
14.2
6.8
9.4
Prior antihypertensives (%)
70.6
78.8
Baseline SBP/DBP (mmHg)
149.7/94.7
169.8/98.1
Gender (% male)
Race (%)
Duration of hypertension (years)
Neutel et al. J Hum Hypertens 2006;20:255–62

42. The majority of patients achieved BP goal
with an olmesartan-based algorithm
Patients
achieving BP
goal at week
24 (%)
<140/90 mmHg
Total Cohort
Stage 1
93.3%
97.5%
87.7%
96.2%
Stage 2
90%
<130/85 mmHg
Total Cohort: 179 patients; mean baseline BP = 161/97 mmHg
Stage 1: 79 patients; mean baseline BP = 150/95 mmHg
Stage 2: 100 patients; mean baseline BP = 170/98 mmHg
81%
Neutel et al. J Clin Hypertens 2004;6:168–74
Neutel et al. J Human Hypertens 2006;20:255–62

43. BP CRUSH: Study Design
Open-label, titration study
AML/OM
5/20 mg
AML/OM
5/40 mg
AML/OM
10/40 mg
AML/OM
AML/OM
10/40 mg +
10/40 mg +
HCTZ 12.5 mg HCTZ 25 mg
Visit 1
Screening
(within 7 days
±6
of Visit 2)
Visit 2
Day 1
Visit 2A
Day 2
Visit 3
Week 4
Visit 4
Week 8
Visit 5
Week 12
Visit 5A
Week 12
+ 1 day
Visit 6
Week 16
Visit 7
Visit 8
Week 20 Week 22
Visit 7A
Week 20
+ 1 day
• Uptitrated if mean SeSBP was ≥120 and <200 mm Hg and/or mean SeDBP was
≥70 and <115 mm Hg.
• Maintained on current dosage if SeSBP <120 mm Hg and SeDBP <70 mm Hg
• Patients on maintenance therapy uptitrated to the next dosing level if mean SeSBP
was ≥130 and <200 mm Hg and/or mean SeDBP was ≥80 and <115 mm Hg

44. Secondary Endpoint:
Proportions of Patients Achieving Cumulative
SeBP Goals by Titration Dose
Patients Achieving SeBP Goal (%)
86.7
90
77.1
80
70
63.8
60
50
49.5
40
30
20
10
0
AM L/OM
5/20 mg
AML/OM
5/40 mg
AML/OM
10/40 mg
90
80
70
63.8
60
56.2
50
44.3
40
31.8
30
20
18.2
10
0
AML/OM
AM L/OM
10/40 + HCTZ 10/40 + HCTZ
12.5 mg
25 mg
AM L/OM
5/20 mg
AM L/OM
5/40 mg
<120/80 mm Hg
100
Patients Achieving SeBP Goal (%)
<130/80 mm Hg
100
90.3
Patients Achieving SeBP Goal (%)
<140/90 mm Hg
100
90
80
70
60
50
43.4
37.1
40
30
20
10
0
25.2
8.5
AM L/OM
5/20 mg
15.7
AML/OM
5/40 mg
Source: Study 8663-404 Data Table 7.10 (18 January 2010)
AM L/OM
AML/OM
AM L/OM
10/40 mg 10/40 + HCTZ 10/40 + HCTZ
12.5 mg
25 mg
AM L/OM
10/40 mg
AML/OM
AM L/OM
10/40 + HCTZ 10/40 + HCTZ
12.5 mg
25 mg

45. Percentage
Compliance in the Treatment of Hypertension
During, Vetter German Survey
Number of Tablets

46. Two HTN Agents in One Pill
Enhances Adherence
Lisinopril/HCTZ combination pill (n=1644)
100%
Lisinopril and diuretic in separate pills (n=624)
% Persistence
90%
80%
70%
69%
11%*
60%
58%
50%
0
1
2
3
4
5
6
7
Months
*p<0.05 vs fixed-dose combination
Source: Dezii C. Managed Care. 2000;9:S2.
8
9
10
11
12

47. Patient Compliance
Δ of Medication
in 1st 6 months
1
Compliance
2nd 6 months
93%
2
75%
*P=< 0.05 vs. patient without Δ of medication
Caro JJ, et al. CMAJ. 1999;160:41.
V072004

48. CHEP: Treatment of Systolic-Diastolic Hypertension
without Other Compelling Indications
Threshold ≥140/90 mmHg and TARGET <140/90 mmHg
Lifestyle modification
A combination of 2 first line drugs may
be considered as initial therapy if the
blood pressure is ≥20 mmHg systolic
or ≥10 mmHg diastolic above target
Initial therapy
Thiazide
diuretic
ACEI
ARB
CONSIDER
• Nonadherence
• Secondary HTN
• Interfering drugs or
lifestyle
• White coat effect
Long-acting
CCB
Betablocker*
Dual combination
Triple or quadruple therapy
*not indicated as first line therapy over 60 y
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers; CCB: calcium channel blocker
2009 CHEP Recommendations. www.hypertension.ca/chep
50

50. Percentage of Total Events Occurring
Between 6am and 12noon
80
70
68
60
49
50
45
38
40
29
30
20
10
0
Symptomatic
Angina
Pectoris
MI
Stroke 1998;23:992 Lancet 1999 ;353:643
Am J Cardiol 1999;83:507 Lancet 1998:2:755
Stroke
Sudden
Death
Aortic
Aneurysm
Rupture

51. Losartan Once-a-Day vs.
Twice-a-Day Dosing
Reductions from Baseline in Ambulatory DBP at Week 4
5
∆ mmHg
0
-5
-10
Placebo (n = 26)
Losartan 100 mg qd (n = 28)
Losartan 50 mg bid (n = 30)
-15
0
4
8
12
16
Hours Postdose
Weber, et al. J Hum Hypertens. 1995;9(suppl):S29.
20
24
28

52. Olmesartan Medoxomil 24 Hour ABPM –
BID vs. QD Dosing
Mean Change in SBP From Baseline at Last Visit
30
Placebo
∆ SBP (mm Hg)
20
Olmesartan medoxomil 10 mg BID
10
Olmesartan medoxomil 20 mg QD
0
-10
-20
-30
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hours Since Treatment
Average hourly difference in Systolic BP using 7-Term Fourier series smoothing
Data compiled from non-black, randomized patients
Data on file, Sankyo Pharma

53. Multiple Antihypertensive Agents
Are Needed to Achieve Target BP
Trial
Target BP (mm Hg) 1
UKPDS
DBP <85
ABCD
DBP <75
MDRD
MAP <92
HOT
DBP <80
AASK
No. of antihypertensive agents
2
3
MAP <92
IDNT
SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.
Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.
Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Cushman WC et al. J Clin Hypertens. 2002;4:393-404.
4

54. ARB Trials
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Heart
failure
ELITE II
Val-HeFT
CHARM
I-Preserve
OPTIMAAL
VALIANT
Post-MI
LIFE
SCOPE
VALUE
CV
ONTARGET
TRANSCEND
Renal
IDNT
RENAAL
IRMA 2
MARVAL
ARB, angiotensin II receptor blocker.

55. Diabetic Nephropathy
Classification for ARB Renal
Outcome Trials
Stage 1
Pre-Mild
Stage 2
Mild
Stage 3
Moderate
Normal Microalbuminuria Proteinuria
ROADMAP (olmesartan)
Stage 4
Severe
Proteinuria
ORIENT (olmesartan)
RENAAL (losartan)
IRMA II (irbesartan)
IDNT (irbesartan)
AMADEO/VIVALDI (telmisartan)
MARVAL (valsartan)
Stage 5
Dialysis
ESRD

56. ROADMAP
Study Design
Patients with type 2 diabetes and normoalbuminuria with at least a risk factor for
cardiorenal disease, i.e., lipid disorders, smoking, obesity, hypertension;
Median 5 years based on a cumulative number of 325 primary endpoint events;
4400 randomized patients (2200 in each group)
Olmesartan
medoxomil 40 mg/d
Placebo
(i.e., conventional anti-HTN Rx
except ARBs and ACE-I )
Primary Outcome:
Time to onset of microalbuminuria
Secondary Outcomes:
Cardiovascular events, Changes in creatinine clearance,
Laser therapy for retinopathy
Secondary Objectives:
Composite cardiovascular endpoints (cardiovascular morbidity
and mortality), Composite renal endpoints (increase of serum
creatinine, decrease of GFR), Microangiopathy retinopathy
(laser treatment)

57. ORIENT
Study Design
Patients with type 2 diabetes, overt proteinuria, and diagnosed diabetic nephropathy;
Treatment period of 3 – 5 years; 500 patients targeted for randomization
Olmesartan medoxomil 10*, 20, or 40
mg/d (in an unforced titration
fashion) in addition to background
therapy with ACE-I** and/or other
antihypertensive treatment
Primary Outcome:
Placebo
in addition to background
therapy with ACE-I** and/or
other antihypertensive
treatment
Composite renal endpoints of: (1) Doubling of serum
creatinine level, (2) Onset of ESRD (as defined by serum
creatinine ≥ 5 mg/dL, or the necessity for hemodialysis or
kidney transplantation) and, (3) Death
* The recommended starting dose for olmesartan medoxomil in the U.S. is 20 mg once-daily
** Background therapy with an ACE-I is acceptable under the condition that the same
dosage/administration regimen as given prior to the study treatment is used

58. ONTARGET:Trial Design
Study design
Study population
Double-blind, randomized, parallel-group study
involving 25,620 patients in 40 countries
≥55 years with history of coronary artery disease,
PAD, cerebrovascular disease, disease,
or diabetes with end-organ damage
MICARDIS 80 mg/day, ramipril 10 mg/day, or
MICARDIS 80 mg/day + ramipril 10 mg/day
Primary endpoint
Composite endpoint of CV mortality, nonfatal
stroke, acute MI, and hospitalization for CHF
Secondary endpoint Newly diagnosed CHF, DM or atrial fibrillation,
Revascularization procedures, development of
dementia/cognitive declines, and neuropathy
Treatment duration Results expected by 2007
Study drugs
The ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

59. A Prospective, Open-label, Dosetitration Study to Evaluate the
Efficacy and Safety of an
Olmesartan– and Amlodipine–
based Treatment Regimen in
Subjects With Hypertension and
Type 2 Diabetes
Study CS-8663-403
Study funded by Daiichi Sankyo, Inc.

60. Azor® CS-8663-403 Study Design
ABPM
ABPM
Screening
(within 3–14 days
of Week –2)
Week
–2
Placebo
run-in
phase (2-3
weeks)
Week
–1
Day –1 (Day –1) Day 0
AML
5 mg
AML/OM
5/20 mg
Week 3
AML/OM
5/40 mg
Week 6
AML/OM
10/40 mg
Week 9
AML/OM
10/40 mg +
HCTZ 12.5 mg
Week 12/
(+1 day)
Week 13
Interim
safety visit
AML/OM
10/40 mg +
HCTZ 25 mg
Week 15
Follow-up
Week 18
Week 20
Week 16
Interim
safety visit
CS-8663-403 Protocol
Version 3.0. 22 April 2009

61. Change From Baseline in Mean 24-hour
Ambulatory SBP (± SEM; Primary
Endpoint) and DBP (± SEM) at Week 12
Change From Baseline in
Ambulatory BP (mm Hg)
0
144.3
N = 165
81.6
Baseline BP (mm Hg)
-5
-10
–11.2
-15
‡
-20
–19.9
-25
‡
P < 0.0001 vs baseline.
SBP
DBP
‡
Source: Study 8663-403 Data
Table D7.1 (4 August 2009).

62. Mean hourly ambulatory SBP (mm Hg)
Hourly Mean Ambulatory SBP at Baseline
and Week 12
160
Ba