clinical inertia short
TRANSCRIPT
1
Treatment Inertia
2
Are you guilty of Treatment Inertia
in the Management of Hypertension
Hypertension awareness, treatment and control: US 1976 to 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
ACEIs introduced
ARBs introduced
NHANES III (Phase 2) 1991–1994
NHANES III (Phase 1) 1988–1991
51%
73% 68%
31%
55% 54%
10%
29% 27%
Ad
ult
s (%
)
Awareness
NHANES II 1976–1980
Treatment
Control
NHANES 1999–2000
70%
59%
34%
JNC VIJNC VJNC IV JNC VII
NHANES 2001–2002
NHANES 2003–2004
71%
60%
33%
76%
65%
37%
Hypertensives on Treatment
Controlled53%
Uncontrolled47%
69% of hypertensive Americans are aware of their disease
58% of hypertensive Americans are receiving treatment for their disease
Burt et al. Hypertention. 1995;25:305-313; Hyman et al. N Engl J Med. 2001;345:479-486; . Hajjar I, Kotchen TA. JAMA. 2003;290:199-206.
5 out of 10 Treated Hypertensive Patients are not at Goal BP
7
Increasing Awareness and Treatment of Hypertension in Canada
86%
56%
82%
34%
66%
13%0
20
40
60
80
100
1992 2006
Ad
ult
s w
ith
hy
pe
rte
ns
ion
(%
) Aware
Treated
Controlled
Percentage of adults with hypertension who are aware, Percentage of adults with hypertension who are aware, treated and controlledtreated and controlled
Leenen et al. CMAJ 2008;178:1441-9; Joffres et al. Am J Hypertens 2001;14:1099-105
8
Increasing Rates of Treatment and Control of Hypertension in Canada
22%
21%
13%
43%
Treated and controlledTreated and not controlledAware, untreatedUnaware, untreated
Joffres et al. Am J Hypertens 2001;14:1099-105; Leenen et al. CMAJ 2008;178:1441-9
19921992Canadian Heart Health Canadian Heart Health
Survey: CanadaSurvey: Canada
66%14%
6%15%
Treated and controlledTreated and not controlledAware, untreatedUnaware, untreated
20062006Ontario Survey on the Prevention Ontario Survey on the Prevention
and Control of Hypertensionand Control of Hypertension
USA63.1
Canada66.0
Mexico21.8
Turkey19.8 Germany
33.6
Spain38.8
Greece49.5
England29.2
Egypt33.5
South Africa47.6
Italy37.5
Worldwide blood pressure control intreated hypertensive patients
Japan55.7
China28.8 Taiwan
18.0
Updated from Kearney et al. J Hypertens 2004;22:11–9
10
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
Percentage of Patients AchievingAdequate Blood Pressure Control
● Target BP set by physician
● Study includes
● 11, 613 patients from France, Germany, Italy, Spain, and United Kingdom
On or belowTarget DBP
37%
Over target DBP63%
Taylor Nielson Healthcare, Epson, Surry, England-Cardiomonitor 2007
Action Taken In Those Patients Not At Their Target BP
18%
82%No Action Taken
Dose TitrationAlternative DrugAdditional Drug
13
Therapeutic Inertia: Action Taken In PatientsTherapeutic Inertia: Action Taken In PatientsNot At Target BPNot At Target BP
41%59%Achieved
targetDid not
achieve target
44.9%55.1%
Medication change
NO change of medication
Proportion of patients not meeting targets and medication changes in Proportion of patients not meeting targets and medication changes in DIOVANTAGE 4DIOVANTAGE 4 observational study across Canada (n=34,033)observational study across Canada (n=34,033)
Tardif et al. Can J Clin Pharmacol 2008;15:e177-87
Total patientsTreatment recommendation in patients not meeting targets
• Over half of the 41% of patients not achieving BP targets did not receive any modification of their current therapy after 3 months
14
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
UKPDS mean blood pressuresUKPDS mean blood pressures
Baseline(mmHg)
Mean BP over9 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
16
UKPDS: Significant Benefits with Tight vs. Less UKPDS: Significant Benefits with Tight vs. Less Tight BP Control in Patients with DiabetesTight BP Control in Patients with Diabetes
-32%
-18%-21%
-44%
-29%
-50
-40
-30
-20
-10
0
Diabetes-related death
All causemortality MI Stroke
Micro-albuminuria
Pa
tie
nts
(%
)
UKPDS 38. BMJ 1998;317:703-13
Relative risk reduction with tight vs. less tight Relative risk reduction with tight vs. less tight BP control (10/5 mm Hg) (n=1148)BP control (10/5 mm Hg) (n=1148)
P=0.019 P=0.17 P=0.13 P=0.013 P=0.009
36% reduction
Primary End Point: Nonfatal MI and Fatal CHD
HR = 0.64 (0.50-0.83)
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154
p=0.0005
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
18Gaede et al. N Engl J Med 2003;348:383-93
Macro and microvascular complications in type 2 diabetesMacro and microvascular complications in type 2 diabetes
STENO-2 (n=160); age 55.1 years;follow-up 7.8 years 0 1
RR=0.47P=0.008
RR (95% CI)0.25 0.50 0.75
Cardiovascular
events
Autonomic
neuropathy
Nephropathy
Retinopathy
RR=0.39P=0.003
RR=0.42P=0.02
RR=0.37P=0.002
Intensivebetter
Usualbetter
Steno-2 Study: Significant Benefits with Steno-2 Study: Significant Benefits with Intensive Treatment in Patients with DiabetesIntensive Treatment in Patients with 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
PROGRESS StudyLowering of BP and Secondary Prevention of Stroke
PROGRESS. Lancet 2001; 358: 1033-1041PROGRESS. Lancet 2001; 358: 1033-1041
CombinationCombination
MonotherapyMonotherapy
HypertensiveHypertensive
Non-HypertensiveNon-Hypertensive
TotalTotal
150150
157157
163163
144144
307307
255255
165165
235235
185185
420420
43% (30 - 54)43% (30 - 54)
5% (-19 - 23)5% (-19 - 23)
32% (17 - 44)32% (17 - 44)
27% (8 - 42)27% (8 - 42)
28% (17 - 38)28% (17 - 38)
0.50.5 1.01.0 2.02.0
TreatTreat(n= 2051)(n= 2051)
PlaceboPlacebo(n= 3054)(n= 3054)
FavoursFavourstreattreat
FavoursFavoursplaceboplacebo
RR (CI 95%)RR (CI 95%)reductionreduction
BP reduction vs placebo:BP reduction vs placebo:Monotherapy: 4.9/2.8 mmHgMonotherapy: 4.9/2.8 mmHgCombination: 12.3/5.0 mmHgCombination: 12.3/5.0 mmHg
StrokeStrokePreventionPrevention
04/11/23 20
Failure of the Stepped Care Approach
Why Has the Stepped Care Approach to the Management of Hypertension Failed?
4 JNC Reports Between 1988 and 2000
Control Rate in the USA BP goal 140/90 mm HG
29%27%
34%
NHANES1988-91
NHANES1991-94
NHANES1991-2000
Con
trol
Rat
e (%
)
Physician Considerations in the Selection of Anti-hypertensive Agents
SideEffects
Efficacy
Outcome Studies
Neutel 2005
1
2
3
ideal
The New Therapeutic Window in Hypertension
IdealIdeal
TraditionalTraditional
Side EffectsSide Effects Efficacy Efficacy
Man Int Veld AJ, Journal of Hypertens 1997;15 (suppl 7): S27-S33
0
20
40
60
80
100
Dose
Eff
icac
y
0
20
40
60
80
100
Fre
edo
m f
rom
sid
e ef
fect
s
Titration vs. Combination
Frishman WH et al,Arch Intern Med 1994;154, 1461-1468
Efficacy: Up-titration vs CombinationC
han
ge
in S
BP
(m
m H
g)
T40 T80 T40T40
HCT12.5 V80 V80V160V80
HCT12.5 Ol20 Ol40 Ol20O20
HCT12.5
Adverse Events
N 144 221BP Reduction (mmHg) 2.9/3.9 15.8/12.6
Adverse Event (%)Bradycardia 0.7 0.9Peripheral Ischemia 0.9 0.4 Bronchospasm 0.0 0.0 Cough 0.7 1.5Fatigue 1.7 3.0 Dizziness 1.8 3.2Headache 2.7 0.4Insomnia 2.0 1.2Somnolence 0.7 0.9 Loss of Libido 1.2 0.4Impotence 0.7 1.1
PlaceboBisoprolol/HCTZ
2.5-10mg
Tolerability of ARB Combination Therapy and Components
Headache Dizziness Fatigue Cough Discontinuations due to adverse
events
Placebo (n=44)
HCTZ monotherapy (n=123)
ARB monotherapy (n=126)
ARB/HCTZ (n=390)Patients(%)
34.1
6.84.5
2.34.5
14.6
6.5
2.44.1 4.1
8.7
5.6 4.8
1.60
10.59.5
6.9
2.33.8
0
5
10
15
20
25
30
35
40
27
Advantages of Combination TherapyAdvantages of Combination Therapy
0
20
40
60
80
100
120
Dose
Pe
rce
nt
Freedom from side effectsEfficacy
Neutel. Nephrol Dial Transplant 2006;21:1469-73.
Ideal
Hypertension awareness, treatment and control: US 1976 to 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
ACEIs introduced
ARBs introduced
NHANES III (Phase 2) 1991–1994
NHANES III (Phase 1) 1988–1991
51%
73% 68%
31%
55% 54%
10%
29% 27%
Ad
ult
s (%
)
Awareness
NHANES II 1976–1980
Treatment
Control
NHANES 1999–2000
70%
59%
34%
JNC VIJNC VJNC IV JNC VII
NHANES 2001–2002
NHANES 2003–2004
71%
60%
33%
76%
65%
37%
Baseline(n=16,469)Baseline
(n=16,469)
00
2020
4040
6060
8080
100100
2323 2020
5252
EOT(n=15,314)
EOT(n=15,314)
8585 8484
9494
12 months(n=13,853)12 months(n=13,853)
7171 7070
9090
24 months(n=6364)
24 months(n=6364)
6868 6666
9090
36 months(n=773)
36 months(n=773)
67676666
9191
Duration of study treatmentDuration of study treatment
SBP 140 mmHgSBP 140 mmHg DBP 90 mmHgDBP 90 mmHg SBP 140 mmHg and DBP 90 mmHg
SBP 140 mmHg and DBP 90 mmHg
Prevalence of controlled BP in CONVINCE
Black et al. Am J Hypertens 2000;13(part 2):61A
Fra
ctio
n w
ith
co
ntr
oll
ed B
P (
%)
Fra
ctio
n w
ith
co
ntr
oll
ed B
P (
%)
BP control in ALLHAT participants:Percentage meeting goal by year of follow-up
Pat
ien
ts m
eeti
ng
go
al (
%)
Pat
ien
ts m
eeti
ng
go
al (
%)
BP <140/90 mmHg SBP <140 mmHg DBP <90 mmHg
Cushman et al. J Clin Hypertens 2002;4:393–404
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
31Gaede et al. N Engl J Med 2003;348:383-93
Macro and microvascular complications in type 2 diabetesMacro and microvascular complications in type 2 diabetes
STENO-2 (n=160); age 55.1 years;follow-up 7.8 years 0 1
RR=0.47P=0.008
RR (95% CI)0.25 0.50 0.75
Cardiovascular
events
Autonomic
neuropathy
Nephropathy
Retinopathy
RR=0.39P=0.003
RR=0.42P=0.02
RR=0.37P=0.002
Intensivebetter
Usualbetter
Steno-2 Study: Significant Benefits with Steno-2 Study: Significant Benefits with Intensive Treatment in Patients with DiabetesIntensive Treatment in Patients with 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
Study protocol requires you to follow a prescribed
drug algorithm
Management Principle
DiagnosisPersistent attempts at nonpharmacologic dx
CostPerception that drug is not
working
Education (HTN is curable)
Concerns over polypharmacy
Confirming diagnosis
Inappropriate nonpharmacologic Rx
Formulary guidelines
Patient pressure
Concern over AEs Concern over metabolic effects Patient Pressure
BP Control
Patient Physician
Opportunities for accepting inadequateBP control
Side effects
Change in lifestyle
Missed visits
Change in HMO plan
Home BP measurements
Reluctance to titrate or add drug
Cost
Uneducatedon BP goal
00 1010 2020 3030 4040 5050 6060 7070 8080
Subjects with SBP <140 mmHg (%)Subjects with SBP <140 mmHg (%)
CONVINCE @ 12 mo(n=13,853)CONVINCE @ 12 mo(n=13,853)
7171
ALLHAT @ 12 mo(n=14,722)ALLHAT @ 12 mo(n=14,722)
53*53*
LIFE @ 12 mo(n=9,194)LIFE @ 12 mo(n=9,194)
26†26†
SBP control in three large trials
*Cushman et al. Am J Hypertens 1998;11(part 2):17A†Dahlöf et al. Am J Hypertens 1999;12(part 2):142A
A well established blood pressure goal results in clinicians being
more aggressive in their management of BP
Management Principle
Goal RatesGoal Rates
Neutel, Smith, Weber, Wang, Masonson. J Clin Hypertens 2004;6:168–74
Drug Algorithm+
BP Goal
Management Principle
Combinationalways more effective than
Titration
Treatment algorithm
OLM: olmesartan; HCTZ: hydrochlorothiazide;AMLO: amlodipine
Step 1week 4
Step 2week 8
Step 3week 12
Step 4week 16
Step 5week 20
Step 6week 24
OLM 40mg/day+ HCTZ 25mg/day+ AMLO 10mg/day
OLM 40mg/day+ HCTZ 25mg/day+ AMLO 5mg/day
OLM 40mg/day+ HCTZ 25mg/day
OLM 40mg/day+ HCTZ 12.5mg/day
OLM 40mg/day
OLM 20mg/day
Target BP: <130/85 mmHg <140/90 mmHg
n=201
Neutel et al. J Clin Hypertens 2004;6:168–74
Yanagisawa et al. Yanagisawa et al. J Med ChemJ Med Chem 1996;39:323–38 1996;39:323–38
Olmesartan: ARB/receptor interactions
OlmesartanOlmesartanATAT11 Receptor Receptor
(transmembrane regions 3–6)(transmembrane regions 3–6)
N
N
NN
NN
HO
O
O
Binding Binding SitesSites
VI V
IVIII
40
Proportion of Patients Achieving Treatment Goal with Various ARBs
32.4
25.9
14.5*16.1*
0
10
20
30
40
50
60
Olmesartan 20 mg Irbesartan 150 mg Losartan 50 mg Valsartan 80 mg
Pa
tie
nts
(%
)
Proportion of patients achieving BP goal (<140/90 mmHg), Proportion of patients achieving BP goal (<140/90 mmHg), retrospective analysis of RCT (n=588) retrospective analysis of RCT (n=588)
*p<0.01 vs. olmesartan
Oparil et al. Am J Hypertens 2005;18:287-94; Oparil et al. J Clin Hypertens 2001;3:283-91, 318
Treat to goal study: Baseline demographics Treat to goal study: Baseline demographics for efficacy cohort (n=197)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
≤130/85
Week 8 Week 16 Week 24
≤130/85
≤130/85
≤140/90
≤140/90
≤140/90
N=198
DBPDBP DBPDBP DBPDBPSBPSBP SBPSBP SBPSBP
-10.7
-16.1-18.2-17.7
-29.3
-33.7
-40
-30
-20
-10
0
35.2
69.3
87.7
58.7
83.2
93.3
20
40
60
80
100
Ch
ang
e in
BP
(m
mH
g)
Pat
ien
ts a
chie
vin
g
BP
go
al (
%)
OLM + HCTZ + AML
OLM + HCTZ
OLM
BP goal
Hypertension management with an Hypertension management with an olmesartan-based algorithmolmesartan-based algorithm
Neutel et al. J Clin Hypertens 2004;6:168–74
Baseline characteristics
Neutel et al. J Hum Hypertens 2006;20:255–62
Gender (% male)
Stage 2(n=113)
69.4
Stage 1(n=85)
70.6
18.8
70.6
149.7/94.7
Prior antihypertensives (%)
Duration of hypertension (years)
Race (%)
- Caucasian
- Black
Age (years)
Baseline SBP/DBP (mmHg)
49.4 (28–80)
6.8
61.9
76.1
14.2
78.8
169.8/98.1
55.3 (35–80)
9.4
<140/90 mmHg
<130/85 mmHg
Stage 1 Stage 2 Total Cohort
97.5%93.3% 90%
87.7% 96.2% 81%
The majority of patients achieved BP goal with an olmesartan-based algorithm
Patients achieving BP goal at week
24 (%)
Neutel et al. J Clin Hypertens 2004;6:168–74Neutel et al. J Human Hypertens 2006;20:255–62
Total Cohort: 179 patients; mean baseline BP = 161/97 mmHgStage 1: 79 patients; mean baseline BP = 150/95 mmHgStage 2: 100 patients; mean baseline BP = 170/98 mmHg
BP CRUSH: Study Design
Open-label, titration study
Visit 5Week 12
Visit 1Screening
(within 7±6 days of Visit 2)
Visit 8Week 22
Visit 2Day 1
Visit 3Week 4
Visit 5AWeek 12 + 1 day
Visit 6Week 16
Visit 7AWeek 20 + 1 day
Visit 2ADay 2
AML/OM 5/40 mg
AML/OM 10/40 mg +
HCTZ 25 mg
AML/OM 10/40 mg +
HCTZ 12.5 mg
AML/OM10/40 mg
Visit 7Week 20
Visit 4Week 8
AML/OM5/20 mg
Visit 5Week 12
Visit 1Screening
(within 7±6 days of Visit 2)
Visit 8Week 22
Visit 2Day 1
Visit 3Week 4
Visit 5AWeek 12 + 1 day
Visit 6Week 16
Visit 7AWeek 20 + 1 day
Visit 2ADay 2
AML/OM 5/40 mg
AML/OM 10/40 mg +
HCTZ 25 mg
AML/OM 10/40 mg +
HCTZ 12.5 mg
AML/OM10/40 mg
Visit 7Week 20
Visit 4Week 8
AML/OM5/20 mg
• 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
Secondary Endpoint:Proportions of Patients Achieving Cumulative SeBP Goals by Titration Dose
Source: Study 8663-404 Data Table 7.10 (18 January 2010)
0
10
20
30
40
50
60
70
80
90
100
49.5
77.1
86.7
AML/OM5/40 mg
AML/OM10/40 mg
AML/OM5/20 mg
63.8
AML/OM10/40 + HCTZ
12.5 mg
AML/OM10/40 + HCTZ
25 mg
90.3<140/90 mm Hg
Pat
ien
ts A
chie
vin
g S
eBP
Go
al (
%)
0
10
20
30
40
50
60
70
80
90
100
18.2
44.3
56.2
AML/OM5/40 mg
AML/OM10/40 mg
AML/OM5/20 mg
31.8
63.8
<130/80 mm Hg
AML/OM10/40 + HCTZ
12.5 mg
AML/OM10/40 + HCTZ
25 mg
Pat
ien
ts A
chie
vin
g S
eBP
Go
al (
%)
0
10
20
30
40
50
60
70
80
90
100
8.5
25.2
37.1
AML/OM5/40 mg
AML/OM10/40 mg
AML/OM5/20 mg
15.7
43.4
<120/80 mm Hg
AML/OM10/40 + HCTZ
12.5 mg
AML/OM10/40 + HCTZ
25 mg
Pat
ien
ts A
chie
vin
g S
eBP
Go
al (
%)
Compliance in the Treatment of HypertensionCompliance in the Treatment of HypertensionCompliance in the Treatment of HypertensionCompliance in the Treatment of HypertensionP
erc
en
tag
e
Number of TabletsDuring, Vetter German Survey
% P
ersi
ste
nce
% P
ersi
ste
nce
Two HTN Agents in One Pill Enhances Adherence
50%50%
60%60%60%60%
70%70%70%70%
80%80%80%80%
90%90%90%90%
100%100%
MonthsMonths
*p<0.05 vs fixed-dose combination Source: Dezii C. Managed Care. 2000;9:S2.*p<0.05 vs fixed-dose combination Source: Dezii C. Managed Care. 2000;9:S2.
Lisinopril/HCTZ combination pill (n=1644)Lisinopril/HCTZ combination pill (n=1644)
Lisinopril and diuretic in separate pills (n=624)Lisinopril and diuretic in separate pills (n=624)
11%*11%*
69%
58%
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
V072004V072004
Patient CompliancePatient Compliance
Δ of Medication
in 1st 6 months
Compliance
2nd 6 months
1 93%
2 75%
*P=< 0.05 vs. patient without Δ of medicationCaro JJ, et al. CMAJ. 1999;160:41.
50
CHEP: Treatment of Systolic-Diastolic Hypertension without Other Compelling Indications
Threshold ≥140/90 mmHg andThreshold ≥140/90 mmHg and TARGET <140/90 mmHgTARGET <140/90 mmHg
CONSIDER
• Nonadherence• Secondary HTN• Interfering drugs or
lifestyle• White coat effect
Dual combinationDual combination
Triple or quadruple therapyTriple or quadruple therapy
*not indicated as first line therapy over 60 yACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers; CCB: calcium channel blocker
Initial therapy
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
Lifestyle modification
Thiazidediuretic
ACEI ARBLong-acting
CCBBeta-
blocker*
2009 CHEP Recommendations. www.hypertension.ca/chep
Percentage of Total Events Occurring Percentage of Total Events Occurring Between 6am and 12noonBetween 6am and 12noon
68
38
49
29
45
0
10
20
30
40
50
60
70
80
SymptomaticAnginaPectoris
MI Stroke Sudden Death
AorticAneurysmRupture
Stroke 1998;23:992 Lancet 1999 ;353:643Am J Cardiol 1999;83:507 Lancet 1998:2:755
-15
-10
-5
0
5
0 4 8 12 16 20 24 28
Losartan Once-a-Day vs. Twice-a-Day Dosing
Losartan Once-a-Day vs. Twice-a-Day Dosing
Reductions from Baseline in Ambulatory DBP at Week 4Reductions from Baseline in Ambulatory DBP at Week 4
Weber, et al. J Hum Hypertens. 1995;9(suppl):S29.
Placebo (n = 26)Losartan 100 mg qd (n = 28)Losartan 50 mg bid (n = 30)
m
mH
gm
mH
g
Hours PostdoseHours Postdose
-30
-20
-10
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
-30
-20
-10
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 TreatmentHours Since Treatment
Average hourly difference in Systolic BP using 7-Term Fourier series smoothingData compiled from non-black, randomized patientsData on file, Sankyo Pharma
Average hourly difference in Systolic BP using 7-Term Fourier series smoothingData compiled from non-black, randomized patientsData on file, Sankyo Pharma
Mean Change in SBP From Baseline at Last VisitMean Change in SBP From Baseline at Last Visit
S
BP
(m
m H
g)
S
BP
(m
m H
g)
Placebo
Olmesartan medoxomil 10 mg BID
Olmesartan medoxomil 20 mg QD
Olmesartan Medoxomil 24 Hour ABPM –BID vs. QD Dosing
Olmesartan Medoxomil 24 Hour ABPM –BID vs. QD Dosing
AASK MAP <92
Target BP (mm Hg)
Multiple Antihypertensive Agents Multiple Antihypertensive Agents Are Needed to Achieve Target BPAre Needed to Achieve Target BP
No. of antihypertensive agents1
UKPDS DBP <85
ABCD DBP <75
MDRD MAP <92
HOT DBP <80
Trial 2 3 4
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.
IDNT SBP <135/DBP <85
ALLHAT SBP <140/DBP <90
ARB TrialsARB Trials
Val-HeFTVal-HeFTELITE IIELITE II
IDNTIDNT
IRMA 2IRMA 2
OPTIMAALOPTIMAAL
LIFELIFE
VALIANTVALIANT
VALUEVALUE
CHARMCHARM
MARVALMARVAL
ONTARGETONTARGET
Heartfailure
CV
Post-MI
Renal
I-PreserveI-Preserve
1996 1997 1998 1999 2000 20022001 2003 2004 2005 2006 2007
SCOPESCOPE
TRANSCENDTRANSCEND
RENAALRENAAL
ARB, angiotensin II receptor blocker.
Diabetic Nephropathy Diabetic Nephropathy Classification for ARB Renal Classification for ARB Renal
Outcome TrialsOutcome Trials
Normal
Stage 1 Pre-Mild
Stage 2Mild
Stage 3 Moderate
Stage 4 Severe
Stage 5 Dialysis
ORIENT (olmesartan)
RENAAL (losartan)
AMADEO/VIVALDI (telmisartan)
MARVAL (valsartan)
Microalbuminuria Proteinuria Proteinuria
IDNT (irbesartan)
ESRD
ROADMAP (olmesartan)
IRMA II (irbesartan)
Placebo Placebo (i.e., conventional anti-HTN Rx (i.e., conventional anti-HTN Rx
except ARBs and ACE-I )except ARBs and ACE-I )
Patients with type 2 diabetes and normoalbuminuria with at least a risk factor for Patients with type 2 diabetes and normoalbuminuria with at least a risk factor for cardiorenal disease, i.e., lipid disorders, smoking, obesity, hypertension; cardiorenal disease, i.e., lipid disorders, smoking, obesity, hypertension;
Median 5 years based on a cumulative number of 325 primary endpoint events; Median 5 years based on a cumulative number of 325 primary endpoint events; 4400 randomized patients (2200 in each group)4400 randomized patients (2200 in each group)
Primary Outcome: Primary Outcome: Time to onset of microalbuminuria Time to onset of microalbuminuria
Secondary Outcomes: Secondary Outcomes: Cardiovascular events, Changes in creatinine clearance, Cardiovascular events, Changes in creatinine clearance, Laser therapy for retinopathyLaser therapy for retinopathy
Secondary Objectives:Secondary Objectives: Composite cardiovascular endpoints (cardiovascular morbidity Composite cardiovascular endpoints (cardiovascular morbidity and mortality), Composite renal endpoints (increase of serum and mortality), Composite renal endpoints (increase of serum creatinine, decrease of GFR), Microangiopathy retinopathy creatinine, decrease of GFR), Microangiopathy retinopathy (laser treatment)(laser treatment)
ROADMAPROADMAPStudy DesignStudy Design
Olmesartan Olmesartan medoxomil 40 mg/dmedoxomil 40 mg/d
Placebo Placebo in addition to background in addition to background
therapy with ACE-Itherapy with ACE-I**** and/or and/or other antihypertensive other antihypertensive
treatmenttreatment
Patients with type 2 diabetes, overt proteinuria, and diagnosed diabetic nephropathy; Patients with type 2 diabetes, overt proteinuria, and diagnosed diabetic nephropathy; Treatment period of 3 – 5 years; 500 patients targeted for randomizationTreatment period of 3 – 5 years; 500 patients targeted for randomization
Primary Outcome: Primary Outcome: Composite renal endpoints of: (1) Doubling of serumComposite renal endpoints of: (1) Doubling of serumcreatinine level, (2) Onset of ESRD (as defined by serumcreatinine level, (2) Onset of ESRD (as defined by serumcreatinine ≥ 5 mg/dL, or the necessity for hemodialysis orcreatinine ≥ 5 mg/dL, or the necessity for hemodialysis orkidney transplantation) and, (3) Deathkidney transplantation) and, (3) Death
ORIENTORIENTStudy DesignStudy Design
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
* * The recommended starting dose for olmesartan medoxomil in the U.S. is 20 mg once-dailyThe 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 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 useddosage/administration regimen as given prior to the study treatment is used
55 years with history of coronary artery disease, PAD, cerebrovascular disease, disease, or diabetes with end-organ damage
Results expected by 2007
The ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
Study population
Study drugs MICARDIS 80 mg/day, ramipril 10 mg/day, or MICARDIS 80 mg/day + ramipril 10 mg/day
Primary endpoint Composite endpoint of CV mortality, nonfatalstroke, acute MI, and hospitalization for CHF
Treatment duration
Study design Double-blind, randomized, parallel-group study involving 25,620 patients in 40 countries
Secondary endpoint Newly diagnosed CHF, DM or atrial fibrillation, Revascularization procedures, development of dementia/cognitive declines, and neuropathy
ONTARGET:Trial DesignONTARGET:Trial Design
A Prospective, Open-label, Dose-A Prospective, Open-label, Dose-titration Study to Evaluate the titration Study to Evaluate the
Efficacy and Safety of an Efficacy and Safety of an OlmesartanOlmesartan–– and Amlodipine and Amlodipine––based Treatment Regimen in based Treatment Regimen in
Subjects With Hypertension and Subjects With Hypertension and Type 2 DiabetesType 2 DiabetesStudy CS-8663-403
Study funded by Daiichi Sankyo, Inc.
Azor® CS-8663-403 Study Design
CS-8663-403 ProtocolVersion 3.0. 22 April 2009
Week 20
Screening(within 3–14 days
of Week –2)
Week 9 Week 18Day 0 Week 3 Week 12/(+1 day)
AML/OM 5/40 mg
AML/OM 10/40 mg +
HCTZ 25 mg
AML/OM 10/40 mg +
HCTZ 12.5 mg
AML/OM10/40 mg
Week 15Week 6
AML/OM5/20 mg
AML5 mg
Week –2
Week –1
Day –1 (Day –1)
Follow-up
ABPM ABPM
Placeborun-in
phase (2-3 weeks)
Week 13Interim
safety visit
Week 16Interim
safety visit
Change From Baseline in Mean 24-hour Ambulatory SBP (± SEM; Primary Endpoint) and DBP (± SEM) at Week 12
Source: Study 8663-403 Data Table D7.1 (4 August 2009).
‡P < 0.0001 vs baseline.
-25
-20
-15
-10
-5
0
SBPDBP–19.9
‡
–11.2
‡
N = 165Baseline BP (mm Hg)144.3 81.6
Ch
ang
e F
rom
Bas
elin
e in
Am
bu
lato
ry B
P (
mm
Hg
)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23100
110
120
130
140
150
160 BaselineWeek 12
Dosing
Mean 24-hour SBP 144.3 mm Hg
Mean 24-hour SBP 124.3 mm Hg
Clock hour
Mea
n h
ou
rly
amb
ula
tory
SB
P (
mm
Hg
)
Hourly Mean Ambulatory SBP at Baseline and Week 12
Source: Study 8663-403 Data Table D7.8 (28 July 2009).
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2355
60
65
70
75
80
85
90
95 BaselineWeek 12
Mean 24-hour DBP 81.6 mm Hg
Mean 24-hour DBP 70.4 mm Hg
Dosing
Clock hour
Mea
n h
ou
rly
amb
ula
tory
DB
P (
mm
Hg
)
Hourly Mean Ambulatory DBP at Baseline and Week 12
Source: Study 8663-403 Data Table D7.8 (28 July 2009).
Secondary Endpoints: Changes From Baseline Secondary Endpoints: Changes From Baseline in Mean Ambulatory SBP and DBP (± SEM) in Mean Ambulatory SBP and DBP (± SEM) During Daytime, Nighttime, and Last 6, 4, and 2 During Daytime, Nighttime, and Last 6, 4, and 2 Hours of Dosing Interval at Week 12Hours of Dosing Interval at Week 12
Source: Study 8663-403 Data Table D7.1 (4 August 2009).
‡P < 0.0001 vs baseline.
Daytime Nighttime Last 6 hours Last 4 hours Last 2 hours
-25
-20
-15
-10
-5
0
SBPDBP
–20.8
‡
–11.1
‡
–11.7
‡
–18.5
‡
–10.4
‡
–18.9
‡
–10.9
‡
–19.1
‡
–19.5
‡
–11.5
‡
N = 165
Ch
an
ge
Fro
m B
as
eli
ne
in
Am
bu
lato
ry B
P (
mm
Hg
)
Baseline BP (mm Hg)149.1 85.7 134.7 74.7 139.5 78.9 142.6 81.4 147.5 85.1
Secondary Endpoint: Change From Secondary Endpoint: Change From Baseline in Mean SeBP (Baseline in Mean SeBP (± SEM)± SEM) During During Each Titration Period, by Titration DoseEach Titration Period, by Titration Dose
Source: Study 8663-403 Data Tables D8.1 & D8.2 (4 August 2009).
‡P < 0.0001 vs baseline.
-30
-25
-20
-15
-10
-5
0
SBPDBP
–10.4‡
–14.0‡
–18.0‡
–4.1‡
–19.3‡
–9.2‡
–22.6‡
–27.6‡
–13.7‡
AML5 mg
N=200
AML/OM5/40 mgN=176
AML/OM10/40 mg
N=163
AML/OM5/20 mgN=188
AML/OM +HCTZ 10/40+ 12.5 mg
N=144
AML/OM +HCTZ 10/40
+ 25 mgN=100
–28.0‡
–8.2‡ –10.4
‡
Baseline BP(mm Hg)
158.8 89.0 158.8 89.0 159.2 89.6 159.4 89.5 159.5 89.7 160.3 89.8
Ch
ang
e F
rom
Bas
elin
e in
BP
(m
m H
g)
Secondary Endpoint: Change From Secondary Endpoint: Change From Baseline in Mean SeBP (Baseline in Mean SeBP (± SEM)± SEM) During During Each Titration Period, by Titration DrugEach Titration Period, by Titration Drug
‡P < 0.0001 vs baseline.Source: Study 8663-403 Data Tables D8.1 & D8.2 (4 August 2009).
-35
-30
-25
-20
-15
-10
-5
0
SBPDBP
–10.4
‡ –14.9
‡
–23.0
‡
–10.8
‡
–30.1
‡
AMLN = 200
AML/OM + HCTZN = 144
AML/OMN = 190
–4.1
‡
Baseline BP(mm Hg)158.8 89.0 158.8 89.1 159.5 89.7
Ch
an
ge
Fro
m B
as
eli
ne
in
BP
(m
m H
g)
Mean Titration Effects (Mean Titration Effects (± SEM)± SEM) in SeBP, by in SeBP, by Titration DrugTitration Drug
‡P < 0.0001 for the change from previous treatment.Source: Study 8663-403 Data Table D8.3 (3 August 2009).
-14
-12
-10
-8
-6
-4
-2
0
SBPDBP
AML/OM to AML/OM + HCTZN = 144
–8.52
‡
–4.81
‡
AML to AML/OMN = 189
–12.53
‡
–6.70
‡
Ch
an
ge
in
BP
(m
m H
g)
Titration Effects in Mean SeBP (Titration Effects in Mean SeBP (± SEM)± SEM), , by Titration Doseby Titration Dose
Source: Study 8663-403 Data Table D8.3 (19 October 2009).
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
SBPDBP
–7.29
–3.89–4.05 –3.70
–1.42
–5.94
–1.33
5 mg to5/20 mgN = 188
5/20 mg to5/40 mg
N = 174
5/40 mg to10/40 mgN = 162
10/40 mg to10/40 + 12.5 mg
N = 144
10/40 + 12.5 mg to10/40 + 25 mg
N = 100
–3.71
–2.05
–1.59
Ch
ang
e in
BP
(m
m H
g)
‡P < 0.0001, †P < 0.005, #P < 0.01, ¶P < 0.05, NSnot significant for the change from previous treatment.
‡
‡ ‡
‡
‡
†
†
NS#
¶
Secondary Endpoint: Proportions Secondary Endpoint: Proportions of Patients Achieving Mean 24-hour of Patients Achieving Mean 24-hour Ambulatory BP Targets at Week 12Ambulatory BP Targets at Week 12
Source: Study 8663-403 Data Table D7.4 (28 July 2009).
*Calculated using the total number of subjects having both baseline and end of study ABPM (N = 165) as the denominator.
<130/80 mm Hg <125/75 mm Hg <120/80 mm Hg0
10
20
30
40
50
60
70
80
70.3
46.1
35.8
Pa
tie
nts
Ac
hie
vin
g A
mb
ula
tory
BP
Ta
rge
t (%
; N
= 1
65
*)
Secondary Endpoint: Proportions of Secondary Endpoint: Proportions of Patients Achieving Daytime and Nighttime Patients Achieving Daytime and Nighttime Ambulatory BP Targets at Week 12Ambulatory BP Targets at Week 12
*Calculated using the total number of subjects having both baseline and end of study ABPM (N = 165) as the denominator.Daytime, 8 AM–4 PM; nighttime, midnight–6 AM.
Source: Study 8663-403 Data Table D7.4 (28 July 2009).
0
10
20
30
40
50
60
70
80
90
50.3
83.0
72.1
29.1
<130/80 <125/75 <120/80 <130/80 <125/75 <120/80
Daytime Nighttime
25.5
67.9
Target (mm Hg)
Pat
ien
ts A
chie
vin
g A
mb
ula
tory
BP
Tar
get
(%
; N
= 1
65*)
Secondary Endpoint: Cumulative SeBP Secondary Endpoint: Cumulative SeBP Goal (<130/80 mm Hg) Achievement by Goal (<130/80 mm Hg) Achievement by Titration Dose Titration Dose
Source: Study 8663-403 Data Table D8.7 (3 August 2009).
0
10
20
30
40
50
60
70
5.0
21.0
42.8
55.2
AML5 mg
N = 200
AML/OM5/40 mgN = 201
AML/OM10/40 mgN = 201
AML/OM5/20 mgN = 200
31.8
AML/OM+ HCTZ10/40 +12.5 mgN = 201
AML/OM+ HCTZ10/40 +25 mg
N = 201
61.7
Pa
tie
nts
Ac
hie
vin
g S
eB
P G
oa
l (%
)
Subgroup Analysis – Metabolic SyndromeSubgroup Analysis – Metabolic SyndromeChanges From Baseline in Mean 24-hour Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (Ambulatory SBP and DBP (± SEM) ± SEM) at Week 12at Week 12
Source: Study 8663-403 Data Tables D7.1 & D7.1s (4 August 2009).
‡ P< 0.0001 vs baseline.
Metabolic Syndrome Total ABPM Cohort
-25
-20
-15
-10
-5
0
SBPDBP
N = 131 N = 165
–19.7
‡
–11.2
‡
–19.9
‡
–11.2
‡
Baseline BP(mm Hg)144.0 81.8 144.3 81.6
Ch
an
ge
Fro
m B
as
eli
ne
in
Am
bu
lato
ry B
P (
mm
Hg
)
Subgroup Analysis – Metabolic SyndromeSubgroup Analysis – Metabolic SyndromeMean 24-hour Ambulatory BP Target Mean 24-hour Ambulatory BP Target Achievement at Week 12Achievement at Week 12
Source: Study 8663-403 Data Tables D7.4 & D7.4s (29 July 2009).
0
10
20
30
40
50
60
70
8071.8
46.6
35.9
Metabolic SyndromeN = 131
Total ABPM CohortN = 165
<130/80 <125/75 <120/80 <130/80 <125/75 <120/80
70.3
46.1
35.8
Target (mm Hg)
Pa
tie
nts
Ac
hie
vin
gA
mb
ula
tory
BP
Ta
rge
t (%
)
Subgroup Analysis – ObesitySubgroup Analysis – ObesityChanges From Baseline in Mean 24-hour Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (Ambulatory SBP and DBP (± SEM) ± SEM) at Week 12at Week 12
BMI, body mass index.
‡P < 0.0001 vs baseline.Source: Study 8663-403 Data Table D7.1s (4 August 2009).
BMI 30 kg/m2
BMI <30 kg/m2
-25
-20
-15
-10
-5
0
SBPDBP–19.4
‡
–11.8‡
N = 110 N = 55
–21.1
‡
–11.0
‡
Baseline BP(mm Hg)
144.5 81.7 144.0 81.5
Ch
an
ge
Fro
m B
as
eli
ne
in
Am
bu
lato
ry B
P (
mm
Hg
)
Subgroup Analysis – ObesitySubgroup Analysis – ObesityMean 24-hour Ambulatory BP Target Mean 24-hour Ambulatory BP Target Achievement at Week 12Achievement at Week 12
Source: Study 8663-403 Data Table D7.4s (29 July 2009).
0
10
20
30
40
50
60
70
80
69.1
43.6
50.9
<130/80 <125/75 <120/80
BMI 30 kg/m2
N = 110
<130/80 <125/75 <120/80
BMI <30 kg/m2
N = 55
32.7
72.7
41.8
Target (mm Hg)
Pa
tie
nts
Ac
hie
vin
gA
mb
ula
tory
BP
Ta
rge
t (%
)
Subgroup Analysis – RaceSubgroup Analysis – RaceChanges From Baseline in Mean 24-hour Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (Ambulatory SBP and DBP (± SEM) ± SEM) at Week 12at Week 12
‡P < 0.0001 vs baseline.Source: Study 8663-403 Data Table D7.1s (4 August 2009).
Black Non-Black
-25
-20
-15
-10
-5
0
SBPDBP–19.7
‡
–11.1
‡
N = 28 N = 137
–20.0
‡
–12.1
‡
Baseline BP(mm Hg)
149.1 87.7 143.3 80.4
Ch
an
ge
Fro
m B
as
eli
ne
in
Am
bu
lato
ry B
P (
mm
Hg
)
Subgroup Analysis – RaceSubgroup Analysis – RaceMean 24-hour Ambulatory BP Target Mean 24-hour Ambulatory BP Target Achievement at Week 12Achievement at Week 12
Source: Study 8663-403 Data Table D7.4s (29 July 2009).
0
10
20
30
40
50
60
70
80
46.4
25.0
50.4
BlackN = 28
Non-BlackN = 137
25.0
75.2
38.0
<130/80 <125/75 <120/80 <130/80 <125/75 <120/80
Target (mm Hg)
Pa
tie
nts
Ac
hie
vin
gA
mb
ula
tory
BP
Ta
rge
t (%
)
Subgroup Analysis – Hypertension StageSubgroup Analysis – Hypertension StageChanges From Baseline in Mean 24-hour Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (Ambulatory SBP and DBP (± SEM) ± SEM) at Week 12at Week 12
Source: Study 8663-403 Data Table D7.1s (4 August 2009).
‡P < 0.0001 vs baseline.
Stage 1 Stage 2
-25
-20
-15
-10
-5
0
SBPDBP
–17.9
‡
–12.4
‡
N = 94 N = 71
–22.7
‡
–10.4
‡
Baseline BP(mm Hg)
139.5 79.9 150.7 83.9
Ch
an
ge
Fro
m B
as
eli
ne
in
Am
bu
lato
ry B
P (
mm
Hg
)
Subgroup Analysis – Hypertension StageSubgroup Analysis – Hypertension StageMean 24-hour Ambulatory BP Target Mean 24-hour Ambulatory BP Target Achievement at Week 12Achievement at Week 12
Source: Study 8663-403 Data Table D7.4s (29 July 2009).
0
10
20
30
40
50
60
70
80
9081.9
55.3
33.8
Stage 1N = 94
Stage 2N = 71
44.7
54.9
23.9
<130/80 <125/75 <120/80 <130/80 <125/75 <120/80
Target (mm Hg)
Pa
tie
nts
Ac
hie
vin
gA
mb
ula
tory
BP
Ta
rge
t (%
)
The Safety and Efficacy of The Safety and Efficacy of Olmesartan Medoxomil Olmesartan Medoxomil ± HCTZ ± HCTZ in Patients with Type 2 Diabetes in Patients with Type 2 Diabetes and Hypertensionand Hypertension
Results of an open-label, multi-center, dose-titrated, single arm ABPM study (866-449)
Study funded by Daiichi Sankyo, Inc.
Mean Change in 24-hour ABPM SBP and DBP at End of Study
-20.4
-11.1
-25
-20
-15
-10
-5
0
Me
an
ch
an
ge
in
BP
(m
m H
g)
SBP DBP
Total Cohortn=172
Baseline mean 24-h ABPM: 146.3/83.3 mm Hg
*P < 0.0001 to baseline
Mean Change in 24-hour ABPM SBP and DBP by Treatment Regimen at End of Study
-10.5
-12.6
-9.8
-6.8
-20.2*
-23.7*
-10.8*
-13.5*
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
Me
an
ch
an
ge
in
BP
(m
m H
g)
SBP DBP
OM20 mgn=3
OM40 mgn=4
OM/HCTZ40/12.5 mgn=25
OM/HCTZ40/25 mgn=140
Baseline mean 24-h ABPM: 146.3/83.3 mm Hg
*P < 0.0001 to baseline
0 4 8 12 16 20 24110
120
130
140
150
160
End of Study
Baseline
Time (h)
Me
an
SB
P (
mm
Hg
)Hourly Mean ABPM SBP at Baseline and End of Study
Mean 24-h SBP: 146.3 mm Hg
Mean 24-h SBP: 126.0 mm Hg
Overall, 61.6% of patients achieved mean 24-h ABPM SBP goal of <130 mm Hg
Hourly Mean ABPM DBP at Baseline and End of Study
Mean 24-h DBP: 83.3 mm Hg
Mean 24-h DBP: 72.2 mm Hg
0 4 8 12 16 20 2460
70
80
90
End of Study
Baseline
Time (h)
Me
an
DB
P (
mm
Hg
)
Overall, 86.6% of patients achievedmean 24-h ABPM DBP goal of <80 mm Hg
Mean Change from Baseline in Cuff SeSBP and SeDBP Throughout the Study, by Treatment Regimen
-21.3
-9.8
-25
-20
-15
-10
-5
0
Me
an
ch
an
ge
in
Se
BP
(m
m H
g)
SeSBP SeDBP
Baseline mean Cuff BP: 158.1/90.0 mm Hg
All data P < 0.0001 to baseline.Values are from treatment exposure throughout the study, regardless of whether patient remained on treatment regimen or were titrated to a different regimen.
Total Cohortn=192
Mean Change from Baseline in Cuff SeSBP and SeDBP Throughout the Study, by Treatment Regimen
-9.5-10.4
-18.7
-21.8
-4.0-5.5
-8.7-9.9
-25.0
-20.0
-15.0
-10.0
-5.0
0.0
Me
an
ch
an
ge
in
Se
BP
(m
m H
g)
SeSBP SeDBP
OM20 mgn=192
OM40 mgn=182
OM/HCTZ40/12.5 mgn=171
OM/HCTZ40/25 mgn=141
Baseline mean Cuff BP: 158.1/90.0 mm Hg
All data P < 0.0001 to baseline.Values are from treatment exposure throughout the study, regardless of whether patient remained on treatment regimen or were titrated to a different regimen.
79.7
70.9
61.6
40.745.9
57.3
35.4
26.6
15.1
0
20
40
60
80
100
BP
Go
al A
chie
vem
ent
(%)
Achievement of BP Goals at End of Study
Assessed by 24-h ABPM, N = 172
Assessed by Cuff BP measurement, N = 192
Baseline mean 24-h ABPM BP: 146.3/83.3 mm Hg
Baseline mean Cuff BP: 158.1/90.0 mm Hg
<140/90mm Hg
<135/85mm Hg
<130/80mm Hg
<120/80mm Hg
<125/75mm Hg
Achievement of BP Goals through the Duration of the Study using Cuff BP Measurement, by Treatment Regimen
31.3
13.510.4
5.2
44.8
23.4
17.7
8.3
64.6
39.6
29.7
17.2
71.4
51.0
41.1
24.0
0
20
40
60
80
100
<140/90 mm Hg <135/85 mm Hg <130/80 mm Hg <120/80 mm Hg
BP
Go
al A
chie
vem
ent
(%)
Cumulative percents are calculated using the total number of subjects in the treatment cohort (N=192) as the denominator.
OM 20 mg
OM 40 mg
OM/HCTZ 40/12.5 mg
OM/HCTZ 40/25 mg
Baseline mean Cuff BP: 158.1/90.0 mm Hg