Clinical inertia short

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


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


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



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


DBP initial 86 11 85 10

DBP final 78 73


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


Goal RatesGoal Rates

Neutel, Smith, Weber, Wang, Masonson. J Clin Hypertens 2004;6:168–74

Drug Algorithm+

BP Goal


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


≤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


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 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 6Week 16


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 (

%)

CJones

IS THERE ANYWAY TO CONDENSE SLIDE # 12, 13, 14

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


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



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).


-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


*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.


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


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


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).


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


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


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


<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


Health & Medicine

Clinical inertia short