Achieving Blood Pressure Goal: From Clinical Trial into Real-World Data

Dr Erwin SpPD

PIT IDI VIII BOGOR 2015

Achieving Blood Pressure Goal: From Clinical

Trial into Real-World Data

Hypertension remains a leading cause of mortalityAnnually over 7 million deaths world-wide associated with hypertension

Hypertension causes a large direct and indirect economic burden

accounted for $73.4 billion in US in 20091

responsible for ~7.6 million deaths worldwide in 20012

The global incidence of hypertension is increasing3

Less than 50% of hypertensive patients in US receive therapy. In Canada and Europe approximately 66-75% were untreated4

Approximately 70% of patients do not reach BP goals.

Population with hypertension (%)

30

Overall

26

28

Males Females

20002025

24

1. Cohen JD. Manag Care 2009;18:51–8;

2. Lawes et al. Lancet 2008;371:1513–8;

3. Kearney et al. Lancet 2005;365:217–23;

4. Wolf-Maier et al. Hypertension 2004;43:10–17.

Kearney et al. Lancet 2005;365:217–23

Flack et al. Managed Care Interface 2002, Nov 28-36

Major cardiovascular events/year*

10 000

20 000

30 000

40 000

50 000

Medicated Unmedicated Total0

DBP/SBP uncontrolled

DBP uncontrolled

SBP uncontrolled

The global incidence of hypertension will

exceed 29% by 2025

Uncontrolled BP results in >40,000 major CV

events per year in the USA

>50% have 2 or more comorbidities

Men

Kannel WB. Am J Hypertens. 2000:13:3S-10S.

Comorbidities:• Obesity• Glucose intolerance• Hyperinsulinemia• Reduced HDL-C• Elevated LDL-C• Elevated TG• LVH

≥ Four

8%

Three22%

Two25%

One26%

None19%

Women

≥ Four 12%

Three20%

Two24%

One27%

None17%

More Than 80% of Hypertensive Patients Have Additional

Comorbidities

Approximately 70% of Patients* Who Receive Treatment Do Not

Reach BP Goal in Europe

Wolf-Maier et al. Hypertension 2004;43:10–17

*Treated for hypertension

BP goal is <140/90 mmHg

60 79 70 81 72

0

20

40

60

80

100

BP goal achieved BP goal not achievedPatients (%)

England Sweden Germany Spain Italy

Blood pressure (BP) control rates in hypertensive patients in

developing economies

Thailand*,#,2

47.8

51.8%

China*,1

27.4%

1Wang et al. Chin J Epidemiol 2012;33:903–6; 2Aekplakorn et al. J Hypertens 2012; 30:1734–42

3Chiang et al. J Formos Med Assoc 2010;109:740–3;4Sison et al. PJC 2007;35:1–9

5Erem et al. J Public Health 2009;31:47–586Hernández-Hernández et al. J Hypertens. 2010;28:24-34

Turkey*,5

24.3%

*Treated population#Control rate: 47.8% in males, 51.8% in females†Control rate: 21% in males, 29% in females

Taiwan†,3

2129%

Philippines*,4

20.0%

BP controlled

BP uncontrolled

24.0%

Latam*,6

Physician-Related Barriers to Effective

Antihypertensive Treatment

Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662;

Chobanian AV, et al. JAMA. 2003;289:2560-2572;

Okonofua EC, et al. Hypertension. 2006;47:345-351.

Therapeutic inertia

Overestimation of adherence to

guideline

Disagreement with guidelines

ISH

Concern about the relationship

between DBP and MI (i.e. J

curve)

Reluctance to treat a seemingly

“asymptomatic condition”

Unfamiliarity with current treatment

guideline

BP thresholds

ISH

Threshold for diabetic patients

Use of monotherapy to treat

patients with difficult-to-control

blood pressure

Belief that in-office BP tends to be

higher than at-home BP

Number of antihypertensive agents needed to reach

blood pressure (BP) goal

MDRD study group, NEJM 1994; 330:877; Kjeldsen et al Hypertension 1998: 31: 1014-1020; Breener et al NEJM 345: 861-69; Bakris et al. Am J Med 2004;116(5A):30S–8;

Lewis et al, NEJM; 2001; 345: 851-860; UKPDS group Lancet, 1998: 352: 854-865; AASK research group Arch Intern Med 168: 832-839; Dahlöf et al. Lancet 2005;366:895–906

van Eijsden et al, Int J Epidemiol 2011, 40: 1176-1186. ALLHAT research group 2002; 288: 2981-2997: Jamerson et al. N Engl J Med 2008;359:241728

Average no. of antihypertensive medications

1 2 3 4

Trial (SBP achieved)

ASCOT-BPLA (136.9 mmHg)

ALLHAT (138 mmHg)

IDNT (138 mmHg)

RENAAL (141 mmHg)

UKPDS (144 mmHg)

ABCD (132 mmHg)

MDRD (132 mmHg)

HOT (138 mmHg)

AASK (128 mmHg)

ACCOMPLISH (132 mmHg)

Initial 2-drug combination therapy

SBP: systolic blood pressure

When and Which Anti-hypertension

Combination?

Guidelines Worldwide Acknowledge That Most Patients

Need Combination Therapy to Achieve BP Goals

Most patients with hypertension will require two or more antihypertensive medications to achieve their BP goals

When BP is > 20/10 mmHg above goal, consideration should be given to initiating therapy with two drugs

Combination treatment should be considered as first choice when there is high CV risk

i.e., in individuals in whom BP is markedly above the hypertension threshold (> 20/10 mmHg), or associated with multiple risk factors sub-clinical organ damage, diabetes, renal or CV disease

Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J. 2007;28:1462–1536; http://www.nice.org.uk/

download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3–107.

Many patients will require more than one drug to achieve adequate BP control

– Pathophysiological reasoning suggests that adding an ACE-I/ARB to a CCB or a diuretic (or vice versa in the younger group) are logical combinations

The use of two or three drugs in combination is often necessary to achieve the target BP control

– A low dose of a diuretic should be included in this combination

JN

C V

IIE

SH

/ES

CN

ICE

The Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension

2009

JS

H

Cardiovascular Risk Stratification

ESHESC Guidelines 2013

Mancia et al. Eur Heart J 2013;34(28):2159-219

Initiation of Antihypertensive Treatment

ESH-ESC Guideline 2013


HYPERTENSION MANAGEMENT ALGORITHM

ESH-ESC 2013


2013 ESH–ESC Recommendation:

Combining blood pressure lowering drugs

Solid lines represent preferred drug combinations in patients with hypertension

ACEI(s): angiotensin-converting enzyme inhibitor(s); ARB(s): angiotensin receptor

blocker(s); CCB(s): calcium channel blocker(s); ESH: European Society of

Hypertension; ESC: European Society of Cardiology

ARB/diuretic and ARB/CCB are

rational combinations available in a

single pill

Preferred combinations

Useful combination

(with some limitations)

Not recommended

Possible, but less

well-tested combinations

Mancia et al. Eur Heart J 2013;34:2159–219

Tolerability and Risk Factor Modification: CCB-induced

Peripheral Edema Minimized by the RAS Inhibitor

Single mode of

action of the CCB

Dual mode of action

of the CCB/RAS

Inhibitor

Illustration modified from www.lotrel.com

RAS inhibitor dilates

arteries and veins

ReducesCCB-induced

peripheral edema

Capillary overload

forces fluid into

surrounding tissue

CCB dilates

arteries

Veins remain

constricted

Messerli et al. Am J Hypertens 2001;14:978–9

ARB• ↓ RAS ↓ SNS

• Arterio- and venodilation

• Effective in high-renin patients

• Congestive heart failure and renal benefits

• Attenuates peripheral edema

• No effect on cardiac ischemia

CCB• ↑ SNS ↑ RAS

• Arteriodilation

• Effective in low-renin patients

• No renal or congestive heart failure benefits

• Peripheral edema

• Reduces cardiac ischemia

negative

sodium balance

reinforces the

effects of the

ARB

Vasodilation

Arterial +

Venous

CCBs and ARBs Interact Synergistically on Vascular and Renal Function,

Sympathetic Nervous System and Renin-Angiotensin System Activity

Natriuresis

Arterial

SNS = sympathetic nervous system; RAS = renin-angiotensin system

SPC

(amlodipine/benazepril)

(n=2,839)

Free combination

(CCB + ACEI)

(n=3,367)

Medication possession ratio†

p<0.0001

88%

69%

0% 20% 40% 60% 80% 100%

Improved compliance with single-pill combination (SPC) therapy

versus free-combination therapy

Gerbino & Shoheiber. Am J Health System Pharm

2007;64:1279–83

†Defined as the total number of days of therapy for medication dispensed/365

days of study follow-up

ACEI: angiotensin-converting enzyme inhibitor; CCB: calcium channel blocker

What did the clinical trials showed on

Amlodipine/Valsartan Combination?

Overall β-blocker CCB ARB ACEI Diuretic

Antihypertensive class prior to randomization in the trial

Ch

an

ge

in

sys

toli

c B

P (

mm

Hg

) fr

om

ba

se

lin

e t

o W

ee

k 8

Randomized, double-blind, multinational parallel-group, 16-week study

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker;

BP: blood pressure; CCB: calcium channel blocker

Incremental BP drops after direct switch to amlodipine/valsartan in

patients previously uncontrolled on monotherapy

Amlodipine/valsartan 10/160 mg

Amlodipine/valsartan 5/160 mg

n= 440 449 76 55 53 70 175 175 92 105 41 390

–5

–10

–15

–20

–25

Allemann et al. J Clin Hypertens 2008;10:185–94

Baseline BP = 150/91 mmHg

Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach BP

Goal <140/90 mmHg

No hydrochlorothiazide add-on was permitted until after Week 8

Randomized, double-blind, multinational, parallel-group, 16-week study Allemann et al. J Clin Hypertens 2008;10:185–94

“Diabetic patients with BP <130/80 mmHg at Week 8 were

47.0% and 49.2% for 5/160 mg and 10/160 mg doses,

respectively”

5 of 10 hypertensive diabetic patients achieved BP goal

(<130/80 mmHg)

How about the real-world experiences on

amlodipine/valsartan combination in

hypertensive Indonesian patients?

Two real-world studies on Amlodipine/Valsartan Combination in Indonesian

PatientsMAX-FORCE and EXCITE Studies: almost total of 1000 patients were recruited

Arini et al. MAX FORCE Poster Publication at The 7th Scientific Meeting of InaSH 2013. Jakarta

Kalim H, et al. EXCITE Poster Publication at The 8th Scientific Meeting of InaSH 2014. Jakarta

Study design Study design

Inclusion criteria: male and female adult patients (age > 18

years) who consented to have their data collected, suffering from

essential hypertension not adequately controlled by monotherapy,

for whom an antihypertensive therapy with amlodipine/valsartan

combination (5/80, 5/160 or 10/160) daily was given at the

discretion of the attending physicians.

Objectives: The clinical EXCITE study evaluated the

effectiveness, safety, tolerability and treatment adherence of

Aml/Val Single Pill Combinations (SPCs) in patients with arterial

hypertension studied in a real-world setting.

Total patients recruited were 500 patients, 464 (92.8%) patients

completed the study, and 35 (7%) patients discontinued the study

due to lost to follow-up. Study period: Mar 2011 to Sept 2012

Inclusion criteria: male and female adult patients (age > 18

years) who consented to have their data collected, suffering from

essential hypertension not adequately controlled by monotherapy,

for whom an antihypertensive therapy with amlodipine/valsartan

combination (5/80, 5/160 or 10/160) daily was given at the

discretion of the attending physicians.

Objectives: This observational study was conducted to assess

safety, tolerability, and effectiveness of single pill combination

(SPC) amlodipine/valsartan in Indonesian hypertensive patients in

daily clinical practice.

Total patients recruited were 488 patients, 480 patients were

analyzed for safety and 468 patients were eligible for ITT

effectiveness analyses. Study period: Feb 2010 to May 2011

Overall Population

Indonesian Real-Life Experiences on Amlodipine/Valsartan SPCPowerful BP reduction showed from two real-world studies

169.1 99.4 164.0 96.4Baseline

MAX-FORCE

Study: Open-

label,

observational,

prospective,

multicenter,

12 weeks

study, with 468

patients eligible

for Intent to

treat analysis

SPC: Single Pill

Combination



EXCITE Study:

Multinational Asia-

Middle East-African

Countries (AMAC)

study, open-label,

observational,

prospective,

multicenter,

26 weeks study. Data

shown on this graph is

only reflected 500

patients from Indonesia

who were eligible for full

set analysis

n=468 n=500

Indonesian Real-World Experiences on Amlodipine/Valsartan SPC in Diverse Type of Patients

Consistently showed powerful BP reduction efficacy



Amlodipine/Valsartan SPC Showed Favorable Safety and Tolerability Profile for Hypertensive Indonesian Patients



• From 480 patients eligible for safety analysis,

10 patients (2.1%) reported AE. Three

patients (0.6%) with mild AE were suspected

to be related to study drug : 2 patients (0.4%)

with edema, and 1 patient (0.2%) with

headache.

• Total of 2 patients (0.4%) with edema already

had edema at baseline.

• No serious AE (SAEs) reported in this

study.

Conclusion: This study showed that in patients

with essential hypertension not adequately

controlled by monotherapy, switching to

amlodipine/valsartan combination resulted in

further decrease in BP and achieved target BP

with good safety, tolerability and effectiveness,

suggesting the use of this combination can be

recommended in daily clinical practice in

Indonesia.

• From 500 patients in the full analysis set, 57

patients (11.4%) reported at least one AE.

The most frequent AEs were dyslipidemia (13

patients, 3%), cough (9 patients, 2%),

headache (7 patients, 1%), and edema (6

patients, 1%).

• 5 (1%) patients reported serious adverse

events (SAE), four patients died due to stroke

or heart attacks, one patient reported a non-

fatal SAE. The events were not suspected to

be related to the study drug.

Conclusion: The Indonesian EXCITE study

analysis showed that in a real-world setting,

amlodipine/valsartan SPC is an effective and

well-tolerated SPC therapy for the

hypertensive population in Indonesia

Summary Hypertension is a major CV risk factor. There are still unmet need in

the treatment of hypertension, with many patients are uncontrolled.

Most of the patients need more than one agent to achieve BP target.

CCB/ARB combination are recommended by guideline as preferred

combination for its efficacy, safety and tolerability profile.

Amlodipine/Valsartan combination provides powerful BP reductions,

favorable safety profile, as well as high BP goal and response rates,

for hypertensive patients including those with comorbidities.

Real-world experiences on SPC of amlodipine/valsartan in Indonesia

show consistent BP reduction powerful effectiveness with good

safety and tolerability in overall hypertensive patients and patients

with comorbidities.

Achieving Blood Pressure Goal: From Clinical Trial into Real-World Data

Health & Medicine

Transcript of Achieving Blood Pressure Goal: From Clinical Trial into Real-World Data