The role of BP management in addressing CVD & stroke:

Evolving therapeutic insights

Kausik Ray, MD

St George’s University of London

United Kingdom

PUBLIC HEALTH CHALLENGE WORLDWIDE

Residual Lifetime Risk for

Hypertension From Age 55

Vasan RS et al. JAMA. 2002;287:1003-1010

Framingham.

Individuals who are normotensive at age 55 have

a > 90% lifetime risk of developing hypertension

Ris

k f

or

Hyp

ert

en

sio

n (

%)

Time (Years)

10 15 20 250

20

40

60

80

100

52

8391

72

56

8893

78

Women

Men

Str

oke

Mo

rtali

ty(f

loati

ng

ab

so

lute

ris

k a

nd

95%

CI)

160 180120 140

50-59

60-69

70-79

80-89

0

4

32

256

Usual SBP (mmHg)Prospective Studies Collaboration, Lancet, v.360, Dec. 14, 2002

Stroke Mortality Rate in Each Decade of Age vs Usual

BP at the Start of that Decade

Age at Risk:

Prospective Studies Collaboration, Lancet, v.360, Dec. 14, 2002

Ischemic Heart Disease Mortality Rate in Each Decade of

Age vs Usual BP at the Start of that Decade

160 180140

Usual SBP (mmHg)

90 100 110

IHD

Mo

rtality

(flo

ati

ng

ab

so

lute

ris

k a

nd

95%

CI)

120

50-59

60-69

70-79

80-89

0

4

32

256

70 80

0

4

32

256

Usual DBP (mmHg)

40-49

50-59

60-69

70-79

80-89

40-49

Age at Risk:Age at Risk:

6

Reducing BP Prevents CV Outcomes in Patients with

Hypertension

Each 2 mm Hg

Rise in SBP2

Risk of Mortality

from Ischemic Heart

Disease

Risk of Mortality

from Stroke

7%

There is an undoubted and well-proven benefit in reducing mean BP in

patients with hypertension to prevent CV events1–3

BP, blood pressure; CV, cardiovascular.

1. Mancia G, et al. Eur Heart J. 2007;28:1462-1536.

2. NICE Hypertension guidelines 2011 http://publications.nice.org.uk/hypertension-cg127.

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

10%

Blood Pressure Guidelines

2014

Lifestyle Modifications

Blood

pressure

in mm Hg

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/ACC/CD

C 2013

JNC 8

2014

Definition of

Hypertension

>140/90

and

daytime

ABPM (or

home BP)

>135/85

>140/90 >140/90 >140/90 Not

addressed

Definitions

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/ACC/CD

C 2013

JNC 8 2014

Drug therapy

in low risk

patients after

non-

pharmacologic

treatment

>160/100

and

daytime

ABPM

>150/95

>140/90 >140/90 >140/90 <60 y. >140/90

>60 y. >150/90

Drug therapy

in higher risk

patients

Risk>20% 10yr

CVD

Diabetes

CRD

> 140/90

And

Daytime

ABPM

>135/85

Thresholds for intervention

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/ACC/

CDC

2013

JNC 8 2014

First line

drug

Non-

black

Age <55

A

Age >55

C

D B

C A

Age <60

A

Age >60

C D

D (most)

A C

D C A

First line

drug

Black

C C D

D (most)

A C

D C A

Second

and third

line drugs

A+C+D

algorithm

A+C+D

algorithm

Add

another

class

Add

another

class

Drug Treatment of Hypertension (NICE)

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/AC

C/CDC

2013

JNC 8

2014

Beta-

blockers as

first line

drug

No

(Step 4)

Yes No

(Step 4)

No

(Step 3)

No

(Step 4)

Choice of

diuretic

chlorthalidon

Indapamide

(not first line)

thiazides

chlorthalidon,

indapamide

thiazideschlorthalidon,

indapamide

thiazides thiazideschlorthalidon,

indapamide

Beta-blockers and diuretics

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/ACC

/CDC

2013

JNC 8

2014

Initiate drug

therapy with

two drugs

Not

mentioned

In patients

with

markedly

elevated BP

>160/100 >160/100 >160/100

Combined drug therapy first line

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/ACC/

CDC

2013

JNC 8

2014

Blood

pressure

targets

<140/90

>80 y.

<150/90

<140/90

Elderly <80 y.

SBP 140-150

SBP <140 in fit

patients

Elderly >80 y.

SBP 140-150

<140/90

>80 y.

<150/90

<140/90

Lower

targets may

be

appropriate

in some

patients,

including

the elderly

<60 y.

<140/90

>60 y.

<150/90

Blood pressure targets

NICE

2011

ESH/ESC

2013

ASH/ISH

2014

AHA/ACC/

CDC

2013

JNC 8

2014

Blood

pressure

target in

patients

with

diabetes

mellitus

Not

addressed

<140/90 <140/90 <140/90

Lower

targets may

be

considered

<140/90

Blood pressure targets in diabetes

Pharmacological Treatment of Hypertension

– Update 2013

Drugs to be preferred in specific conditions

(ESH/ESC)

.

Ambulatory BP monitoring (ABPM)- ESC 2013

• LVH, CIMT correlate better with ABPM than with office BP

• 24-h av BP consistently has a stronger relationship with morbidity and fatal

events than office BP

• ABPM is superior in young and old, men and women, untreated and treated

hypertensive patients, in patients at high CV risk and in patients with CVD or

renal disease

• Night-time BP may be a stronger predictor of events than daytime

• The night-day ratio is a predictor of CV events but no better than av 24-h BP.

• CVD events are higher in those with a lesser drop in nocturnal BP than in

those with greater drop

Home BPM- ESC 2013

Measure morning and evening on 7 consecutive days gives a

better measure of BP

Home BP is more closely related to hypertension-induced

complications than office BP, particularly LVH

meta-analyses of prospective studies show that prediction of CV

morbidity and mortality significantly better with home BPM than

with office BP

Studies in which both ABPM and HBPM show that home BP is as

prognosticaly significant as home BP to outcomes

OUT OF OFFICE BP Measures-ESC 2013

Blood Pressure variability

Background

What is BPV?

• BP normally fluctuates during the day and can vary from day to day in

response to environmental challenges, eg, stress, activity, carrying out

tasks, etc 1

• Pronounced fluctuations in BP can occur over short- and long-term

observation periods

• BPV has been observed:

– over a 24-hour period with ABPM showing hour-to-hour variability

– between clinic visits (visit-to-visit variability) in the short and long term

• Episodic hypertension is common2

– In a cohort of patients with previous TIAs, only 12% had stable

hypertension, but 69% had episodic hypertension (some systolic

BP readings ≤140 mmHg, and some >140 mmHg)

1. Mann SJ. J Clin Hypertens 2009;11:491-7.

2. Rothwell PM. Lancet. 2010;375:938-948.

ABPM, ambulatory BP monitoring; BP, blood pressure;BPV, BP variability; TIA, transient ischemic attack.

Dipper Daytime BP

HMBP

BP

Variability

24h

Average

BP

Clinic BP

25

BP Is Variable: 24h Short-term

Thomas G.et al. N Engl J Med 2006;354:2368-74

Morning BP

Nighttime BP

Noon 3 PM 6 PM 9 PM Midnight 3 AM 6 AM 9 AM

Intra-individual BPV over time varies from one patient to another

Adapted from Rothwell PM. Lancet. 2010;375:938-948.

Patient 1 with lower BPV Patient 2 with higher BPV

Weeks

40

60

80

100

120

140

160

180

200

220

Blo

od p

ressu

re

(mm

Hg)

1 2 3

SBP

DBP

40

60

80

100

120

140

160

180

200

220

Blo

od p

ressu

re

(mm

Hg)

1 2 3

Weeks

BPV, BP variability.

Time (months)Number at risk

Valsartan

Amlodipine 7596

7649

7497

7499

7458

7458

7332

7319

7205

7177

6905

6853

7065

7016

6727

6680

6141

6078

3840

3864

1532

1520

6562

6504

Pro

po

rtio

n o

f P

ati

ents

Wit

h F

irst

E

ven

t (%

)

7

6

5

4

3

2

1

0

0 6 12 18 24 30 36 42 48 54 60 66

Valsartan-based regimenAmlodipine-based regimen

HR = 1.19; 95% CI = 1.02-1.38; P = 0.02

Julius S et al. Lancet. June 2004;363.

VALUE-CHD events

CAMELOT

• DESIGN, SETTING, AND PARTICIPANTS:

• Double-blind, randomized, multicenter, 24-month trial (enrollment

April 1999-April 2002) comparing amlodipine or enalapril with

placebo in 1991

• patients with angiographically documented CAD (>20% stenosis

by coronary angiography) and diastolic blood pressure <100 mm

Hg.

• A substudy of 274 patients measured atherosclerosis progression

by intravascular ultrasound (IVUS).

CAMELOT BP Results

Overall Mean Reduction in BP

Norvasc -4.8/2.5 mm Hg

Enalapril -4.9/2.4 mm Hg

Placebo +0.7/0.6 mm Hg

– Reductions in the Norvasc and

enalapril groups were statistically

significant vs placebo (P<.001)

– There was no statistically

significant difference between

Norvasc and enalapril

Months After Randomization

Nissen et al, for the CAMELOT investigators. JAMA. 2004;292:2217-2226.

Norvasc® (amlodipine besylate) EnalaprilPlacebo

Sys

tolic

Pre

ssur

e (m

m H

g)

132

130

128

126

124

122

120

Dia

stol

ic P

ress

ure

(mm

Hg)

80

78

76

74

72

0 1 2 6 9 12 15 18 21 24

CAMELOT Primary Composite End Point

Adverse CV Events*

No. at riskPlacebo 655 588 558 525 488Enalapril 673 608 572 553 529Norvasc 663 623 599 574 535

31% Risk Reduction for Norvasc® (amlodipine besylate) vs Placebo (P=.003)

15% Risk Reduction for Enalapril vs Placebo (P=.16)

*CV death, nonfatal MI, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina, hospitalization for CHF, fatal/nonfatal stroke or TIA, any new diagnosis of PVD. Nissen et al, for the CAMELOT investigators. JAMA. 2004;292:2217-2226.

Cu

mu

lati

ve E

ven

ts,

Pro

po

rtio

n

Months0 6 12 18 24

0

0.25

0.20

0.15

0.10

0.5

Placebo

Enalapril

Norvasc

23.1%20.2%

16.6%

Nissen SE, et al, for the CAMELOT investigators. JAMA. 2004;292:2217-2226.

Why?

• Amlodipine has a 50-hour half-life, resulting in nearly

constant blood pressure reduction, whereas enalapril has an

11-hour half-life.

• The current study measured blood pressure during the

daytime clinic visits and may have underestimated nighttime

and early morning differences. Since many coronary events

occur in the early morning hours, just prior to awakening, the

continuous effects of amlodipine may have proven

advantageous.

Study design

atenolol ±

bendroflumethiazideamlodipine ±

perindopril

19,257

hypertensive

patients

PROBE

design

ASCOT-BPLA

Investigator-led, multinational randomised controlled trial

conducted in hypertensive patients, 40 -79 yrs, with no prior history

of CHD, but with 3 additional cardiovascular risk factors (male sex,

> 55 yrs, smoking etc )

ASCOT- BLOOD PRESSURE REDUCTION

NORVASC vs. AtEnOLOL

Compared with those allocated the atenolol-based regimen, blood-pressure values were lower

throughout the trial in those allocated the amlodipine based regimen.

ASCOT-BPLA: summary of all endpoints

The area of the blue square is proportional to the amount of statistical information

Amlodipine perindopril better Atenolol thiazide better0.50 0.70 1.00 1.45

Primary

Non-fatal MI (incl. silent) + fatal CHD

Secondary

Non-fatal MI (excl. silent) + fatal CHD

Total coronary endpoint

Total CV events and procedures

All-cause mortality

Cardiovascular mortality

Fatal and non-fatal stroke

Fatal and non-fatal heart failure

Tertiary

Silent MI

Unstable angina

Chronic stable angina

Peripheral arterial disease

Life-threatening arrhythmias

New-onset diabetes mellitus

New-onset renal impairment

Post hoc

Primary endpoint + coronary revasc procs

CV death + MI + stroke

2.00

Unadjusted hazard

ratio (95% CI)

0.90 (0.79-1.02)

0.87 (0.76-1.00)

0.87 (0.79-0.96)

0.84 (0.78-0.90)

0.89 (0.81-0.99)

0.76 (0.65-0.90)

0.77 (0.66-0.89)

0.84 (0.66-1.05)

1.27 (0.80-2.00)

0.68 (0.51-0.92)

0.98 (0.81-1.19)

0.65 (0.52-0.81)

1.07 (0.62-1.85)

0.70 (0.63-0.78)

0.85 (0.75-0.97)

0.86 (0.77-0.96)

0.84 (0.76-0.92)

BLOOD PRESSURE VARIABILITY REDUCTION Within-visit variability of systolic blood pressure in ASCOT-BPLA

The mean within-visit SD was 5.91 (95% CI 5.87–5.94) and the mean range was 11.21 (11.14–11.29)

in the atenolol group and 5.42 (5.38–5.45) and 10.28 (10.21–10.35) in the amlodipine group (both

p<0.0001). Bars are 95% CI.

Stroke Systolic blood pressure

Variables in model HR (95% CI) p value

Treatment (Rx) 0.78 (0.67–0.90) 0.001

Usual BP

Rx + mean 0.84 (0.72–0.98) 0.025

Visit-to-visit BP variability

Rx + mean + SD 0.96 (0.82–1.12) 0.59

Rx + mean + CV 0.95 (0.82–1.11) 0.55

Rx + mean + VIM 0.96 (0.82–1.12) 0.58

Within-visit and visit-to-visit BP variability

Rx + within-visit SD 0.84 (0.72–0.98) 0.024

Rx + mean + VIM + WVSD 0.99 (0.85–1.16) 0.89

SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean;

WVSD, within-visit standard deviation

Hazard ratios (95% CI) for the effect of treatment

(amlodipine versus atenolol) on risk of stroke

Parameters calculated using all BP measurements from 6 months onwards. Mean, SD, CV,

and VIM are entered into the model as deciles

Coronary Events Systolic blood pressure

Variables in model HR (95% CI) p value

Treatment (Rx) 0.85 (0.77–0.94) 0.002

Usual BP

Rx + mean 0.88 (0.80–0.98) 0.019

Visit-to-visit BP variability

Rx + mean + SD 1.00 (0.90–1.11) 0.98

Rx + mean + CV 1.00 (0.90–1.11) 0.99

Rx + mean + VIM 1.00 (0.90–1.10) 0.99

Within-visit and visit-to-visit BP variability

Rx + within-visit SD 0.88 (0.79–0.97) 0.013

Rx + mean + VIM + WVSD 1.01 (0.91–1.12) 0.88

SD, standard deviation; CV, coefficient of variation; VIM, variability independent of mean;

WVSD, within-visit standard deviation

Hazard ratios (95% CI) for the effect of treatment

(amlodipine versus atenolol) on risk of coronary events

Parameters calculated using all BP measurements from 6 months onwards. Mean, SD, CV,

and VIM are entered into the model as deciles

BLOOD PRESSURE VARIABILITY REDUCTION

Comparisons of systolic blood pressure variability after 3-

month antihypertensive treatment– Amlodipine reduced systolic BPV daytime, nighttime, and 24-hour variability

– Amlodipine significantly decreased Systolic BPV in the 3 time frames (P<0.008 for all)

1. Zhang Y, et al. Hypertension. 2011;58:155-160.

BPV after 3 month’s

treatment

0

2

46

8

10

12

14

16

18

Daytime Nighttime Daily ARVSysto

lic B

P v

aria

bili

ty,

mm

Hg

P = 0.04P = 0.01

P = 0.03

Placebo

Candesartan

Indapamide SR

Amlodipine

P = 0.08* *

***

*

*P <0.05 versus

placebo.

BPV, BP variability;

ARV, average real variability; SR, sustained

release.

Summary

• Hypertension is common and a public health problem

• Consensus on guidelines to achieve a BP <140/90

• Amlodipine remains a first line option for pharmacologic treatment in all

recently released guidelines

• Physicians should increasingly recognise measures beyond clinic BP

(e.g. ABPM) as mentioned in 2013 ESC guidelines

• BP variability is a powerful predictor of both stroke and CHD

• CCBs reduce variability compared with other agents and this seems to

explain differences in stroke and CHD outcomes between amlodipine-

based and atenolol-based treatment in ASCOT

• Beyond BP lowering reducing BVP may be the next target for Tx