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Merck Serono Satellite Symposium

“Dual control of blood pressure and heart rate for

cardioprotection”

Hotel Excelsior, Dubrovnik, Croatia

28 September 2013

Dual Control of Blood Pressure and

Heart Rate for Cardioprotection

Paolo Palatini

University of Padova, Padua, Italy

Jan Steen, 1626 - 1679

Heart Rate and All-Cause Mortality

The Framingham Study

Kannel WB et al 1987;113:1489

0

10

20

30

40

50

60

Men, 35-64 ys Men, 65-94 ys

Heart Rate

(bpm)

30-67

68-75

76-83

84-91

92-220

Heart rate and the cardiovascular riskPaolo Palatini and Stevo Julius*

Journal of Hypertension 1997, 15: 3-17

Association Between Resting Heart Rate and

Mortality or CV Events

Positive association with total and/or

cardiovascular mortality in over 70 Studies

Modified from J Hypertens 2006;24:603

Association independent of other risk factors

Consistency similar to that for smoking

Association present in different clinical

settings

Association still present after exclusion of first

years after baseline evaluation

Association with mortality less consistent for

women

Role of elevated heart rate in the

development of cardiovascular

disease in Hypertension(A review of 11 studies)

Palatini P, Hypertension 2011; 58(5):745-50

0

10

20

30

40

50

60

< 65 65-74 75-84 > 84

CHD

CVD

All cause

Gillman et al., Am Heart J 1993; 125: 1148

Ag

e-a

dju

ste

d 2

-year

rate

per

1000

Heart Rate (bpm)

ASSOCIATION OF HEART RATE WITH MORTALITY

RATE AMONG MEN WITH HYPERTENSION(The Framingham Study)

Mortality Rate by Quintile of Clinic Heart Rate

in the ISH Patients from the Syst-Eur Study

Palatini P et al, Arch Int Med 2002;162:2313

0

10

20

30

40

50

< 64 64-68 69-73 74-79 >79

0

10

20

30

40

50

< 67 67-71 72-75 76-79 >79

MEN

WOMEN

Mo

rtality

rate

(%

)M

ort

ality

rate

(%

)

Heart Rate (bpm)

Kaplan-Meier plots of primary composite end point for

high risk hypertensive patients stratified by HR quintile

and BP control. The VALUE Study

Julius S, Palatini P et al, Am J Cardiol 2012, 109;5: 685 - 692

High HR

BP controlled

Low HR

BP controlledLow HR

BP uncontrolled

High HR

BP uncontrolled

Pathogenetic Mechanisms For The

Relationship Between Heart Rate

And CV Risk

0.00

0.04

0.02

0.01

0.03

Heart rate (bpm)

40 60 80 100 12045 52 58 65 72 78 85 92 98 105 112

0

2

4

6

8

10

12

14

16

18

Heart rate (bpm)

Rela

tiv

e f

req

uen

cy (

%)

Heart Rate Distribution for the HARVEST Men before

and after application of “Mixture Analysis”

Coeff of Skewness, 0.58 (P<0.0001). Coeff of Kurtosis, 0.8213 (P=0.0001)

Kolmogorov-Smirnov test for Normal distribution: reject Normality (P=0.0027)

Palatini P et al, Hypertension 1997; 30: 1267

0.00

0.04

0.02

0.01

0.03

0.00

0.04

0.02

0.01

0.03

Heart rate (beats/ min) Heart rate (beats/min)

Heart Rate Distribution for Two Subpopulations With

"High" and "Normal" Heart Rate Identified by Mixture

Analysis in Three Populations

40 60 80 100 120 40 60 80 100 120

MALES FEMALES

0

20

40

60

80

100

Hypertension

Normotension

Persistent

tachycardia

No

tachycardia

2=19.2;P=0.001

Transient

tachycardia

Palatini P et al, J Hypertens 2006,24:1873

Frequency of Hypertension During a 6-year Follow-up in

1050 Stage 1 Hypertensives Divided by Heart Rate Status

7-year Risk Of Overweight Or Obesity Related To

Heart Rate In 1008 Participants From The

HARVEST*

0,8

0,9

1

1,1

1,2

1,3

1,4

1,5

Hazard

rati

o

Adapted from Palatini P et al, Obesity 2011,19:618

Baseline Heart Rate Follow-up Heart Rate

*Results of a multivariable Cox regression

20-year Risk Of Metabolic Abnormalities For A

Baseline Heart Rate ≥ 80 bpm In 637 Healthy

Participants From Japan

0

2

4

6

8

Obesity Abdominal

Obesity

Insulin

resistance

Diabetes

Od

ds r

ati

o

Shigetoh Y et al, Am J Hypertens 2009;22:151

Grassi G. et al., J Hypertens 1998

Relationships between HR, MSNA and Venous NE Values in NT, HT and CHF Patients

40 50 60 70 80 90 100 1100

20

40

60

80

100

40 50 60 70 80 90 100 1100

400

800

1200

1600

0 400 800 1200 16000

20

40

60

80

100

MSNA(bursts/min)

MSNA(bursts/min)

NE(pg/ml)

HR (beats/min) HR (beats/min)

NE (pg/ml)

n = 243

r = 0.38

P < 0.0001

n = 243

r = 0.32

P < 0.0001

n = 243

r = 0.48

P < 0.0001

0

3

5

8

10

0

10

20

30

0

3

5

8

10

LF

: H

F

Sympathetic predominance (n=59)

Normal ANS tone (n=104)

Normotensive controls (n=28)

LF:HF Ratio in 163 Young Hypertensive Subjects

from the HARVEST and 28 Normotensive Controls

*

*

*

Lying Standing Mental stress

Palatini P et al, J Hypertens 2006, 24:1375

0%

10%

20%

30%

40%

Frequency of Hypertension According to Autonomic

Nervous System Activity in the HARVEST

6-year Follow-up in 163 Subjects

P=0.02

Subjects with normal ANS activity

Subjects with sympathetic predominance

Palatini P et al, J Hypertens 2006, 24:1375

4

4,5

5

5,5

6

Evolution of Cholesterol According to Autonomic

Nervous System Activity in the HARVEST

6-year Follow-up in 163 Subjects

Palatini P et al, J Hypertens 2006, 24:1375

P=0.01

Subjects with normal ANS activity

Subjects with sympathetic predominance

Sympathetic

overactivity

Tachycardia

arteriolar

constriction

Coronary

events

veno con-

striction

Hypertension

plasma

volume

hematocrit

muscle

blood flow

Insulin

resistance

cardiac

output

Obesity

lipid

abnormalities

endothelial

dysfunction

artery wall

stress

inflammation

LV systolic

dysfunction

LV apoptosis

collagen

fibrosis

LV stiffness

Heart

failure

Sudden

Death

O2 consumption,

ventricular

arrhythmias

Palatini P, Curr Hypertens Rep 2013

Ohasama Study, Sendai n=1277

Jichi Medical School - 1 n=762

Jichi Medical School - 2 n=379

New York Prognostic Effects of ABPM n=1296

Perugia, PIUMA study n=3345

Chieti n=2254

Padua, HARVEST Study n=1209

Australian National BP Study n=713

Ambulatory Blood Pressure in referred hypertensive

patients: an INTERNATIONAL database

(ABP- INTERNATIONAL, N = 11,235)

New York, NY, USA

ANBP Study, Australia

Perugia, Italy

Chieti, Italy

Padua, ItalySendai, Japan

Jichi-1, Japan

Jichi-2, Japan

Palatini P et al, Int J Cardiol 2103,

Feb 7 [Epub ahead of print]

1.20

1.10

1.00

0.90

24-hour Night-time Night:dayDaytimeOffice

P=0.043 P<0.001 P=0.005 P=0.002

*Adjusted also for average 24h heart rate

HRs And 95% CIs of CVE for a 10 bpm Increment In

age-and-sex adjusted Heart Rates Or a 10%

Increment in the Night:Day Ratio*

1.30

P<0.001

Palatini P et al, Int J Cardiol 2103,

Feb 7 [Epub ahead of print]

Palatini P et al, Int J Cardiol 2103,

Feb 7 [Epub ahead of print]

The Cooper Clinic Mortality Risk IndexClinical Score Sheet for Men

• Age (years)

• Heart rate (bpm)

• Blood pressure (mmHg)

• Diabetes

• Smoking

• Body mass index (Kg/m2)

• Cardiorespiratory fitness (VO2 Max)

Modified from Janssen I et al, Am J Prev Med 2005;29:194

20-44 45-49 50-54 55-59 60-64 65-690 3 6 8 9 10 points

<80 ≥800 2 points

<140/90 ≥140/900 2 points

yes no0 4 points

never former current0 1 4 points

low moderate high2 0 0 points

<35 ≥350 3 points

2013 ESH/ESC Guidelines for the management of

arterial hypertension

BP measurements should always be associated with

measurement of heart rate, because resting heart rate

values independently predict CV morbid or fatal events

in several conditions, including hypertension [62,63]

Journal of Hypertension 2013, 31:1281–135

Heart Rate reduction in Hypertension.

An additional goal in antihypertensive treatment?

Heart Rate Distribution in Subjects With Hypertension (n=38,145)

Heart rate (bpm)

0

5

10

15

20

25

1.43.7

8.0

13.9

19.420.8

0.9 0.5 0.5

% P

ati

en

ts

<55 55-

60

60-

65

65-

70

70-

75

75-

80

100-

105

105-

110

>110

14.5

9.6

4.32.6

80-

85

85-

90

90-

95

95-

100

Farinaro E et al, Nutr Metab Cardiovasc Dis 1999:9;196

>30%

Diuretics =

Beta-blockers

Vasodilators

Dihydropyridines =

Phenylalkylamines

Benzothiazepines

ACE inhibitors =

AII receptor blockers =

Centrally acting drugs

Imidazoline receptor agonists =

Action of Antihypertensive Agents on Heart Rate

Ca-A

Larger(16.2)

Average

(10.0)

Smaller

(4.7)

Relationship between tertile of Heart rate reduction

and effect of treatment on mortality in AMI.

A meta-regression of randomized clinical trials

0.6 0.8 1.0

Larger(15.3)

Average

(9.5)

Smaller

(4.0)

0.6 0.8 1.0

All-cause death Cardiac death

P for trend = 0.017 P for trend = 0.0015

Modified from Cucherat M, Eur Heart J, 2007;28:3012

Odds ratio Odds ratio

Heart

rate

red

uct

ion

, b

pm

Relationship Between Follow-up Heart Rate And Outcome In The INVEST Study

Mean follow-up heart rate (bpm)

0

10

20

30

40

50

Ad

ve

rse

ou

tco

me

in

cid

en

ce

(%

)

<50 55-

60

60-

65

65-

70

70-

75

75-

80

>10080-

85

85-

90

90-

95

95-

100

Kollock R et al, Eur Heart J 2008;29:1327

50-

55

60

0

1.0

2.0

3.0

4.0

Es

tim

ate

d h

aza

rd r

ati

oAdverse outcome

Hazard ratio

Kollock R et al, Eur Heart J 2008;29:1327

50

60

70

80

90

100

Baseline Bisoprolol

He

art

ra

te, b

pm

Effect of Low-Dose Bisoprolol on 24-Hour Heart Rate

in Patients with Dilated Cardiomyopathy

Adapted from Anthonio RL et al, Am J Cardiol 1999;83:1286

0 3 6 9 12 15 18 21 24Time

The role of fixed-dose combination therapy in

the management of hypertension

Prof. Davor Miličić

Department of Cardiovascular Diseases

University of Zagreb

Croatia

Global burden of hypertension

Hypertension is the primary major cause of premature death

972 million with hypertension estimated in 2000 predicted to rise to 1.56 billion by

2025

80% increase in hypertension expected in economically developing regions

Kearney et al. Lancet 2005;365:217-23

WHO findings on hypertension

The #1 global risk factor for premature mortality causing 7.5 million deaths per

annum

Responsible for 51% of stroke and 45% of ischaemic heart disease deaths

Global health risks. WHO 2009

Management of hypertension today

The most common CV disorder affecting 27-55% of adults1

A major risk factor for CV and renal disease1,2

Level of protection achieved against CV diseases is related to the degree of BP

reduction2

However, only 20-55% of treated patients achieve and maintain internationally

recognised targets 1,2

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

2. Struijker-Boudier H et al. Int J Clin Pract 2007;61:1592-602.

Poor BP control in practice populations1

1. Paulsen M et al. Family Practice 2011; published online, May 19, 2011

2. Burnier M et al. Int J Clin Pract 2009;63:790-8.

Cross-sectional survey of 5413 hypertensive patients in Denmark1

“Approximately 7 out of 10 hypertensive patients in

Europe do not achieve target BP” 2

Most treated patients in Eastern Europe do not achieve target BP

Adapted from Grassi G et al. Eur Heart J 2011;32:218-25.

Uncontrolled BP

% of patients displaying office

BP controlled (<140/90 mmHg)

or uncontrolled ≥140/90 mmHg)

7,860 treated patients in the BP-CARE survey in Central

and Eastern Europe (9 countries)

Causes of inadequate BP control

Patient/society Misdiagnosis Doctor

Poverty, lack of health

insurance

Improper BP recording

technique

Physician inertia, poor

motivation to deliver patient

education

Lack of education, health

beliefs

White coat syndrome Multiple guidelines

Difficulty in implementing

lifestyle change

Masked hypertension Insufficient use of multiple

agents or insufficient dosing

Compliance issues relating

to cost, side-effects,

inconvenience, pill burden

Failure to identify secondary

hypertension

Authentic resistant

hypertension

Interactions with other

prescribed medication

Adapted from Elijovich F et al. Ther Adv Cardiovasc Dis 2009;3:231-40.

Inadequate BP control is associated with increased risk of fatal events

n=5128Fully adjusted models§

Hazard ratio (95% CI)

Hypertension category All-cause mortality CVD mortality

Treated controlled 1.00 1.00

Treated uncontrolled 1.57 (1.28-1.91)* 1.74 (1.36-2.22)*

Untreated 1.34 (1.12-1.62)* 1.37 (1.04-1.81)**

Risk of CVD mortality increased by 74% in uncontrolled hypertensives 1

Data from NHANES III in US hypertensive adults (1988-2006)§ adjusted for age, race/ethnicity, smoking, hypercholesterolaemia, obesity, diabetes, CKD, HF, stroke

* p<0.01; ** p<0.05

1. Gu Q et al. Am J Hypertens 2010;23:38-45.

Multiple therapies are required to achieve target BP1

Number of drugs needed to achieve BP 140/90 mmHg

Patients 1 2 3 4 5 +

Men (all ages) n 333 400 408 248 104

Men (all ages) % 22.3% 26.8% 27.3% 16.6% 7.0%

Women (all ages) n 154 263 387 317 219

Women (all ages) % 11.5% 19.6% 28.9% 23.7% 16.3%

1. Adapted from Marshall T. J Hum Hypertens 2005;19:317-9.

2. Gradman A et al. J Am Soc Hypertens 2010;4:42-50.

3. Mancia et al. J Hypertens 2009; 27:2121-58

≥75% of patients require multiple therapies to achieve target 2

Evidence has continued to grow that in the vast majority of hypertensive patients, effective

BP control can only be achieved by combination of at least two antihypertensive drugs 3

Pathophysiology of essential hypertension: multiple causes

Adapted from Sever P, Messerli FH. Eur Heart J 2011;32:2499-506.

• Autoregulation

• Ion transport inhibitors

• Sympathetic nervous system

• Renin-angiotensin-aldosterone system

• Other hormonal systems

• Renal mechanisms

• Vascular wall contractility and structure

• Rarefaction

Rationale for combination therapy:1

Combines drugs acting in different physiological systems1

Blocks counter-regulatory responses1

Treats moderate/severe hypertension1

Reduces BP variability vs monotherapy1,3

>75% of patients require combination therapy

to achieve BP target2

1. Sever P, Messerli FH. Eur Heart J 2011;32:2499-506.

2. Gradman A et al. J Am Soc Hypertens 2010;4:42-50.

3. Rothwell P et al. Lancet 2010;375:895-905.

Criteria for an optimal fixed dose combination1

Component drugs should act via different and complementary mechanisms

BP-decreasing effect of combination is greater than that of components alone

Incidence of side-effects should be reduced or at least not increased

Combination should be efficacious in once-daily treatment

Combination should provide protection against target organ damage

Combination therapy is recommended in ESH/ESC guidelines2

1. Struijker-Boudier H et al. Int J Clin Pract 2007;61:1592-602.

2. Mancia G et al. J Hypertens 2009;27:2121-58. DOI:10.1097/HJH.0b013e328333146d.

Combination therapy is more effective than increasing the dose of monotherapy

Adapted from Wald D et al. Am J Med 2009;122:290-300.

A meta-analysis of 42 trials and 10968 patients shows that combining two different antihypertensive

classes gives approximately 5 times greater additional fall in BP than doubling the dose of a single drug.

Combination of complementary therapies may improve drug efficacy

Adapted from Law M et al. BMJ 2003;326:1427-31.

Effects of 2 different drugs on BP separately and in combination

(summary results from 119 randomised placebo-controlled comparisons from 50 trials)

Fixed dose combinations improve compliance and persistence

*Patients regarded as persistent if remaining on therapy during the last month

** Compliance measured by Medication Possession Ratio (MPR)

Adapted from Hess G. Pharmacy & Therapeutics 2008;33:652-66.

Retrospective cohort of 14449 hypertensive patients receiving fixed dose combination and switched

to free combination

Guidelines recommend use of combination therapy

JNC 7

2003 1“More than two-thirds of hypertensive individuals cannot be controlled

on one drug and will require two or more antihypertensive agents

selected from different drug classes.”

ESH/ESC

2007 2“Regardless of the drug employed, monotherapy allows to achieve

BP target in only a limited number of hypertensive patients. Use of

more than one agent is necessary to achieve target BP in the

majority of patients.”

ESH 2009 3 “Evidence has continued to grow that in the vast majority of hypertensive

patients, effective BP control can only be achieved by combination of at

least two antihypertensive drugs.”

1. Chobanian A et al. JNC 7 guidelines. Hypertension 2003;42:1206-52.

2. Mancia G et al. ESH/ESC guidelines. J Hypertens 2007;25:1751-62.

3. Mancia G et al. Reappraisal of European guidelines. Blood Press 2009;18:308-347.

Complementary modes of action

+

Amlodipine3

Potent calcium channel blocker

↑ Vasodilatation

↓ Peripheral resistance

↓

↓ Blood pressure

Bisoprolol1,2

Highly selective beta blocker

Sympathetic control

Blocks sympathetic effects

↓

↓ Heart rate

↓ Cardiac output

↓ Blood pressure

Bisoprolol and amlodipine short product characteristics

1. Cruickshank JM. Int J Cardiol 2007;120:10-27;

2. Palatini P et al. Drugs 2006;66:133-144.

3. Murdoch D and Heel RC. Drugs 1991;41:478-505.

Complementary cardioprotection beyond blood pressure control

1. Murdoch D and Heel RC. Drugs 1991;41:478-505;

2. Cruickshank JM. Int J Cardiol 2007;120:10-27;

3. Palatini P et al. Drugs 2006;66:133-144.

Concor AM provides a significant relative reduction in blood pressure within 4 weeks

Adapted from Rana R & Patil A. Indian Pract 2008;61:225-34.

Observational open-labelled, non-comparative survey of 801 patients with stage 2 hypertension in

169 indian centres.

82.5% of patients achieved BP goal (<140/90 mmHg)

Concor AM significantly reduces heart rate

Adapted from Rana R & Patil A. Indian Pract 2008;61:225-34.

Observational open-labelled, non-comparative survey of 801 patients with stage 2

hypertension in 169 Indian centres.

Good tolerability profile: adverse events

After 4 weeks of treatment with Concor AM (5 mg + 5 mg) once daily,

90% of patients report good to excellent tolerability

Adapted from Rana R & Patil A. Indian Pract 2008;61:225-34.

Observational open-labelled, non-comparative survey of 801 patients with stage 2

hypertension in 169 Indian centres.

Adverse events reported during the study

Conclusion

Hypertension is the number one global risk factor for premature

mortality

Approximately 7 out of 10 hypertensive patients do not achieve target

BP

Causes for inadequate BP control involve many factors, one of the

most important being poor patient compliance

More than 75% of patients require combination therapy to achieve

target BP

Fixed dose combinations significantly improve patient compliance and

number of controlled hypertensive patients