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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