Conflict of Interest
This presentation by Franz H.
Messerli is sponsored by
Boehringer Ingelheim. Therefore
any mentioning of a Boehringer
Ingelheim product should be
considered as biased information
and automatically be treated as
suspicious.
“In the past 100 years, only
during the 1918 flu pandemic
was cardiovascular disease
not the number-one cause of
death”.
AHA Year End Statistics 2005
What is the residual lifetime risk
of becoming hypertensive in a
normotensive person at age 55?
•
•
•
•
•
10 – 30 %
30 – 50 %
50 – 70 %
70 – 90 %
>90 %
Risk for Hypertension (%)
Residual Lifetime Risk for
Hypertension From Age 55
100
Women
Men
80
60
72
78
83 88
91 93
52 56
40
20
0
10
15
20
25
Time (Years)
Individuals who are normotensive at age 55 have
a > 90% lifetime risk of developing hypertension
Vasan RS et al. JAMA. 2002;287:1003-1010 Framingham.
Percent Alive
Excess Mortality in Harlem
100
90
80
70
60
50
40
30
20
10
0
U.S. White
Bangladesh
Harlem
0
5
15
25
35
45
55
65
Age (yr)
McCord C, Freeman HP. N Engl J Med. 1990 Jan 18;322(3):173-7.
10 leading causes of death among non-Hispanic blacks and nonHispanic whites
30
26.8
23.5
21.6
20
Black,
non-Hispanic
6.5 4.4
10
0
H e a rt
dis e a s e
C a nc e r
S t ro k e
4.3
2.8
D ia be t e s Unint e nt io na l H o m ic ide
injury
Cause of death
30
2.7
C hro nic
lo we r
re s pira t o ry
dis e a s e
2.7
H IV
2.6
N e phrit is
2.1
S e pt ic e m ia
A ll o t he rs
29.2
23.1
20.2
20
White,
non-Hispanic
6.7 5.7
10
0
Cause of death
H e a rt
dis e a s e
C a nc e r
S t ro k e
4.1
2.8
2.7
C hro nic Unint e nt io na lInf lue nza a ndA lt zhe im e r's
lo we r
injury
pne um o nia
dis e a s e
re s pira t o ry
dis e a s e
2.6
D ia be t e s
1.5 1.3
N e phrit is
S uic ide
A ll o t he rs
National Vital Statistics System, United States, 2002
Arterial Blood Pressure (mmHg)
Arterial Pressure of Franklin D. Roosevelt from 1935
until his death on April 12, 1945
350
D-Day
Election
Yalta
?
300
250
200
150
100
50
EKG: LVH
Proteinuria:
+
+ +
0
M
A
M
J
J
A
1935 1937 1939 1941 1944
Messerli, FH, NEJM, 332:1038-1039, 1995
Month and Year
S
O
N
D
J
1945
F
M
A
• “The treatment of the
hypertension itself is a
difficult and almost hopeless
task in the present state of
our knowledge and in fact, for
aught we know … ”
• “… the hypertension may be
an important compensatory
mechanism which should not
be tampered with, even were
it certain that we could
control it.”
Paul Dudley White, MD,
Heart Disease, First Edition 1931
Syst-Eur: Fatal and Nonfatal Stroke
(in 4695 Randomized Patients)
Events per 100 Patients
6–
5–
Placebo
4–
-42%
P < 0.003
3–
2–
Active
Treatment
1–
0–
I
0
Staessen J et al. 1997
I
1
I
2
I
3
Time Since Randomization (Years)
I
4
“Systolic hypertension in the
presence of a normal or reduced
diastolic pressure is rarely
considered responsible for target
organ damage.”
Engelman K, Braunwald E. Ch.37, “Elevation of Arterial
Blood Pressure,” Harrison’s Principles of Internal Medicine.
6th Ed. 1970.
Syst-Eur: Fatal and Nonfatal Stroke
(in 4695 Randomized Patients)
All Endpoints
Stroke
Cardiac
CHF
MI
P < 0.001
P = 0.003
- 29%
P = 0.12
- 30%
P= 0.12
Staessen J, et al. 1997.
- 42%
- 26%
P= 0.03
-100
- 32%
-50
Active Better
0
50%
Placebo Better
Data Selection:
• Randomized trials lasting at least
one year, which used as first line
agents diuretics and/or betablockers and reported morbidity
and mortality outcomes in elderly
hypertensive patients.
Meta-Analysis of Prospective Clinical Trials
in Hypertension in the Elderly
Active
Treatment
Outcome
Events/
First Drug # Trials Patient
Control
Events/
Patients
Odds Ratio and
95% Confidence Interval
All Cause Mortality
Diuretics
7
681/5838
907/6618
ß-blockers
2
227/1521
384/2678
0.4
0.6
0.8
1.0
1.2
1.4
Meta-Analysis of Prospective Clinical Trials
in Hypertension in the Elderly
Active
Treatment
Outcome
Events/
First Drug # Trials Patient
Control
Events/
Patients
Odds Ratio and
95% Confidence Interval
Coronary Heart Disease
Diuretics
ß-blockers
8
2
365/5876
115/1521
531/6661
197/2678
Cardio-Vascular Disease
Diuretics
7
332/5838
510/6618
ß-blockers
2
130/1521
230/2678
0.4
0.6
0.8
1.0
1.2
1.4
Relative risk of major events with
atenolol vs placebo (n = 6825)
End point
RR
95% CI
All-cause mortality
Cardiovascular
mortality
MI
Stroke
1.01
0.99
0.89-1.15
0.83-1.18
0.99
0.85
0.83-1.19
0.72-1.01
Carlberg B et al. Lancet 2004; 364:1684–1689.
•
Cochrane review:
Beta blockers should not be
first line for hypertension
February 2, 2007 Sue Hughes
• The available evidence does not support the use
of beta blockers as first-line drugs in the
treatment of hypertension [1].
•
• The review bases this conclusion on "the
relatively weak effect of beta blockers to
reduce stroke and the absence of an effect
on coronary heart disease when compared
with placebo "
Analysis 01.01. Comparison 01 Beta-blocker vs
Placebo or No treatment,
Outcome 01 Total mortality
: 24 January 2007
Cochrane Database of Systematic Reviews
Published by John Wiley & Sons, Ltd
Antihypertensive Therapy and
Cardioprotection
Beta
Blockers
Diuretics
Primary
Prevention
no
yes
Secondary
Prevention
yes
?
Myths and Misperceptions…
"Which of the following class of
drugs have been proven to reduce
mortality in hypertensive patients?"
•
•
•
•
Beta-blockers
ACE inhibitors
Diuretics
CCBs
78%
65%
53%
17%
Kaboli PJ, et al. J Clin Hypertens 2007;9:416-423.
SYST EUR: Effect of Calcium Antagonist
Treatment on Dementia
Cases per 100 Patients
10
Placebo
8
6
-55%
P=0.0008
4
Active
Treatment
2
0
0
2
4
6
8
Time since Randomization (Years)
Forette F., et al.
Arch Intern Med
In Press 2002
Effect of Antihypertensive
Therapy on Cognitive
Dysfunction/Dementia
Study
SHEP
SYST-EUR
RX
Thiazide
Diuretic
Calcium
antagonist
None
55%
Reduction
Effect
Forette F, et al. Lancet. 1998;352(9137):1347-51.
Outcome Evidence for
Betablockers in CV Disease
None
Hypertension
Some
+
+
Heart Failure
ACS
+
+
Post MI
Stable Angina
+
HOCM
+
Perioperative
Strong
+
Bangalore S, Messerli FH et al. JACC in press 2007
Percentage of Patients Continuing
Prescribed Drug Regimen after 1 Year
100
Percent
80
60
40
20
0
ARB
ACEI
CA
BB
D
Mancia G, et al. AJH 2003;16:1066–73
Telmisartan vs Amlodipine Using 24-h ABPM1
Baseline ABPM
BP (mm Hg)
Placebo
(n = 58)
SBP
160
Telmisartan
(40–120 mg)
(n = 62)
140
120
Amlodipine
(5–10 mg)
(n = 65)
DBP
100
80
0
0800
1200
1600
2000
2400
0400
0800
Time of Day
1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of the
angiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit. 1998;3:295–302.
Effects of Telmisartan vs Amlodipine
Derived from 24-h ABPM1
End of Therapy (Week 12) – Systolic BP
BP (mm Hg)
160
Placebo
(n = 58)
150
Telmisartan
(40–120 mg)
(n = 62)
140
Amlodipine
(5–10 mg)
(n = 65)
130
120
0800
1200
1600
2000
2400
0400
0800
Time of Day
1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of the
angiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit. 1998;3:295–302.
Effects of Telmisartan vs Amlodipine
Derived from 24-h ABPM1
BP (mm Hg)
End of Therapy (Week 12) – Diastolic BP
110
Placebo
(n = 58)
100
Telmisartan
(40–120 mg)
(n = 62)
90
Amlodipine
(5–10 mg)
(n = 65)
80
70
60
0800
1200
1600
2000
2400
0400
0800
Time
1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of the
angiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit. 1998;3:295–302.
Effect of ARBs on BP at Trough
( placebo subtracted )
46 studies, 13451 pts
The Cochrane Collaboration, Heran BS et al. October 2008
Effect of ACE-Is on BP at Trough
( placebo subtracted )
92 studies, 12954 pts
The Cochrane Collaboration, Heran BS et al. October 2008
Blood Pressure Reduction at
Trough
mm Hg
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
# of Studies
# of Patients
# of Drugs
Systolic
Diastolic
ACE
inhibitors
92
12954
14
ARBs
DRIs
46
6
13451
3694
9
11
Messerli FH, Bangalore S. Circulation. 2009;119(3):371-3
Dose Response of ARB Withdrawal Rate
46 studies, 13451 pts
The Cochrane Collaboration, Heran BS et al. October 2008
Dose Response of ARB Withdrawal Rate
46 studies, 13451 pts
The Cochrane Collaboration, Heran BS et al. October 2008
Dose Response of ACE-I Withdrawal Rate
RR
92 studies, 12954 pts
The Cochrane Collaboration, Heran BS et al. October 2008
ACE-Inhibitor Related Angioedema –
How Uncommon?
Incidence:
0. 1%
First week incidence
Subsequent incidence
0. 2%
0. 5%
1/2,500 pts.
1/500 pts/year
Messerli FH, Nussberger. Lancet 2000;356:608–9
The Risk of Angioedema (AE)
• Among angioedema that
are life-threatening
(larynx, respiratory tract): 20 – 22%
• Among life-threatening
angioedema that
are fatal:
1 – 16 – 24%
Messerli FH, Nussberger. Lancet 2000;356:608–9
ACE-Inhibitors and Angioedema (AE)
Number of patients
Worldwide ACE-I use
> 30,000,000
Episodes of Angioedema/year
60,000
Episodes of life-threatening
Angioedema/year
12,000
Episodes of fatal
Angioedema/year
>1,000
Messerli FH, Nussberger. Lancet 2000;356:608–9
Asphyxia Due to ACE Inhibitor Mediated Angioedema
Age
Sex
Race
Diagnosis
ACE Inhibitor
Duration of
Exposure
56
F
AA
HTN, DM, CHF
fosinopril
5 months
Tongue
51
F
AA
HTN, DM, CHF
benazepril
21 months
Tongue, Lips
63
M
AA
HTN
enalapril
8 month
Tongue,
Oropharynx,
Hypopharynx,
Larynx
54
M
AA
HTN Nephr.
Syn.
lisinopril
10 hours
Tongue,
Oropharynx
65
M
AA
HTN
enalapril
chronic
Tongue, Larynx
71
F
AA
HTN
lisinopril
chronic
Tongue, Larynx
Angioedema
Dean DE, et al. J Forensic Science 2001;46:1239–43
Angioedema with ACE-Inhibitors
• n = 85
• Rx for hypertension n = 82
• Rx for heart failure n = 3
• Median duration of ACE-I Rx: 12 months
• Range: 1 day – 13 years
• Median time between 1st attack and ACE-I Rx
withdrawal: 12 months
• Range: 1 day – 12 years
Lorenza et al. CMJ, 2006;175:1065
LIFE: Prespecified Adverse Events of
Special Interest
•
•Angioedema
•Bradycardia
Losartan (%)
6 (0∙1%)
Atenolol (%)
p-value
11 (0∙2%)
0∙237
66 (1%)
391 (9%)
<0∙0001
•Cancer
356 (8%)
315 (7%)
0∙118
•Cold extremities
178 (4%)
269 (6%)
<0∙0001
•Cough
133 (3%)
113 (2%)
0∙220
•Dizziness
771 (17%)
727 (16%)
0∙247
•Hypotension
121 (3%)
75 (2%)
0∙001
•Sexual dysfunction
164 (4%)
214 (5%)
0∙009
•Sleep disturbance
B Dahlof et al. Lancet 2002;359:995-1003
30 (0∙7%)
38 (0∙8%)
0∙333
VALUE: Incidence of
angioedema and facial edema
Valsartan
n=7,622
Amlodipine
n=7,576
p-value
Angioedema
10 (0∙13%)
10 (0.13%)
NS
Face edema
13 (0.17%)
24 (0.32%)
NS
Kaplan-Meier Curves for the Primary
Outcome in the Three Study Groups
The ONTARGET Investigators. N Engl J Med 2008;10.1056/NEJMoa0801317
Discontinuation of Study Medications and Selected
Reasons for Permanent Discontinuation
The ONTARGET Investigators. N Engl J Med 2008;10.1056/NEJMoa0801317
MESSERLI’s Take Home Lessons
from ONTARGET, ACCOMPLISH
and HYVET
1. ONTARGET establishes outcome equivalence for
Ramipril and Telmisartan.
MESSERLI’s Take Home Lessons
from ONTARGET, ACCOMPLISH
and HYVET
1. ONTARGET establishes outcome equivalence for
Ramipril and Telmisartan.
2. Outcome equivalence seems likely (but not proven)
for ARBs and ACEI as a class.
Dual Blockade of the RAS
Addition of ARB to Maximal Recommended Dose
of ACEI
Double-blind, randomized, crossover trial
24 patients
Irbesartan 300 mg/d
Type 1 diabetics with
nephropathy*
Irbesartan 300 mg/d
R
Placebo
40 mg of enalapril
for >3 months
Day 1
Placebo
Week 8
Mean age = 42 y; mean duration of diabetic nephropathy = 13 y.
*Nephropathy defined as persistent albuminuria >300 mg/24 h.
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II
receptor blocker; RAS = renin-angiotensin system.
Jacobsen P et al. Kidney Int. 2003;63:1874-1880.
Week 16
Measurements:
• Primary end point: albuminuria
• Secondary end points:
− glomerular filtration rate (GFR)
− 24-hour blood pressure
Addition of ARB to Maximum
Recommended Dose of ACEI
After 8 Weeks of Therapy
25% Reduction
Albuminuria (mg/24 hr)
600
(P<.001)
400
200
0
Placebo
Irbesartan 300 mg/d
+ Enalapril 40 mg/d
+ Enalapril 40 mg/d
Mean reductions in 24-hour blood pressure: irbesartan + enalapril (-8/-4 mm Hg) over placebo + enalapril, (P=.002 and
P=.003, respectively, for SBP and DBP). ACEI = angiotensin-converting enzyme inhibitor.
Jacobsen P et al. Kidney Int. 2003;63:1874-1880.
AVAPRO backup slide.
NonSense of Dual RAS Blockade
• “..a combination of ACE
inhibitor and ARB should not be
used in the ONTARGET type of
population. There was a strong
trend in ONTARGET toward
more dialysis in patients in the
combination group, and other
side effects were also
increased…”
ONTARGET: Change in eGFR from Run-in
(intention to treat analysis)
Mann JE, Schmieder RE et al. Lancet 2008
Safety and tolerability of ACE inhibitor
versus the combination of ACE inhibitor
and ARB in LV dysfunction: a systematic
review and meta-analysis of randomized
controlled trials.
Lakhdar R, Al-Mallah MH, Lanfear DE.
Division of Cardiology, Yale University
School of Medicine
J Card Fail. 2008 Apr;14(3):181-8
RESULTS: Nine trials that enrolled 18,160
patients met the inclusion criteria
• CONCLUSION:
• The current cumulative evidence
suggests that patients with LVD have
an increased risk of adverse events...
This excess risk, coupled with a lack of
mortality benefit, suggests that ARBs
should not routinely be added to ACEI
therapy in LVD.
J Card Fail. 2008 Apr;14(3):181-8
J Am Coll Cardiol, 2009; 53:468-470
“Unless data emerge to the
contrary, dual RAS
blockade is dead until
proven otherwise…
Messerli FH, J Am Coll Cardiol, 2009; 53:468-470
“The treatment of the hypertension
continues to be a difficult task in
the present stage of our
knowledge, but important studies
in progress offer much hope for
the future.”
Paul Dudley White, MD,
Heart Disease, Third Edition 1944
Columbia University
St. Luke’s Roosevelt Hospital
Division of Cardiology
Franz H. Messerli, MD