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Continental Divide
Continental Divide:
Hypertension guidelines-US vs Europe
Lionel Opie MD
Professor and Head,
Heart Research Institute
University of Cape Town
Cape Town, South Africa
Franz Messerli MD
Associate Section Head, Hypertension
Ochsner Clinic Foundation
New Orleans, LA
Joseph Izzo MD
Vice Chair, Department of Medicine
SUNY at Buffalo
Buffalo, NY
Heartbeat – June 2003
Continental Divide
Three key differences
• Simplified classification system
• Aggressive treatment recommendations
• What is the role of thiazide diuretics?
Heartbeat – June 2003
Continental Divide
Simplified BP classification
BP Classification
SBP mm Hg
Normal
<120
and
<80
Prehypertension
120–139
or
80–89
Stage 1 hypertension
140–159
or
90–99
Stage 2 hypertension
>160
or
>100
Heartbeat – June 2003
DBP mm Hg
JNC 7
Continental Divide
Aggressiveness and thiazide
How assertive should clinicians be in
treating hypertension?
• How quickly clinicians should try to
get to goal blood pressures?
What is the role of thiazide diuretics?
• Does JNC 7 say diuretics are
preferred agents or are they just one
recommendation of many?
Heartbeat – June 2003
Izzo
Continental Divide
Two quotes
"Thiazide-type diuretics should be used as
initial therapy in most patients with
hypertension, either alone or in
combination."
JNC 7
"The major classes of hypertensive
agents--diuretics, beta blockers,
calcium antagonists, ACE inhibitors,
ARBs--are suitable for initiation and
maintenance of therapy"
Heartbeat – June 2003
European guidelines
Continental Divide
Problems with "prehypertensive"
The prefix "pre" has negative connotations
"To my way of thinking, to label a person
whose blood pressure is 120/80 as
prehypertensive is simply
inappropriate."
Framingham has shown that if you are age
50-55, the odds of becoming
hypertensive in the next 25 years are
>90%
Heartbeat – June 2003
Messerli
Continental Divide
Integrated risk factors
The European guidelines integrate
additional risk factors better than JNC 7
for risk stratification
• Comorbidities
• Target organ disease
In fairness, JNC 7 is the short report
Heartbeat – June 2003
Messerli
Continental Divide
Data beyond randomized trials
European guidelines acknowledge eventbased trials are too short to assess
lifelong hypertension therapy
Used surrogate end points to supplement
strong clinical end points
• Subclinical organ damage
• LVH
• Microalbuminuria
Heartbeat – June 2003
Messerli
Continental Divide
Socioeconomic factors
Large differences in wealth and access in
the US
European guidelines state up front that
Europe is relatively homogenous and
due to state health care, cost is not
paramount
JNC 7 has no mention even of ethnic/racial
differences, which we know govern
many aspects of wealth and access
Heartbeat – June 2003
Opie
Continental Divide
Population issues
We don't know enough about the response
rates of different populations
• Trends favor thiazide diuretics in
blacks, ACE inhibitors in whites
The overarching principles don't change by
race so should not form a fundamental
basis for initial therapy
Socioeconomic issues can be somewhat
addressed by generics
Heartbeat – June 2003
Izzo
Continental Divide
Population differences
The US population may not be similar in
needs to the European population
• Obesity and salt intake are very
different than in Northern Europe
Diuretics must be given along with other
agents in the US to get good BP control
Control rates are better in the US than in
Europe, possibly due to more aggressive
treatment
Izzo
Heartbeat – June 2003
Continental Divide
Obesity and the metabolic syndrome
"The European guidelines clearly state that
treatment-induced alterations in
cholesterol, potassium, glucose
tolerance, etc, although they hardly can
be expected to increase cardiovascular
events during the short term of a trial,
may have an impact during the longer
course of the patient's life."
Heartbeat – June 2003
Messerli
Continental Divide
ALLHAT: De novo diabetes
Chlorthalidone
Lisinopril
Amlodipine
12.0
Events (%)
10.0
8.0
6.0
4.0
2.0
0.0
Heartbeat – June 2003
JAMA 2002; 288:2981-2997
Continental Divide
Treating the metabolic syndrome
"It was very disappointing for me to see
that there are no guidelines given [in
JNC 7] how to treat patients with the
metabolic syndrome in terms of
antihypertensive therapy."
Even in diabetic patients, thiazides lead the
list of antihypertesnive drugs
Heartbeat – June 2003
Messerli
Continental Divide
Indications for individual drug classes
Compelling
indication
Initial therapy
options
Clinical trial
basis
Diabetes
Thiazide, beta
blocker, ACE
inhibitor, ARB,
CCB
NKF-ADA
guideline,
UKPDS, ALLHAT
Chronic kidney
disease
ACE inhibitor,
ARB
NKF guideline,
Captopril Trial,
RENAAL, IDNT,
REIN, AASK
Recurrent stroke
prevention
Thiazide, ACE
inhibitor
PROGRESS
Heartbeat – June 2003
JNC 7
Continental Divide
ALLHAT: Primary end point
Chlorthalidone
Lisinopril
Amlodipine
12.0
Events (%)
10.0
8.0
6.0
4.0
2.0
0.0
Heartbeat – June 2003
JAMA 2002; 288:2981-2997
Continental Divide
Trial basis for treatment decisions
Indication
Clinical trial basis
Heart failure
ACC/AHA Heart Failure Guideline,
MERIT-HF, COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE, ValHEFT, RALES
Post-MI
ACC/AHA Post-MI Guideline, BHAT,
SAVE, Capricorn, EPHESUS
High CAD risk
ALLHAT, HOPE, ANBP2, LIFE,
CONVINCE
Diabetes
NKF-ADA guideline, UKPDS, ALLHAT
Chronic kidney
disease
NKF guideline, Captopril Trial,
RENAAL, IDNT, REIN, AASK
Recurrent stroke
prevention
PROGRESS
Heartbeat – June 2003
Continental Divide
ALLHAT: Fasting glucose levels
Chlorthalidone
Lisinopril
Amlodipine
Fasting glucose
>126 mg/dL (%)
35
30
25
20
15
10
5
0
Heartbeat – June 2003
Baseline
2 years
4 years
JAMA 2002; 288:2981-2997
Continental Divide
Indications for individual drug classes
Compelling
Indication
HF
Diuretic BB
*
Post-MI
ACEI
*
*
*
*
High
coronary
disease risk
*
*
*
Diabetes
*
*
*
Heartbeat – June 2003
ARB
CCB
*
AldoANT
*
*
*
*
*
Continental Divide
ALLHAT: Blood sugar and diabetes
Blood sugar tends to be higher on
thiazide, although the impact remains
debatable
ALLHAT mean blood sugar:
Thiazide:
126.3 mg/dL
ACE inhibitor:
121.5 mg/dL
New-onset diabetes:
Thiazide:
11.6%
ACE inhibitor:
8.1%
Heartbeat – June 2003
Izzo
Continental Divide
Attenuating the thiazide effect
ACE inhibitor or an ARB completely
attenuates the hyperkalemia and
hyperglycemia effects caused by
diuretics
"I come back to the value of combination
therapy and that's where the strength
of both documents could lie."
Doctors should be thinking about
combination drugs earlier
Heartbeat – June 2003
Izzo
Continental Divide
Inappropriate wording
"Thiazide should be used in drug treatment
in most patients, either alone or
combined." -- JNC 7
JNC 7 doesn't prevent anyone from treating
a patient with the metabolic syndrome
with a thiazide alone
"Except nobody should do that. . . . This is
inappropriate wording."
Heartbeat – June 2003
Messerli
Continental Divide
Treating diabetic patients
All the studies show 14% to 34% more
new-onset diabetes in the diuretic or
conventional therapy arm
Even in the INSIGHT study, new-onset
diabetes was 23% higher in the diuretic
arm
"Clearly I think this should be taken into
account."
Heartbeat – June 2003
Messerli
Continental Divide
Thiazide diuretic definitions
JNC 7 says "thiazide-type diuretics"
• What do you understand by low-dose
thiazide?
• Are thiazide diuretics the same as
chlorthalidone?
Heartbeat – June 2003
Opie
Continental Divide
Low-dose thiazide
We have defined lower dose as 12.5 or 25
mg of hydrochlorothiazide
Maximum dose we recommend is 50 mg
Little is known about 50-mg dose, since
that hasn't been studied very recently,
and the old studies were flawed
Heartbeat – June 2003
Izzo
Continental Divide
Chlorthalidone equivalency
No literature or good head-to-head trials
on the equivalence of chlorthalidone
and hydrochlorothiazide
"My own opinion is that the potency of
hydrochlorothiazide is roughly half
that of chlorthalidone."
Heartbeat – June 2003
Izzo
Continental Divide
Chlorthalidone dosing
ALLHAT doses are above the 25 mg of
hydrochlorothiazide we typically
employ
Chlorthalidone is somewhere between
150% and 200% more effective than
the same milligram amount of
hydrochlorothiazide
There is a lot of diuretic on board in these
studies, and the hyperglycemia seems
to be dose-dependent
Izzo
Heartbeat – June 2003
Continental Divide
Treating diabetic patients
MR FIT study found the mortality rate was
unfavorable in the clinics using
hydrochlorothiazide and favorable in the
clinics using chlorthalidone
"We do not have any head-to-head
comparisons, and we probably never
will, but this is rather powerful evidence
that the two drugs are not the same"
Heartbeat – June 2003
Messerli
Continental Divide
Not enough data
No good dose-response data with diuretics
"Are you really suggesting we should
preferentially use an agent we really
don't know that much about?"
Heartbeat – June 2003
Opie
Continental Divide
Diuretic history
Diuretics were originally used in multiples
of the doses used today (gave rise to
the worries about side effects)
Doses were lowered over time without
the guidance of controlled clinical
trials
Found reasonable efficacy with lower
doses
Heartbeat – June 2003
Izzo
Continental Divide
ACE-inhibitor history
ACE inhibitors also started with much
higher doses than are used today
ACE inhibitors and ARBs may be dosed too
low now since they have no dosedependent side effects
"We do not have very good clinical
pharmacology to back up any of these
recommendations that we're making."
Heartbeat – June 2003
Izzo
Continental Divide
Head to head
NIH spent $100 million on ALLHAT
For less than $1 million someone could do a
simple head-to-head trial
• Chlorthalidone vs hydrochlorothiazide
using simple surrogate end points
Heartbeat – June 2003
Messerli
Continental Divide
Beta blockers
JNC 6 recommended diuretics and/or beta
blockers as initial therapy
• What are the data for beta blockers
reducing mortality?
JNC 7 downgraded beta blockers to the
level of the other drugs
• What led to the downgrading of the
beta blockers?
Heartbeat – June 2003
Opie
Continental Divide
Beta-blocker data
There were relatively poor data
supporting beta blockers as a major
approach
JNC 6 recommendation was not
particularly supportable
Beta blockers are good to have as an
option, especially with prevalence of
cardiac disease, since the heart is
their major target organ
Heartbeat – June 2003
Izzo
Continental Divide
Elderly
Both the European and the JNC 7 guidelines
are focused on the elderly
• Some mention of teenagers
• Not much mention of the middle-aged
(40-60) hypertension patients
Heartbeat – June 2003
Opie
Continental Divide
Uncomplicated hypertension
Beta blockers are still lumped with ARBs,
ACE inhibitors, calcium-channel blockers
Inappropriate because the evidence is
meager for beta blockers in
uncomplicated hypertension
• Three independent studies showing no
risk reduction with beta blockers for
noncardiac end points
Heartbeat – June 2003
Messerli
Continental Divide
Beta blockers in cardiac disease
Beta blockers make sense in the post-MI
patient
Possibly in diabetes, but not in the cases of
uncomplicated hypertension
"I think [beta-blockers] should have been
kicked off, just the same as the alpha
blockers were, of the basket in which
the other drugs are in now. And this is
true for both guidelines."
Heartbeat – June 2003
Messerli
Continental Divide
Good indications for beta blockers
Many good indications for beta blockers
• CHF
• Post-MI
• SVT
• Subaortic stenosis
"I use beta blockers all the time, just not
for uncomplicated hypertension."
Heartbeat – June 2003
Messerli
Continental Divide
Including beta blockers
JNC 7 was designed to be a document
that could be looked at prospectively
or retrospectively for events
associated with hypertension
"Was it reasonable to include beta
blockers across the entire spectrum of
early to late disease? . . . The answer
clearly is yes."
Heartbeat – June 2003
Izzo
Continental Divide
Beta-blocker heterogeneity
The beta blockers are one of the most
heterogeneous drug classes around
• Carvedilol, celiprolol, etc may be more
beneficial in the uncomplicated
hypertensive patient
No outcome data yet
Heartbeat – June 2003
Messerli
Continental Divide
ALLHAT and the elderly
ALLHAT is seen by many as the main study
influencing JNC 7
ALLHAT studied a population aged mean 67
years, with five-year follow-up
Earlier studies have found diuretics
ineffective in whites under the age of 60
• Did that age factor get discussed in
JNC 7?
Heartbeat – June 2003
Opie
Continental Divide
ALLHAT influence
JNC 7 is not just an ALLHAT study,
although it did have many ALLHAT
investigators on the committee
JNC 7 used the totality of evidence
• Clinical trials
• Expert opinion
• No evidence-ranking system
• Sifted through as much evidence as
we could
Heartbeat – June 2003
Izzo
Continental Divide
Age
Age is a trend that affects clinical judgment
Diuretics affect systolic pressure better in
an older person than in a younger
"But those are the kinds of things that we
feel expert clinicians should be able to
interpret and use on their own."
65 + one day doesn't automatically mean
diuretic
Heartbeat – June 2003
Izzo
Continental Divide
Population vision
JNC 7 comes out right up front that
hypertension is a graded effect, starting
from 115/75, with a gradually
increasing risk
This breadth of approach was missing from
the European guidelines
Heartbeat – June 2003
Opie
Continental Divide
Minimal benefits
Meta-analysis has shown increased risk for
130/80 compared with 115/75, but no
one has shown reducing the former to
the latter actually helps
"The benefits are probably so small that it's
awfully hard to convince anybody that
lowering the blood pressure within the
normotensive range actually did reduce
morbidity and mortality."
Heartbeat – June 2003
Messerli
Continental Divide
Best guess
Lacked intervention trial data for
“prehypertensive” patients
Vigorous lifestyle modification
recommended for "prehypertensive"
patients
Framingham study showed lower blood
pressure was at any age, the lower it
stayed throughout your life
Heartbeat – June 2003
Izzo
Continental Divide
Responsibility of the patient
Best available information is to emphasize
a nonpharmacological approach
The concept of "prehypertension" is an
attempt to put responsibility on
patients to take better care of
themselves
It was an attempt to avoid using drugs
unnecessarily
Heartbeat – June 2003
Izzo
Continental Divide
Fat city
The US is the fattest nation on Earth
New Orleans is the fattest city in the US
"Here the attitude is that everybody needs
to have a good time first and all other
considerations are second. So I'm not
really happy about that prehypertensive
term for this reason, because it doesn't
motivate my patients to do anything."
Heartbeat – June 2003
Messerli
Continental Divide
Action steps
Other terms don't motivate patients either
European guidelines use classifications so
narrow that normal variation can
change a patient's classification
JNC 7 made every 20/10 increase double
the risk and that becomes an action
step shared by the physician and the
patient
Heartbeat – June 2003
Izzo
Continental Divide
High-risk categories
European guidelines use a higher-risk
category for systolic >180, JNC 7 does
not
There are no specifics in treatment
approach that change between systolic
180 and 160
JNC 7 tried to focus on vigorous early
treatment, and higher categories make
people complacent at the lower levels
Heartbeat – June 2003
Izzo
Continental Divide
Clarity of message
JNC 7 delivers its message very clearly
"Motivation improves when patients have
positive experiences with, and trust in,
the clinician. Empathy builds trust and is
a potent motivator."
-JNC 7
The phrase "thiazide-type diuretics should
be used" may not be the best phrasing
Heartbeat – June 2003
Opie
Continental Divide
Specialists vs general practitioners
European guidelines offer a wonderful
balance of approaches, but it is a
document for specialists
Busy US primary care providers don't have
time to read and use highly detailed
documents
"We knew we had to have a punched-up,
short document to get their attention at
all."
Heartbeat – June 2003
Izzo
Continental Divide
Box summaries
European guidelines have 16 boxes
summarizing major guidelines and
position statements
"The physician who is more interested can,
at his or her leisure, just expand and
read on, or not."
Heartbeat – June 2003
Messerli
Continental Divide
Aggressive early treatment
JNC 7 more intense and aggressive in its
approach than European guidelines
Diuretic therapy is known to take up to
three months to be fully effective
Diuretic therapy is salt dependent
"Can you really reconcile the desire to get
there quickly with blood-pressure
reduction with the prime use of a
diuretic?"
Opie
Heartbeat – June 2003
Continental Divide
Algorithm for treatment
Lifestyle modifications
Not at goal blood pressure (<140/90 mm Hg)
(<130/80 mm Hg for those with diabetes or chronic kidney
disease)
Initial drug choices
Without compelling
indications
Stage 1 hypertension
Stage 2 hypertension
(SBP 140–159 or DBP 90–99 mm Hg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
(SBP >160 or DBP >100 mm Hg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
With compelling
indications
Drugs for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
Not at goal
blood pressure
Heartbeat – June 2003
Optimize dosages or add additional drugs until goal blood pressure is
achieved.
Consider consultation with hypertension specialist
JNC 7
Continental Divide
Doctors don't titrate
Early effective doses make sense because
doctors don't titrate drugs
"I'd rather have them use effective doses
relatively early in the game than hope
that they will titrate when we know
they don't do it."
Heartbeat – June 2003
Izzo
Continental Divide
European aggression
Not that much of a difference between the
US and European approach on early
treatment
ACE inhibitors and ARBs also have a lead-in
time and are salt-dependent
"I'm not so sure whether it would, in this
regard, make a big difference whether
you actually start on a diuretic or you
start on an ACE inhibitor or calcium
antagonist."
Messerli
Heartbeat – June 2003
Continental Divide
Summary: Izzo
The fundamental differences are stylistic
JNC 7 is a digest but one with enough
breadth to handle typical problems seen
by physicians treating hypertension
The unsaid theme is "lower is better"
Put more pressure on patients and
physicians to do a more vigorous job of
managing hypertension
Heartbeat – June 2003
Izzo
Continental Divide
Summary: Izzo
The diuretic recommendation is more
interpretive than some would say
"Most" can mean 51% or 99% should be
on a diuretic--there should be lots of
combination therapy used
"These are only guidelines and they're not
intended to replace educated physician
judgment, just to be sign posts along
the way."
Heartbeat – June 2003
Izzo
Continental Divide
Summary: Messerli
Major issues with JNC 7
• Lack of distinct guidelines for
metabolic syndrome
• All drug classes considered equally
compelling in diabetic patient
Heartbeat – June 2003
Messerli
Continental Divide
Summary: Messerli
"The responsible physician's judgment is
paramount in managing patients, and I
only hope that this judgment is also
paramount in reading the guidelines."
"And this is true for the European
guidelines as well as the American
guidelines."
Heartbeat – June 2003
Messerli
Continental Divide
Continental Divide:
Hypertension guidelines –
US vs Europe
Lionel Opie MD
Professor and Head,
Heart Research Institute
University of Cape Town
Cape Town, South Africa
Franz Messerli MD
Associate Section Head, Hypertension
Ochsner Clinic Foundation
New Orleans, LA
Joe Izzo MD
Professor of Medicine
Kaleida Health/Millard Fillmore Hospital
Buffalo, NY
Heartbeat – June 2003