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Frontiers of Hypertension Treatment |
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A More Rigorous Approach to Blood Pressure
Graham MacGregor
St. George's Hospital Medical School, London, UK
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In Japan, the
most common cause of death is stroke, cerebral hemorrhage,
cerebral thrombosis, which are
directly related to the level of blood pressure, and
heart failure. As the population increasingly ages,
hypertensive heart failure is the most common cause
of heart failure. Coronary heart disease is becoming
more common in Japan, associated
with the increasing consumption of a Western diet.
Blood pressure is
the major risk for cardiovascular disease.
Recently published data show that the risks of blood
pressure have been underestimated by about 50%. Importantly,
it is not just elevated blood pressure, but blood
pressure throughout the entire range that is associated
with increased risk. A person with a systolic blood
pressure (SBP) of 145 mm Hg is at much greater risk
for stroke than a person with a SBP of 120 mm Hg.
More people have
blood pressure levels in the upper range of normal
than have very severe hypertension. More strokes occur
in persons with blood pressure in the upper range
of normal than in persons with severe hypertension,
at least in Western countries. Population measures must be adopted to lower blood pressure in the entire population, and
in particular to stop the increase in blood pressure
with age. In Japan, 80%
of the population over 60 years of age has blood pressure
above the upper range of normal.
Cardiovascular (CV)
disease (stroke, heart failure, MI) is totally preventable
if diet and lifestyle are changed. Population strategies
must be adopted to have a true effect on reducing
CV disease, rather than the current high-risk strategy
that identifies and treats persons with elevated blood
pressure and other risk factors. Population strategies
include addressing smoking, fat intake, salt intake
(the single biggest risk factor for death in Japan),
and consuming more fruits, vegetables and potassium,
as well as decreased weight decrease and increased
exercise.
Salt intake and blood pressure
The relation between
salt intake and stroke is well-documented, including
data from Japan in
the 1950s. Some 50 studies show the role of controlling
salt intake to control blood pressure in the population,
particularly because of the rise of blood pressure
with age. Migration studies from Kenya and
Ethiopia clearly show that moving from a low to a high salt intake environment
results in increased blood pressure, partly due to
increased salt intake. A 50% reduction in salt intake
resulted in marked differences in blood pressure compared
to no reduction in an important intervention study
in Portugal.
Interestingly, chimpanzees
have dramatic increases in blood pressure when fed
the same amount of salt as in a typical Japanese diet,
which reduces in about 3 months after stopping the
increased salt intake. It would seem the diet would
have the same effect in humans. Kidney function,
either diminished ability to excrete sodium or to
hold sodium, is involved with the genetic causes of
hypertension or hypotension. In total, the evidence
for salt is stronger than for any other dietary constituent
for cardiovascular disease.
A reduced salt intake
resulted in a decrease in stroke in Japan. A public health campaign in Japan to
reduce salt intake in the 1960s, at the same time
that there was an increase in weight, fat consumption,
and cigarette smoking and a decrease in exercise,
resulted in a reduction in stroke. The DASH Sodium
study in the US showed
that a diet high in fruit and vegetables reduced blood
pressure, and that salt restriction further reduced
blood pressure.
A greater reduction
in salt intake results in a greater reduction in blood
pressure. A dose-response reduction in blood pressure
in relation to salt restriction was shown in a meta-analysis
by MacGregor and colleagues.
The WHO has set
a target of 5 grams of sodium per day. The Japanese
Ministry of Health has set a target of 10 grams of
sodium per day. A reduction in the daily sodium intake
from the usual 12-14 grams per day to 8 grams per
day would result in a reduction in SBP of 7 mm Hg
in hypertensives and 4 mm Hg in normotensives in Japan. A 6 gram reduction in daily salt intake would result in a 24% reduction
in stroke.
Other harmful effects
of salt include sodium and water retention, left ventricular
hypertrophy, aggravating effect on asthma, direct
cause of stomach cancer, and aggravating bone demineralization
by leaching out calcium out of the bones into the
urine.
Processed foods
are responsible for most of the salt consumed, making
reduction in the salt content of processed foods over
time a key population strategy. In the UK, the
salt content of all processed foods is being slowly
reduced, with no noticeable change in taste. A similar
approach is needed in Japan, to
reduce over time the salt content of soy sauce, pickles,
and other high-salt foods.
Benefits of treatment
The benefit of treatment
is clear. Treatment should include lifestyle changes
including reduction of salt intake to a maximum of
5 grams daily, reduction of fat and alcohol, increased
intake of fruits and vegetables, and increased exercise.
All risk factors, such as elevated blood sugar and
lipids, are treated. The need for 2 or more drugs
to control blood pressure renders irrelevant the question
of which of the five classes of drugs to use to initiate
treatment.
The ALLHAT study
compared 3 major classes of antihypertensive agents,
diuretics (chlorthalidone), ACE inhibitors (lisinopril),
and calcium channel blockers (amlodipine). Amlodipine
was slightly more effective than chlorthalidone in
reducing stroke, but not statistically significant,
while lisinopril was slightly less effective in stroke.
Each drug had the same effect on CHD. The study design,
which did not allow adding these drugs together as
would be done in real clinical practice, makes analysis
problematic. The lisinopril group, as would be expected,
had higher blood pressure, perhaps explaining the
difference in stroke. Very small differences in blood
pressure can make quite big differences in outcome.
The conclusion that
diuretics should be first-line treatment is not supported
by the study data. Hypokalemia is one danger of diuretic-based
treatment. The SHEP study, in isolated systolic hypertension
in the elderly, showed that chlorthalidone-based treatment
reduced cardiovascular events by about 50%, provided
that potassium was not lowered. In a subgroup in which
potassium was lowered to less than 3.5 by chlorthalidone,
treatment was not beneficial. Thus, caution must be
used with diuretics to prevent a fall in plasma potassium.
The ANBP2 study,
a well-controlled comparison between diuretics and
ACE inhibitors, showed that the blood pressure and
outcome were identical between the two groups. MacGregor
states the finding of the ALLHAT study is questionable,
and all drugs are equivalent provided the same blood
pressure target is achieved. The more important issues
are how to combine the drugs to reach target levels
and controlling blood pressure—7 of 10 people
have uncontrolled blood pressure.
The benefit of reducing
blood pressures in the normal range is shown by the
HOPE and PROGRESS studies. In HOPE, patients with CV risk and normal
blood pressure had fewer CV events on ramipril versus
placebo. In PROGRESS, in post-stroke patients, stroke
and CHD were reduced with the combination of a diuretic
and ACE inhibitor versus placebo—independent
of the initial blood pressure. The benefit was greatest
in persons with normal versus elevated blood pressure.
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Antihypresentive Therapy and Cardiovascular Prognosis: Recent Evidence from Clinical Outcome Trials
Jan A. Staessen
University of Leuven, Leuven, Belgium
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Reducing blood pressure
improves prognosis based on evidence from clinical
intervention studies. Systolic hypertension is a major
but reversible risk factor and is a risk factor particularly
for stroke and dementia. Controlling blood pressure
is the key to preventing these events and may substantially
increase quality of life. Management of blood pressure
should be an integrated part of the overall risk management
of patients.
Studies in the US, UK, Sweden,
and New
Zealand show a curvilinear relation between increasing age and the risk of
stroke. By 60 years of age, the annual incidence of
stroke is about 100/100,000 people. Stroke risk is
2-fold greater for 75-84 years of age and 3-fold greater
over 85 years. In Japan, the major complication of hypertension is stroke.
Ischemic heart disease
is the leading cause of death and stroke is becoming
the second leading cause of death worldwide. The aging
population worldwide likely will result in an increase
in stroke. The age-specific incidence of dementia
is curvilinear, with about a 10% incidence at 65 years
of age and a 40% or higher incidence over 80 years. The Syst-Eur trial showed a 55% reduction
in the incidence of dementia in patients on active
treatment; primarily a decrease in neurodegenerative
dementia. In contrast, in the SHEP trial, the incidence
of dementia was lower and there was no difference
between the two treatment groups.
Systolic blood pressure
(SBP) is a known indicator of risk, particularly in
the elderly. The prevalence of isolated systolic hypertension
(ISH), defined as a SBP of at least 160 mm Hg, increases
with age; at 60 years it is about 8%, at 70-80 years
it is 20-25%.
Primary prevention data
A meta-analysis
of placebo-controlled, randomized clinical trials,
including three trials of ISH, showed a significant
30% decrease in fatal and non-fatal stroke with treatment.
Syst-Eur, a double-blind
trial, randomized patients to placebo or active treatment
(calcium channel blocker, nitrendipine) with the possible
addition of enalapril and hydrochlorothiazide. A 42%
reduction in the primary endpoint of combined fatal
and nonfatal stroke in the active treatment group
caused an early termination of the trial. At the end
of the double-blind trial, a difference of about 10
mm Hg between the placebo and active treatment groups
was found.
In the extended
follow-up of Syst-Eur, in which all the study patients
were offered the same active treatment as in the study,
a 30% reduction in fatal and non-fatal stroke was
found. When comparing the participants in the extended
follow-up (n=3,516) and the non-participants (n=397),
the fatal and non-fatal stroke incidence was the same
in the patients on placebo switched to active treatment.
The initial benefit
for the patients on active treatment in the double-blind
trial may explain the difference in the stroke reduction
in the trial and in the extended follow-up.
The clinical message
is to initiate treatment immediately when systolic
hypertension is diagnosed and treat to target levels
to prevent stroke. A delay in treatment is associated
with a 30% higher incidence in stroke.
In the ALLHAT trial,
a significantly greater proportion of patients remained
on first-line treatment (an indication of being controlled
by the first-line drug and lack of side effects) in the chlorthalidone
and amlodipine groups, compared to the doxazosin and
lisinopril groups. More patients in the lisinopril
group required combination therapy to control blood
pressure, compared to the chlorthalidone, amlodipine,
and doxazosin groups, which were similar in the need
for combination therapy. The average follow-up was
5 years. Chlorthalidone was associated with the best
control of blood pressure, and with amlodipine blood
pressure was 1 mm Hg higher, and with lisinopril and
doxazosin it was 2 mm Hg higher.
For the primary
endpoint of coronary heart disease (CHD) there was
no difference between the three treatment groups in
ALLHAT. For combined CHD (coronary revascularization
and hospitalized angina), a marginally higher risk
was seen with doxazosin compared to chlorthalidone.
For stroke, no difference between amlodipine and chlorthalidone,
but a significant increased risk for stroke with lisinopril
and doxazosin (p=0.02 and p=0.04, respectively) was
seen.
In active-control
trials, calcium channel blockers were associated with
a 10% less risk for fatal and non-fatal stroke compared
to beta blockers and diuretics. ACE inhibitors are
associated with a 10% increased risk of stroke as
first-line treatment compared with diuretics and beta
blockers.
Secondary prevention data
The PROGRESS trial
randomized patients to perindopril only or perindopril
plus indapamide. A 28% reduction in stroke incidence
was found overall. For the perindopril plus indapamide
group, a 43% reduction in stroke recurrence was found,
compared to no change in the perindopril only group.
The difference in SBP was 12 mm Hg in the perindopril
plus indapamide compared to only 5 mm Hg in the perindopril
only group.
The PROGRESS investigators
concluded that the small difference in blood pressure
between the groups was responsible for the difference
in stroke recurrence. However, the PATS study, conducted
in China, with a design similar to PROGRESS, showed
that just a 5 mm Hg difference in blood pressure between
the two groups was associated with a 30% lower stroke
recurrence rate with the addition of indapamide. In
the PATS study, even in the normotensive patients
(n=90) there was a 40% reduction in stroke recurrence
with indapamide.
Benefit
of lowering blood pressure
A meta-regression
analysis of 30 trials in hypertension by Staessen
and colleagues showed a curvilinear relationship between
the achieved difference in the SBP and the odds ratio
for stroke. Clinically important, just a difference of 1 to 5
mm Hg in SBP was associated with a reduction in stroke
incidence. In the HOPE trial, a 3 mm Hg greater reduction
in SBP was associated with a 30% reduction in fatal
and non-fatal stroke.
The incorporation
of the LIFE and ALLHAT data in the meta-regression
analysis suggests that much of the outcome in these
studies can be explained by the blood pressure reduction.
In LIFE, s a significant 1 mm Hg difference in SBP
between the losartan and atenolol groups and a 3 mm
Hg in SBP in the diabetic subgroup was seen. In the
ALLHAT study, a 1 mm Hg difference in SBP with amlodipine
and a 2 mm Hg difference with lisinopril and doxazosin,
all compared to chlorthalidone, was seen. In the elderly
patients in ALLHAT, a 3 mm Hg difference in SBP was
seen with lisinopril compared to chlorthalidone.
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Advances in the Treatment of Hypertensive Patients with Diabetes
Toshiro Fujita
University of Tokyo, Tokyo, Japan
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Diabetes mellitus
(DM) is associated with an increased risk of hypertension
and an increase in cardiovascular (CV) mortality.
Blood pressure reduction is a prime factor responsible
for reducing the incidence of CV events and renal
disease progression in patients with DM. However,
what is sufficient treatment of hypertension to prevent
CV is not conclusive, and dispute remains concerning
the target blood pressure and choice of antihypertensive
agents in patients with DM.
The association
between diabetes and hypertension has been demonstrated
by several epidemiological studies. In a Japanese
epidemiological study, 8% of the general population
had diabetes and 27% had hypertension, while 4% had
both diabetes and hypertension. The prevalence of
diabetes was 3-fold greater in hypertensive than in
non-hypertensive subjects, and the prevalence of hypertension
was 2-fold greater in diabetic than non-diabetic subjects.
The association of diabetes and hypertension is very
common in Japan.
Persons with diabetes
are at very high risk. Data suggest that diabetes
is one of the greatest risks for cerebral, cardiac,
and renal target organ damage. An epidemiologic study
from Finland
showed that the long-term risk for myocardial infarction
(MI) was highest in persons with diabetes whether
or not they had a previous MI, compared to persons
without diabetes. The incidence of a future MI in
diabetic patients without a prior MI was the same
as that in non-diabetics with a prior MI. The Hisayama
epidemiologic study in Japan revealed
that diabetics had a 2.5- to 3-fold greater incidence
of cerebral infarction and coronary heart disease.
Clinical trials with AHA in
diabetic patients with HTN
Aggressive blood
pressure control is crucial to reduce CV events in
diabetic patients with hypertension. The SHEP randomized,
placebo-controlled, double-blind study compared diuretic-based
care with placebo in 4,736 elderly patients with isolated
systolic hypertension over an average of 4.5 years.
Post-hoc examination of the diabetic cohort suggested
that the benefit of AHA therapy was at least as great
in diabetics as in non-diabetics.
The Syst-Eur study
reported key data about the safety and efficacy of
treating hypertension in elderly patients with diabetes
with calcium antagonists. In the diabetic cohort of
492 patients, treatment of hypertension was associated
with cardiovascular risk reduction. All-cause mortality,
cardiovascular death and fatal and non-fatal cardiovascular
events were all significantly reduced with anti-hypertensive
therapy in the diabetic cohort compared to the non-diabetic
cohort.
Tight blood pressure
control, compared to less tight control, was shown
in the UKPDS study to be more effective to inhibit
the incidence of cardiovascular events compared with
intensive plasma glycemic control, versus conventional
control, in persons with type 2 diabetes. Diabetes-related
endpoints were reduced 24% with tight blood pressure
control, compared to less-tight control, while the
reduction was only 12% with intensive glycemic control.
Similarly, tight blood pressure control reduced microvascular
endpoints by 37% while the reduction was only 25%
with intensive glycemic control. Tight blood pressure
control in UKPDS was only 144/82 mm Hg, which is higher
than the currently recommended target blood pressure
in persons with diabetes.
The primary aim
of the HOT study was to define the optimal target
blood pressure in treated hypertension patients, by
evaluating the effect of three different diastolic
blood pressure (DBP) target levels on cardiovascular
morbidity and mortality. There was a trend towards
greater benefit the lower the target diastolic blood
pressure. In the diabetic cohort, there was a trend
towards greater benefit with lower DBP, and the risk
of major cardiovascular events was 50% lower in the
group with a DBP less than 80 mm Hg compared to less
than 90 mm Hg. Although the difference in blood pressure
between the 3 groups was less than anticipated at
only 4 mm Hg, the risk of cardiovascular events was
markedly decreased. This observation strongly supports
the result of the UKPDS that there is a definite benefit
in targeting lower treated blood pressure in patients
with diabetes and hypertension. Based on the HOT results,
the target diastolic blood pressure should be less
than 80 mm Hg in patients with diabetes.
The Japanese Society
of Hypertension guidelines recommend a target blood
pressure of less than 130/80 mm Hg in persons with diabetes. The 2002 recommendation
from the American Diabetes Association was also <
130/80 mm Hg.
A
steep annual increase in the number of patients on
hemodialysis in seen in Japan. The prevention of
end-stage renal disease (ESRD) is a major problem
in Japan. Diabetic
nephropathy is the leading cause of ESRD in Japan, while
the incidence of chronic glomerulonephritis has been
decreasing.
The benefit of renin-angiotensin
blockade in patients with diabetic nephropathy is
supported by trial evidence. In 1985, captopril was
shown to markedly decrease urinary protein excretion
in patients with diabetes. In patients with type 1
diabetic nephropathy, captopril was shown to have
a reno-protective effect, with a 2-fold decrease in
the number of patients with a doubling of serum creatinine,
compared to placebo. This was associated with a significant
48% risk reduction. In the RENAAL study, losartan
was shown to inhibit the progression of ESRD in patients
with type 2 diabetic nephropathy. The number of patients
with a doubling of serum creatinine was less in the
losartan group compared to placebo, with a 28% and
25% risk reduction, respectively. Angiotensin receptor
blockers (ARBs) are similar to ACE inhibitors for
its anti-proteinuric effect and it inhibits renal
disease progression in patients with diabetic nephropathy.
The IDNT study suggested
that the ARB might be superior to calcium antagonists
in patients with diabetic nephropathy. Irbesartan
and amlodipine were associated with a
risk
reduction in the doubling of serum creatinine, ESRD,
and death. Therefore, ARBs are well-established to
inhibit the progression of diabetic nephropathy.
The IRMA study with
the ARB irbesartan showed that the renoprotective
effect of ARBs may be independent of blood pressure
lowering. In patients with mild diabetic nephropathy
associated with microalbuminuria, the incidence of
diabetic nephropathy was reduced in a dose-dependent
fashion with irbesartan, although the blood pressure
reduction in both irbesartan groups and placebo group
was similar. Blood pressure reduction was higher than
recommended, at an average of 133-144 mm Hg SBP. A
clear linear relation has been shown between level
of mean arterial blood pressure and decrease in glomerular
filtration rate. Thus, blood pressure must be lowered
below 130/80 mm Hg or more to inhibit the progression
of renal disease. Although ACE inhibitors and ARBS
are preferred treatment in patients with diabetic
nephropathy, there is no data to show whether antihypertensive
agents affecting the renin-angiotensin system are
superior to the other classes of AHA when blood pressure
is tightly controlled.
Beyond
blood pressure lowering
Ramipril significantly
decreased myocardial infarction and cardiovascular
death in patients with diabetes, despite small reductions
in blood pressure, in the MICRO-HOPE study. Thus,
ACE inhibitors might possess a beneficial effect beyond
blood pressure lowering on the cardiovascular system
in diabetic patients.
In the CAPPP study
that compared captopril to diuretics and beta blockers,
captopril was more effective in reducing the primary
endpoint of myocardial infarction, stroke, and cardiovascular
death. This was mostly attributed to reduction of
cardiac death.
In the ABCD study,
the ACE inhibitor significantly reduced the incidence
of fatal and non-fatal myocardial infarction, compared
to the calcium antagonist nisoldipine. Cardiovascular
mortality and total mortality were significantly reduced
with losartan compared to atenolol in the LIFE study
in patients with diabetes. In the STOP Hypertension-2
study, the ACE inhibitor significantly reduced MI
compared to calcium antagonist. In the UKPDS, there
was no difference between captopril and atenolol for
cardioprotective effect in diabetic patients. Hence,
when ACE inhibitors are more effective than beta blockers
for cardioprotection in diabetic patients is not conclusive,
although there are no reports of the beta blocker
being better.
In the IDNT study
that reported the renoprotective effects were greater
with irbesartan compared to amlodipine, the cardiovascular
outcomes were nearly the same with the ARB and calcium
antagonist. Detailed analysis shows that non-fatal
myocardial infarction reduction was reduced by 41%
with amlodipine compared with placebo. Thus, it remains
controversial whether ACE inhibitor and ARB are better
than calcium antagonists for cardioprotection.
Results of several
clinical trials suggested that an ACE inhibitor and
ARB might be more effective to inhibit the incidence
of coronary arterial diseases than a calcium antagonist,
diuretics and beta blockers, but discrepant results
have been shown. Thus, the superiority of renin angiotensin
blockade remains controversial.
In the HOPE study,
the benefit was only partly attributed to the modest
reduction of 3-4 mm Hg in office blood pressure. However,
the 24-hour blood pressure reduction was underestimated,
because of the more pronounced nighttime blood pressure
reduction. The effect of ramipril might be attributable
to the moderate reduction in nocturnal blood pressure.
In the Syst-Eur study, office blood pressure was poorly
related to CV events, but 24-hr blood pressure and
especially nighttime blood pressure were more tightly
related to CV events. Thus, aggressive control of
office blood pressure and tight control of blood pressure
are very important to prevent CV events.
Diurnal blood pressure
pattern in diabetic patients show that the lack of
a fall in nighttime blood pressure was related to
the presence of microalbuminuria in contrast to diabetic
patients with a nighttime blood pressure reduction.
Patients with type 1 diabetes
and higher nighttime blood pressure had increasing
amounts of microalbuminuria, suggesting that nighttime
blood pressure should be tightly controlled, even
in diabetic patients with normal levels of blood pressure
and microalbuminuria, for both cardioprotection and
renoprotection.
To achieve target
blood pressure, most hypertensive patients with diabetic
nephropathy require several antihypertensive agents.
In the RENAAL study, about 80% of patients required
losartan and a diuretic to achieve target blood pressure
levels.
Several clinical
studies have demonstrated that all patients with diabetes
and especially those with renal insufficiency should
have their blood pressure lowered to less than 130/80
mm Hg and in most patients this will require 3 or
more agents.
The anithypertensive
cocktail for patients with hypertension and diabetes
should include an ACE inhibitor or an ARB, plus a
diuretic and calcium antagonist for cardioprotection
and renoprotection.
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