Systolic Hypertension in
the Elderly: Pushing the Frontiers of Therapy -- A Suggested
Gordon S. Stokes, MD, FRACP
J Clin Hypertens 6(4):192-197,
2004. © 2004 Le Jacq Communications, Inc.
Abstract and Introduction
In elderly patients with systolic
hypertension resistant to treatment with conventional therapy,
increased aortic pulse wave reflection and a high augmentation
index are often present. These findings are indicative of
endothelial dysfunction and deficient generation of nitric
oxide, a potent vasodilator in the arterial tree. In such
patients, treatment with the nitric oxide donor
extended-release isosorbide mononitrate characteristically
produces prompt and sustained falls in both pulse wave
reflection and systolic blood pressure. The adjunct use of
this nitrate produces useful additional decreases in systolic
blood pressure ranging from 10 to 45 mm Hg, often achieving
target blood pressure goals in isolated systolic hypertension.
By combining this endothelium-independent nitric oxide donor
with angiotensin-converting enzyme inhibitors or angiotensin
II receptor blockers, the potential exists to address both the
nitric oxide deficiency and endothelial dysfunction of the
vascular endothelium in these patients. Other possibilities
for synergism with this combination include complementary
hemodynamic, circadian, and metabolic actions together with
prevention of nitrate tolerance. Isosorbide mononitrate may
also be used successfully with calcium channel blockers, ß
blockers, and diuretics.
Systolic hypertension is a risk factor
for stroke and heart attack in elderly patients. With the
trend for increased longevity among the general population,
this form of hypertension has become an important public
health issue. The incidence of hypertension in people over the
age of 60 years has been estimated as >60%.
Isolated systolic hypertension (ISH), which accounts for 65%
of the overall incidence of uncontrolled hyperten-sion,
is a prevalent form of systolic hypertension in the elderly.
Also, systolo-diastolic hypertension may lead to ISH when the
diastolic blood pressure (DBP) responds to therapy but the
systolic blood pressure (SBP) does not.
ISH may be resistant to conventional
antihypertensive agents. Effects of combination
antihypertensive therapy on SBP in older hypertensive patients
have been reported in a number of placebo-con-trolled,
randomized trials.[3-8] These trials have shown
significant differences between active treatment and placebo
groups for both DBP and SBP values; however, the average SBP
reached with long-term treatment in the active groups was
usually above the currently recommended target of 140 mm Hg.
In the European Working Party on High Blood Pressure in the
Elderly (EWPHE) trial, for example, the average value (± SD)
reached at 5 years was 150 ± 20 mm Hg (based on 108 patients).
In the Systolic Hypertension in the Elderly Program (SHEP) the
corresponding value at 5 years was 155 ± 21 mm Hg (based on
773 patients). In the Swedish Trial in Old
Patients with Hypertension (STOP-Hypertension) the average SBP
at 2 years was 166 ± 20 mm Hg (based on 385 patients).
In the Systolic Hypertension in Europe (Syst-Eur) trial at 2
years, SBP was 151 mm Hg. In both SHEP and The
Second Australian National Blood Pressure Study (ANBP2) there
was a failure to achieve target SBP in approximately 30% of
patients.[4,7] In Syst-Eur the corresponding
failure rate was 56.5%. It must be kept in mind
that these statistics underestimate the true incidence of
treatment-resistant hypertension, because exclusion criteria
would have kept some severely hypertensive patients from the
Pathophysiology of ISH
Increased Pulse Pressure: Role
of Wave Reflection
The high SBP of ISH is characterized by
widened arterial pulse pressure, a change that results from
the effects of age and age-associated cardiovascular disease
on the arterial tree. With advancing age, there
is small artery constriction that boosts the reflected
component of the pulse wave. Additionally,
there is large artery stiffening that increases the velocity
of transmission of the reflected wave so that it moves from
diastole to late systole, thereby increasing SBP.
The aortic pulse waveform can be quantified by percutaneous
applanation tonometry of the radial or carotid artery, and the
magnitude of the reflected component may be expressed as the
augmentation index (a measure of the increase in pulse
pressure caused by wave reflection [Figure 1]). Augmentation
by pulse wave reflection is characteristically increased in
treatment-refractory ISH, being responsible for up to 40% of
the pulse pressure in this condition.
Augmentation Index Is Related
to Endothelial Dysfunction
There is considerable evidence that
increase in the augmentation index denotes deficient
vasodilative endogenous nitric oxide (NO) generation
associated with endothelial dysfunction.[12,13]
Endothelial dysfunction is found with aging,
chronic hyper-tension, atherosclerosis,
diabetes, long-term cigarette smoking,
and obstructive sleep apnea. Likewise,
decreased vascular NO production has been reported in chronic
hypertension, diabetes, and obstructive sleep apnea.[19-21]
In normal arteries, fluid shear stress and pulsatile stretch
are responsible for the release of NO and other autacoids,
which maintain the constrictor and dilator functions of the
vessel wall.[23,24] We have suggested that the
increase in pulse wave reflection in ISH results from
impairment of these functions and particularly from a loss of
NO-dependent arterial vasodilatation.[25,26]
Implications for Choice of Therapy
Not all patients with ISH have a high
augmentation index. White coat hypertension, characterized by
a discrepancy between office blood pressure (BP) readings and
automated ambulatory or home BP recordings, is more prevalent
in the elderly. Tachycardia, cutaneous flush,
and other features of a high output state are sometimes
present. In such patients, the primary or ejection peak of the
arterial pulse waveform is increased rather than the wave
reflection, and the augmentation index may be normal. The
prognosis and the role of pharmacotherapy in this group are
controversial. Conversely, finding a raised augmentation index
in patients with ISH has important implications for their
prognosis and for selection of an appropriate drug regimen.
Such patients frequently have other risk factors for
cardiovascular disease, such as hyperlipidemia or diabetes
mellitus, and a history of vasculopathy. Augmentation index is
strongly correlated with cardiovascular risk.
Indeed, ISH with a high augmentation index may be considered a
final common pathway to which vascular disease due to age,
hypertension, atherosclerosis, or diabetes all lead. Whatever
the primary etiology, the presence of endothelial dysfunction
tends to increase pulse wave reflection, and thereby pulse
pressure and SBP.
Therapeutic Management of ISH
This review will not attempt to provide
a comprehensive account of the clinical management of ISH,
which has been dealt with recently in subsections of the
seventh report of the Joint National Committee on Prevention,
Evaluation, and Treatment of High Blood Pressure (JNC 7) and
the 2003 European Society of Hypertension-European Society of
Cardiology guidelines.[29,30] Current management is
based on evidence from large-scale clinical trials, which
showed that reduction of SBP to <140 mm Hg (and reduction
of DBP to <90 mm Hg) decreases the incidence of
cardiovascular morbid events in elderly hypertensive subjects
up to the 9th decade of life. Thus, 140 mm Hg
should be the general therapeutic goal for SBP in ISH, with a
lower goal of 130 mm Hg being set for patients with diabetes
mellitus or renal disease. In the elderly, the SBP goal is
more difficult to reach than the DBP goal and commonly
requires combination therapy employing two or more drug
classes in addition to lifestyle measures.
The following drug classes, given singly
or in combinations, have been shown to be effective for
long-term BP reduction: diuretics (thiazide or thiazide-like),
ß blockers, angiotensin II inhibitors (angiotensin-con-verting
enzyme [ACE] inhibitors or angiotensin II receptor blockers),
and calcium channel blockers. For many patient groups (possibly
excluding some with diabetes, renal disease, or heart failure)
there is no proven rationale for preferring one drug class
over another, and the most important criterion is the ability
of the regimen chosen to achieve goal BP with minimal side
effects. However, some findings suggest that diuretics and
calcium channel blockers may have a greater effect in the
elderly. Patients who do not reach goal BP based on office
readings may require automated or home BP recording to exclude
the possibility of a white coat effect. The preferred arbiter
of effective BP control (although not yet recommended for
general use) is 24-hour ambulatory monitoring showing
acceptable daytime and nighttime average BP values with an
absence of sustained peaks. The path forward for managing
patients who fail to reach goal despite trials of various
combinations of conventional antihypertensive drugs is the
subject of the remainder of this review.
Management of Patients With
In patients with ISH who fail to reach
goal BP after a thorough trial of appropriate therapy, a
second look at the diagnosis is advisable even if routine
assessment for underlying causes was undertaken earlier. Tests
for renal or renovascular disease, primary hyperaldosteronism,
and obstructive sleep apnea may be required in selected cases.
Additionally, noninvasive evaluation of arterial stiffness may
have a role in therapeutic design for elderly individuals with
difficult-to-manage hypertension. This approach, advocated by
an expert committee of the European Society of Hypertension,
but not by some other national guidelines committees, incurs
expense and may not be justified for routine clinical
assessment. The evaluation, which includes determination of
central augmentation index, can be performed by one of several
commercially available tonometric devices that record pulse
wave contour. Based on a comparison of pulse wave reflectance
between normotensive, normocholesterolemic elderly volunteers
and vasculopathic hypertensive patients, it is
suggested that values for aortic augmentation index >120%
should be regarded provisionally as abnormal.
Systolic hypertension associated with a
raised augmentation index may prove refractory to
antihypertensive agents. Some antihypertensive agents (such as
diuretics and negative inotropes) reduce the ejection
component of the pulse pressure by decreasing cardiac stroke
volume without reducing pulse wave reflection. Others have the
capacity to decrease wave reflection by restoring impaired
vascular NO generation but may take a long time to produce
this effect fully. For example, it has been shown that ACE
inhibitors may take up to 3 years to reverse impaired
acetylcholine-responsive vasorelaxation in essential
hypertensives.[33-35] With such agents some
continued elevation of augmentation index and SBP may be
expected unless adjunctive treatment is given with a direct,
endothelium-independent vasodilator. A nitrate (or an NO donor)
is a logical choice.
Role of Extended-Release Nitrate
Patients with ISH found to have an inadequate response to
conventional combination antihypertensive treatment and a
raised augmentation index have responded well to adjunctive
therapy with extended-release nitrates.[26,37,38]
Characteristically, within 1-3 hours of administration of a
single 60 mg dose of isosorbide mononitrate (ISMN), SBP fell
by 10-45 mm Hg and augmentation index decreased by 50% of
baseline value. The change in augmentation index exceeded
corresponding values found for captopril and eprosartan in
placebo-controlled comparative studies against the nitrate and
was greater than values reported in the literature for various
ACE inhibitors, angiotensin II receptor blockers, diuretics,
and ß blockers. In a placebo-controlled study
in which ambulatory BP was measured during short-term
withdrawal of chronic once-daily administration of ISMN, we
showed that the antihypertensive effect of a regular morning
dose lasted 10-12 hours. BP remained controlled
without cumulative or rebound effects during continued
Role of Angiotensin II Inhibitors:
Separate and in Combination With ISMN
Short-term treatment with
moderate-to-high doses of ACE inhibitors or angiotensin II
receptor blockers has been associated with relatively minor
decreases in augmentation index; however, these
drugs are known to have beneficial effects on NO
bioavail-ability. Also, they can improve
endothelium-dependent vasodilatation with long-term use[33,41]
and can repair resistance artery structure.[42-44]
Moreover, the vasodepressor actions of ISMN and angiotensin II
inhibitors in systolic hypertension of the elderly appear to
be additive. In acute studies, we have shown that effects of
ISMN on SBP and augmentation index were undiminished by
therapy at baseline with angiotensin II inhibitors.[26,38]
In an acute study, the effect of ISMN on SBP was shown to be
augmented by coadministration of L-argi-nine (a substrate for
endogenous NO formation) if angiotensin II inhibitors were not
also used. However, if angiotensin II
inhibitors were used, L-arginine had no effect on the BP
response to ISMN in the presence of either acute
or chronic ISMN therapy. This could indicate
that angiotensin II inhibition augmented the vasodilator
effect of ISMN through a mechanism similar to that exerted by
L-arginine, perhaps involving limitation of superoxide
It is not known whether tolerance to
nitrates, long recognized as a problem in the treatment of
coronary vascular disease with nitrates, can
complicate nitrate use for systolic hypertension. Follow-up
studies of 14 patients with ISH who were treated for up to 9
years with an extended-release formulation of ISMN as an
adjunct to conventional antihypertensive therapy suggested
that there was no major loss of effect with the elapse of time
(G.S.S., unpublished data, 2004). The finding may have
resulted from once-daily dosing. When used for the relief of
angina pectoris, the extended-release formulation has been
reported to cause tolerance if given twice daily, but not if
given once daily. Another factor that could
have prevented tolerance development was the coadministration
of ACE inhibitors, known to counter nitrate tolerance in
cardiac patients. More data from prospective,
long-term studies of nitrates in ISH are needed to determine
whether nitrate tolerance develops and if so, whether it can
be modified by appropriate dosing schedules or cotherapies.
The Possibility of Utilizing Additive/Synergistic
Actions Between ISMN and Angiotensin II Inhibitors in Therapy
Potential additive/synergistic antihypertensive effects exist
with respect to combined therapy with ISMN and angiotensin II
inhibitors in an appropriately selected elderly patient
population. The principal basis of the combined action is
improvement of endo-thelium-dependent NO production by
angiotensin II inhibitors together with
endothelium-independent NO donation by ISMN. Another
consideration is that ISMN has selective hemodynamic effects
different from angiotensin II inhibitors. ISMN produces a
greater fall in SBP than in DBP and a greater decrease in the
reflection component of the pulse wave than in the ejection
component. Also, ISMN produces its effect
principally on vascular tone, whereas angiotensin II
inhibitors have cardiac, renal, and metabolic activity
independent of antihypertensive activity. Finally, angiotensin
II inhibitors are known to have an antihypertensive effect
overnight and thus should cover the period
12-24 hours after dosing with ISMN (given once daily to avoid
Further research is necessary to
determine whether the long-term process of restoring vascular
NO generation by treatment with angiotensin II inhibitors
might gradually reduce the capacity for NO donors to lower the
augmentation index in these patients. If this were so, the
resulting diminution in nitrate effectiveness over time would
need to be distinguished from true nitrate tolerance.
Combination Therapy With ISMN and
Other Antihypertensive Agents
ISMN has been shown to produce an
additive antihypertensive effect when combined with calcium
channel blockers, ß blockers, or diuretics.[11,26,37,38]
Some grounds exist also for expecting synergistic activity
between these agents and nitrates. Thus, calcium channel
blockade has been shown to restore endothelium-dependent
vasodilation in essential hypertension and to
enhance the effects of an ACE inhibitor on endogenous NO
production. Beta blockade may prevent any
tendency for ISMN-induced cardioacceleration. Diuretics may
oppose nitrate-induced plasma volume expansion, thought at one
stage to be a counter-regulatory mechanism in nitrate
Introduction of Adjunct
Therapy With ISMN
A starting dose of 30-60 mg (as an isosorbide mononitrate
extended-release formulation) is recommended to be given once
daily in the morning. This may be increased rapidly to 120 mg
once daily if required to reach target SBP. If the patient has
a history of headaches, the 30-mg starting dose should be used
in conjunction with oral paracetamol 1 g. If headache occurs,
it often abates after the first few doses. The dosage can
usually be increased to 120 mg daily without reappearance of
headache. Apart from headache, which is reported in about 10%
of patients, side effects are rare.
Although orthostatic hypotension from
nitrates may be encountered in patients with low cardiac
output states, it has not occurred in our ambulant study
An important contraindication to the
introduction of nitrates in this, as in other clinical
settings, is the concurrent use of sildenafil for erectile
In summary, there is evidence to
indicate that the use of once-daily, long-acting nitrate
preparations have a role as adjunct therapy in achieving
target SBP for ISH patients. It is suggested that such nitrate
therapy should be undertaken in ISH patients who have failed
to achieve target SBP after an adequate trial of combined
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Gordon S. Stokes, MD, FRACP,
Hypertension Unit, Block 1B, Royal North Shore Hospital, St.
Leonards, NSW 2065, Australia. E-mail: firstname.lastname@example.org.
Gordon S. Stokes, MD, FRACP,
Hypertension Unit, Royal North Shore Hospital, St. Leonards,