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Drugtreatmentofisolatedsystolichypertension
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Volume16,Issue6

Pp.10951097.

NephrologyDialysisTransplantation
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Nephrol.Dial.Transplant.(2001)16(6):10951097.doi:10.1093/ndt/16.6.1095

Drugtreatmentofisolatedsystolichypertension
Peter A. van Zwieten
+

Author Affiliations

Introduction
Until the 1980s diastolic blood pressure (DBP) was assumed to be the most relevant haemodynamic parameter as a predictor of
prognosis in hypertensive patients. Accordingly, most clinical studies particularly addressed DBP, and DBPvalues were put forward as
goals for treatment [1]. Since then a radical change in thinking, based upon epidemiological studies has led to the recognition of
elevated systolic blood pressure (SBP) as a risk factor at least as important as high DBP [15]. Certain studies would even indicate that
SBP is a more relevant predictor of prognosis than DBP, in particular with respect to the risk of stroke [1]. For this and other reasons,
the term isolated systolic hypertension (ISH) has been introduced for those subjects with elevated SBP and normal (or even lower)
DBP. This condition is found particularly in elderly hypertensives, since SBP is known to rise with advancing age, whereas DBP usually
levels off and then tends to decrease in the elderly. Consequently, pulse pressure (SBP minus DBP) will increase in such patients. It
appears that elevated pulse pressure is an even better predictor of cerebro and cardiovascular events in elderly hypertensives than a
high SBP as such [1,2]. Indeed, ISH is the most common type of hypertension in the elderly, and it is the most prevalent type of
untreated hypertension among persons over 60 years of age.
According to modern definitions, expressed in the JNCVI [16] and 1999 WHO/ISHGuidelines [7] ISH is now defined as BP >140/<90
mmHg. These criteria are more stringent than the older definition of ISH at >160/<90mmHg. The development of ISH with
increasing age is explained by a deterioration of arterial compliance, in particular that of the large conduit arteries. Such increasing
arterial stiffness is caused by structural and functional changes in the vascular wall, affecting collagen, extracellular protein matrix,
and elastin. The proliferation of connective tissue results in intimal thickening and fibrosis. The increasing vascular stiffness causes a
reduction in arterial compliance and the decrease of the Windkessel function of the large arteries. Accordingly, pulse pressure and
pulse wave velocity increase, associated with an earlier and enhanced reflection of pressure waves from the periphery [1,2], thus
causing a disproportionate increase in SBP. DBP, however, does not increase and may even be lowered as a result of increased arterial
stiffness.
Isolatedsystolichypertensionasariskfactor
The widened pulse pressure found so typically in the elderly reflects both an increase in systolic and a decrease in diastolic pressure.
Several studies, including the Framingham study, documented the risk of high SBP in particular with respect to stroke and, less clearly,
ischaemic heart disease [8]. Similarly, in the MRFIT study SBP was found to be a stronger predictor of outcome than DBP [9]. However,
it should be realized that too low a DBP is also dangerous [1012]. These observations once more emphasize the important role of
widened pulse pressure as a risk factor. Conversely, several intervention studies in patients with ISH, to be discussed in a subsequent
paragraph, have demonstrated the beneficial effect of the treatment of ISH, and more generally of treatment of hypertension in the
elderly. At least on theoretical grounds it seems desirable to lower SBP in such patients, without simultaneously lowering DBP, in order
to avoid a further widening of pulse pressure.
BenefitoftreatmentofISH
In general terms, the beneficial effect of treatment of ISH runs in parallel with that of the treatment of hypertension in the elderly. In
general, this issue has been addressed since the 1990s by means of intervention trials. Several trials such as STOP1, STOP2, and MRC
Elderly have clearly shown that treatment of hypertension in the elderly protects against the complications of hypertension, particularly
stroke (for review see [13]). In most of these trials no clear distinction was made between ISH and ordinary hypertension. There is no
doubt, however, that a major percentage of the elderly hypertensive patients enrolled in these studies displayed the haemodynamic
characteristics of ISH. A few clinical trials have deliberately addressed a population of patients with ISH as such.
SystolicHypertensionintheElderlyProgram(SHEP)]14[

Patients with welldefined ISH were treated with lowdose chlorthalidone (with the option to add atenolol or reserpine), and this was
compared with administration of placebo. Chlorthalidone treatment caused the following reductions: nonfatal stroke: 37%; nonfatal
MI: 33%; LV failure: 54%. There were obvious trends for a decrease in TIAs (25%) as well as in total (13%), cardiovascular (20%),
cerebrovascular (29%), and coronary (15%) mortality.
SystolicHypertensioninEurope(SYSTEUR)[15]

In a large number of patients with ISH, the calcium antagonist nitrendipine (with optional addon enalapril and/or hydrochlorothiazide)

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was compared in a doubleblind randomized design with placebo. Active treatment with nitrendipine caused a significant and striking
reduction in the incidence of stroke by 42%, and there was also a clear tendency towards a reduction of myocardial infarction. This
reduction did not achieve statistical significance however, probably because the trial had been stopped prematurely for ethical
reasons. Total mortality (all causes) was not influenced by active treatment. Interestingly, the rate of vascular dementia was reduced
(by 50%) in the study area with nitrendipine treatment [16].
SYSTChinatrial[17]

Chinese patients with ISH were treated with nitrendipine or placebo. The trial design was very similar to that of SYSTEUR. Active
treatment with nitrendipine significantly reduced the following endpoints: total stroke: 38%; stroke mortality: 58%; all cause
mortality: 39%; cardiovascular mortality: 39%; fatal and nonfatal cv events: 37%.
INSIGHTstudy[18]

The INSIGHT study has dealt with a population of hypertensive patients with an additional risk factor, such as diabetes mellitus,
hypercholesteraemia, etc. Treatment consisted of nifedipine (in the GITS form: AdalatOROS) vs hydrochlorothiazide. INSIGHT was not
a selective ISHtrial, but it contained a subgroup of patients with ISH. This subgroup was analysed separately [19]. These patients
appeared to be more responsive to treatment with nifedipineGITS than those with ordinary hypertension. Interestingly, in this study
patients with ISH whose DBP significantly decreased under treatment were smokers with evidence of atherosclerosis.
A series of outcome trials in patients with ISH was recently subjected to a metaanalysis [20]. Active treatment reduced total mortality
by 13%, cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30% and coronary events by 23%. Drug
therapy appeared to offer better protection against stroke than against acute coronary syndromes. The absolute benefit was best in
patients older than 70 years, and in those with a history of cardiovascular complications or a high pulse pressure (i.e. wide blood
pressure amplitude).
In a series of smaller studies it has been shown that in ISH patients thiazide diuretics are more protective than blockers [2123].
Newer drugs such as ACEinhibitors [24] and AT1blockers [25] are also suitable for blood pressure control in ISH, although data on an
epidemiological scale are not yet available. Omapatrilat, a combined inhibitor of neutral endopeptidase and ACE showed a stronger
effect on SBP than on DBP [26].
NewapproachesinthetreatmentofISH
At least on theoretical grounds it would seem desirable to find antihypertensive drugs which reduce SBP more markedly than DBP:
(i) Spironolactone, an aldosterone antagonist, is not only a (rather weak) natriuretic agent. It also inhibits the synthesis of collagen and
myocardial and vascular fibrosis provoked by aldosterone [27]. For this reason spironolactone may counteract the arterial stiffness
which underlies the pathogenesis of ISH. Studies [2] have indeed documented favourable effects of spironolactone in ISH patients. More
detailed and larger studies are therefore clearly indicated to further address this matter,
(ii) Eplerenone is a newer aldosterone antagonist with much weaker endocrine activities than spironolactone, so that one would expect
fewer endocrine sideeffects such as gynaecomastia;
(iii) Nitrates, as NO generators, may also be considered as a potential new approach in the treatment of ISH. Isosorbide dinitrate has
been shown to selectively lower systolic blood pressure without changing diastolic pressure in elderly patients with isolated systolic
hypertension [2,28]. It took 8 weeks of treatment before the effect on systolic blood pressure became manifest. The selective effect on
systolic blood pressure is assumed to be explained by the drug's influence on pressure wave reflection in the large conduit arteries.
Similar findings concerning systolic pressure have been obtained with transdermal nitroglycerine and molsidomine [2,28]. It is
therefore believed that these beneficial effects are explained by the increased release of NO as the underlying principle. So far no data
are available concerning the protective effects of longterm nitrate treatment on the sequelae of hypertension.
Conclusionsandrecommendations
Isolated systolic hypertension is characterized by a widened pulse pressure. It has been recognized as an important entity, which
requires consistent treatment. Apart from the wellknown advices for lifestyle modification, drug treatment is required in the majority
of patients with ISH.
The data so far available indicate that lowdose thiazide diuretics and slow/longacting calcium antagonists are the drugs of first
choice. A slow reduction of systolic pressure in the mostly elderly patients is mandatory. A target level of SBP around 140mmHg seems
desirable. Newer drugs such as ACEinhibitors, AT1blockers and omapatrilat are effective in lowering SBP in ISH patients, but large
scale data concerning their protective effects are not available. Finally, aldosterone antagonists and nitrates (as NO generators) deserve
further investigation as drugs which may reduce arterial stiffness, the pathogenetic mechanism underlying ISH.
Footnotes
Correspondence and offprint requests to: P. A. van Zwieten, Departments of Pharmacotherapy, Cardiology and Cardiothoracic
Surgery, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
European Renal Association-European Dialysis and Transplant Association

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