How to lower systolic blood pressure with medication

Abstract

Systolic hypertension is a major health economy problem within our aging society. Increased arterial stiffness is the vascular phenotype of systolic hypertension, especially of the large arteries. Elevated systolic blood pressure is even more associated with cardiovascular morbidity and mortality than diastolic blood pressure. Treatment of systolic hypertension in the elderly should be based on nonpharmacological measures and medical therapy if the systolic hypertension cannot be controlled by conservative therapy alone. The HYVET study provided evidence-based medicine data showing that, in the very elderly, lowering blood pressure to a level of 150/80 mmHg is still very beneficial. Antihypertensive therapy needs to be tailored in the elderly because of comorbid conditions, such as ischemic heart disease, heart failure, atrial fibrillation, renal insufficiency and diabetes. Angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers should be considered in combination with diuretics or with a dihydropyridine calcium antagonist. β-blockers seem to be less effective for cardiovascular disease protection in comparison with other antihypertensive drug classes, such as diuretics, dihydropyridines, angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers. Major effort is required to reduce the therapeutic inertia and increase therapeutic adherence for better blood pressure control in the elderly with systolic hypertension.

Expert Rev Cardiovasc Ther. 2012;10(11):1367-1373. © 2012  Expert Reviews Ltd.

• Abstract
• Facing the Problem
• Pathophysiology of Systolic Hypertension in the Elderly
• Treatment Goals
• Nonpharmacological Treatment
• Pharmacological Treatment
• Which Antihypertensive Drug Regimens Are Suitable for Treating Elderly Patients?
• To What Age Should We Treat Hypertension?
• Personalized Treatment Strategies
• Therapeutic Adherence
• Expert Commentary & Five-year View
• References

Authors and Disclosures

Daniel Duprez

Cardiovascular Division, University of Minnesota, 420 Delaware St SE, MMC 508, Minneapolis, MN 55455, USA Tel.: +1 612 624 4948 Fax: +1 612 626 4411

Financial & competing interests disclosure
The author has received research grant from Novartis, has received honoraria from Novartis, Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

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 DBP‐values 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 [1–5]. 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 cardio‐vascular 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 JNC‐VI‐ [16] and 1999 WHO/ISH‐Guidelines [7] ISH is now defined as BP >140/<90 mmHg. These criteria are more ‘stringent’ than the older definition of ISH at >160/<90 mmHg. 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.

Isolated systolic hypertension as a risk factor

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 [10–12]. 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.

Benefit of treatment of ISH

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 STOP‐1, STOP‐2, 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.

Systolic Hypertension in the Elderly Program (SHEP) ]14[

Patients with well‐defined ISH were treated with low‐dose chlorthalidone (with the option to add atenolol or reserpine), and this was compared with administration of placebo. Chlorthalidone treatment caused the following reductions: non‐fatal stroke: −37%; non‐fatal 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.

Systolic Hypertension in Europe (SYST‐EUR) [15]

In a large number of patients with ISH, the calcium antagonist nitrendipine (with optional add‐on enalapril and/or hydrochlorothiazide) was compared in a double‐blind 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].

SYST‐China trial [17]

Chinese patients with ISH were treated with nitrendipine or placebo. The trial design was very similar to that of SYST‐EUR. Active treatment with nitrendipine significantly reduced the following endpoints: total stroke: −38%; stroke mortality: −58%; all cause mortality: −39%; cardiovascular mortality: −39%; fatal and non‐fatal cv events: −37%.

INSIGHT study [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: Adalat‐OROS®) vs hydrochlorothiazide. INSIGHT was not a selective ISH‐trial, 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 nifedipine‐GITS 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 meta‐analysis [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 β‐blockers [21–23]. Newer drugs such as ACE‐inhibitors [24] and AT1‐blockers [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].

New approaches in the treatment of ISH

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 side‐effects 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 long‐term nitrate treatment on the sequelae of hypertension.

Conclusions and recommendations

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 well‐known advices for life‐style modification, drug treatment is required in the majority of patients with ISH.

The data so far available indicate that low‐dose thiazide diuretics and slow/long‐acting 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 140 mmHg seems desirable. Newer drugs such as ACE‐inhibitors, AT1‐blockers 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.

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.

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