Send Orders for Reprints to reprints@benthamscience.ae 146 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2014, 12, 146-151

Recommendations for the Treatment of Hypertension in Elderly People

Alberto F. Rubio-Guerra* and Montserrat B. Duran-Salgado

Clinical Research Unit, Hospital General de Ticoman, Mxico DF, And Mexican Group for Basic and Clinical Research in Internal Medicine, Mexico City, Mexico

Abstract: High blood pressure is a major cardiovascular risk factor. The prevalence of hypertension increases with aging. As a consequence of changes in arterial wall that leads to arterial stiffness, the majority of elderly patients suffer isolated systolic hypertension. The evidence strongly supports that hypertension in the elderly is associated with an increase in stroke risk and cardiovascular mortality and morbidity. Several trials have shown the benefits of treating hypertension in elderly patients. Even in the very old patients, the use of antihypertensive agents such as calcium channel blockers, thiazide and thiazide-like diuretics, and inhibitors of the renin-angiotensin system reduce the risk of complications in those patients. However, most patients will need two or more drugs to reach the recommended goals.

Hypertension in the elderly has special conditions that must be assessed in the evaluation of the patient (as pseudohypertension and white coat hypertension), and issues that may affect the therapeutic choice and the response to treatment, as comorbidities and polypharmacy.

Keywords: Elderly, hypertension, isolated systolic hypertension, recommendations, treatment.

INTRODUCTION

The proportion of elderly individuals ( 65 years) is growing rapidly. It is expected that in the United States, 20% of population will reach this group of age by 2030 [1]. With the aging, the prevalence of hypertension increases. In fact, an age-dependent increase in both systolic and diastolic blood pressure up to the 6th decade of life has been described. It has been estimated that 67% of individuals aged between 60 older are hypertensive [2], whereas in people above the age of 70, the prevalence increases to 60-70% [3].

Hypertension in the elderly has several differences when compared with younger hypertensive patients, as increased blood pressure lability, and a greater risk of orthostatism. In elderly subjects, a rise in systolic blood pressure (SBP) occurs whereas diastolic blood pressure (DBP) slowly decreases; then, the majority of elderly subjects suffers isolated systolic hypertension. In elderly people, high SBP is a more reliable marker of cardiovascular risk than elevated DPB. Also in elderly people, pulse pressure (difference between SBP and DBP) has more impact on cardiovascular outcomes than DPB [3-7].

CONSEQUENCES OF HYPERTENSION IN THE ELDERLY

Isolated systolic hypertension and elevated pulse pressure are associated with left ventricular hypertrophy, and increases the risk for fatal and nonfatal coronary events and stroke, and also for end-stage renal disease [6].

*Address correspondence to this author at the Clinical Research Unit, Hospital General de Ticoman, Mxico DF, and Mexican Group for Basic and Clinical Research in Internal Medicine, Motozintla # 30. Col Letran valle Mxico D.F. C.P. 03600, Mexico City, Mexico; Tel/Fax: (52 555) 539 35 84; E-mail: clinhta@hotmail.com

Hypertension is accompanied by remodeling in small arteries, that raises vascular resistances, compromises arteriolar dilatory capacity and increases the risk of organ ischemia [7].

In the kidney, hypertensive changes in small arteries lead to nephroangiosclerosis, which contributes to the development of chronic kidney disease [8]. The Framingham study showed a greater cardiovascular risk for elderly patients than for younger patients at all levels of blood pressure [9].

Finally, some studies have shown that there is a dependent relationship between the occurrence of arterial hypertension and the risk of developing dementia in elderly individuals; in fact both; vascular dementia and Alzheimer disease are more common in hypertensive than in normotensive patients [10]. High pulse pressure increase the risk of dementia in elderly [3, 10].

DIAGNOSIS AND PATIENT EVALUATION

All international guidelines define hypertension when systolic blood pressure 140 mm Hg, and diastolic blood pressure 90 mm Hg on at least 3 different measurements taken in at least two separate office visits [11, 12]. Isolated systolic hypertension is defined as systolic values 140 mm Hg, and diastolic blood pressure < 90 mm Hg [11, 12]. Clinical evaluation of elderly patients with hypertension is quite similar to the evaluation of younger patients, however, is important to bear in mind three issues when attending elderly patients for hypertension; pseudohypertension, white coat hypertension, and postural and postprandial hypotension [8].

Pseudohypertension is defined as falsely elevated pressures that occur by indirect cuff measurements. This condition is due to medial sclerosis, which prevents compression of brachial artery; under those circumstances,

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the registers obtained with the sphygmomanometer are higher than those obtained by intra-arterial registers [8]. Pseudohypertension should be suspected in patients with high pressure values but without end organ damage, or in those with hypotension symptoms in spite of the indirect values of blood pressure remains high [8]. Although the gold standard for pseudohypertension is the measurement of intra-arterial blood pressure, this invasive method is not available in most facilities. Differential diagnosis is usually performed with the Osler maneuver, which consists of inflating the cuff over the systolic level of pressure, meanwhile the radial artery is palpated, the maneuver is positive if the artery remains palpable but no arterial pulsations are present [8].

White coat hypertension is defined as high blood pressure measurements at office but with normal ambulatory registers. It is due to a sympathetic response during the measurement, secondary to stress [13]. The prevalence of white coat hypertension increases with aging. We found it in 25% of elderly patients referred to our unit with diagnosis of uncontrolled isolated blood pressure (whereas in younger patients in our country, the prevalence is around 16-20%), and we also found that 75% of patients with white coat hypertension were women [13]. In order to avoid white coat hypertension, several out-of-office readings of blood pressure are needed. Self-measurement or ambulatory monitoring of blood pressure is effective to confirm or refute the diagnosis of white coat hypertension, and to avoid unnecessary antihypertensive treatments that may produce side effects in these patients [8, 13].

Postural and postprandial hypotension: Both conditions are common due to venous pooling, in the legs (postural) or mesenteric (postprandial) beds, the reduction of baroreceptor sensitivity may be involved too [3]. Postural hypotension is defined as a decrease in SBP 20 mm Hg or DPB 10 mm Hg within 3 minutes of standing. It is a common feature in elderly patients and may limit antihypertensive therapy. Therefore, it is recommended in older patients, to measure blood pressure in the sitting position and after standing in each visit [1].

Patients must be evaluated for postprandial hypotension when they suffer, within 2 hours after meal, syncope or falls. The measurement of blood pressure after meal when symptoms are present is recommended. In this regard, self-measurement or ambulatory monitoring of blood pressure is a good option. Whereas drugs that depleted volume should be avoided in those patients, we lack of an effective treatment for this disorder, -glucosidase inhibitors have shown are useful but poorly tolerated [1].

In elderly hypertensive patients, a silence between the first and the third Korotkoff sound may occur, it is called the auscultatory gap, and may lead to errors if the evaluation of Korotkoff sound begins during the auscultatory gaps. A preliminary determination of systolic blood pressure by palpation helps to avoid the mistake of a false low systolic blood pressure record [14].

Masked Hypertension

Masked uncontrolled hypertension (normal seated clinic blood pressure but an elevated out-of-office blood pressure

values) has a high prevalence in patients with treated and well-controlled clinic blood pressure. A recent article shown that this disorder is most frequently seen in subjects under 60 years [15]. However, the results of the study confirm the utility of self measurement or ambulatory monitoring of blood pressure in the valuation of hypertensive patients, independently of their age.

In the elderly, a careful abdominal auscultation is strongly recommended, because narrowing of the renal artery, usually due to atherosclerosis, is relatively common in individuals over 65 years. This complication must be suspected in patients 65 years with new onset or accelerated diastolic high blood pressure [3]. In patients with stenosis of renal artery, an abdominal murmur is often present. A renal Doppler ultrasound and an angiographic study may confirm the diagnosis. The importance of the diagnosis is that treatment with inhibitors of the renin angiotensin system in patients with renal artery stenosis may lead to acute renal failure or heart failure, and in some patients, the possibility of a revascularization procedure [3].

SHOULD WE TREAT HYPERTENSION IN THE ELDERLY?

For many decades, the value of treating hypertension in the elderly was rejected, and the rise in blood pressure was considered as an adaptation for aging or compensatory changes to vascular stiffness. Even more, lowering blood pressure in the elderly was considered as harmful because it could cause vascular collapse.

Several trials, as The Systolic Hypertension in the Elderly Program [16], the Systolic Hypertension in Europe [17] and the Systolic Hypertension in China trial [18], have shown that the treatment of hypertension in elderly patients produces a significantly cardiovascular risk lowering, specially the in risk of fatal and non-fatal stroke. Both, the Systolic Hypertension in Europe (SYST_EUR) trial, and the Systolic Hypertension in China (SYST-CHINA) trial, were prematurely terminated for ethical reasons, due to the early detection of a clinical relevant reduction in the primary end-point.

In the 22-year follow-up of the participants in the Systolic Hypertension in the Elderly Program (SHEP), treatment of isolated systolic hypertension with chlorthalidone (with or without atenolol), was associated with longer life expectancy at 22 years of follow-up [19]. And in the SYST-EUR trial, active treatment with nitrendipine (with or without enalapril) was associated with a lower incidence of dementia [20].

SHOULD THE VERY ELDERLY PATIENT RECEIVE PHARMACOLOGICAL TREATMENT?

The hypertension in the very elderly trial (HYVET), evaluated hypertensive patients aged 80 years or older, shown a significantly 30% reduction in stroke and a 21% reduction in mortality after treatment with indapamide, and perindopril added if needed [21]. The results of this trial showed that the use of antihypertensive therapy in older patients with hypertension was associated with a clear reduction in cardiovascular risk. A meta-analysis based on

148 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2014, Vol. 12, No. 3 Rubio-Guerra and Duran-Salgado

6701 patients > 80 years, shown that treating hypertension in very old patients reduces stroke and heart failure, with no effect on total mortality [22], providing clear evidence about the cardiovascular benefits of pharmacological treatment in hypertensive patient 80 years age and older.

GOAL OF ANTIHYPERTENSIVE THERAPY

Previous guidelines recommended a blood pressure goal < 140/90 mm Hg in most hypertensive patients, or < 130/80 in diabetic hypertensive patients. However, current evidence suggest a BP goal of less 150/90 in elderly patients [2]. Recently, the Eighth Joint National Committee (JNC8) suggests a goal of SBP < 150 mmHg and goal DBP < 90mmHg, as a grade A recommendation [12].

The 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension (11), suggest initiating antihypertensive treatments when SBP is 160 mm Hg, (Class 1, Level A), and adds that treatment may be considered in elderly (younger than 80 years) when SPB is between 140 and 159 mm hg if agents is well tolerated (Class IIb, level C).

In patients with isolated systolic hypertension an excessive reduction of DBP should be avoided, because a possible interference with coronary perfusion, especially in subjects with coronary artery disease [2].

Large, prospective studies have shown that reductions not only in isolated systolic hypertension, but as well as combined systolic-diastolic hypertension, lead to a reduction in morbidity and mortality in elderly hypertensive patients. Both, the European Working Party on hypertension in the elderly trial (EWPHE), and the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) trial significantly reduced cardiovascular and cerebrovascular mortality [6], in the STOP-Hypertension, a significant reduction in total mortality was also observed, although it was not a primary endpoint [6].

SPECIAL CONSIDERATIONS IN ELDERLY PATIENTS

Two issue require special attention in the evaluation of elderly hypertensive patients because may have implications in the therapeutic plans, comorbidities and polypharmacy.

Comorbidities

Assessment of comorbidities is of great importance in older patients, not only because issues as diabetes mellitus or

dyslipidemia contribute to an increase in cardiovascular risk but they may also lead to polypharmacy.

Diabetes mellitus increases the risk of postural hypo- tension and other complications as chronic kidney disease. Nevertheless, the management of hypertension associated with diabetes mellitus or chronic kidney disease in older patients do not differ from those in younger patients [6].

Depression is a common problem in elderly subjects. The disease may interfere not only with the blood pressure control, but also with the prognosis of the patient. It is recommendable to perform a screening test for depression in hypertensive patients because this cost-effective tool may improve outcomes [23]. Most antidepressant agents may affect blood pressure: notriptyline, amoxapine and desipramine may cause refractory hypertension, whereas amitriptyline, doxepin and imipramine may cause postural hypotension [1]. Interestingly two studies reported no significant differences in blood pressure when duloxetine was compared with placebo, and may be a safe option in elderly hypertensive patients with depression [24].

Osteoarthritis and chronic pain conditions that require continuous use of non-steroidal antiinflammatory drugs (NSAID) must be also assessed. All NSAID increase blood pressure values, and may interfere with the action of antihypertensive agents as ACE inhibitors and blockers, but not with those of calcium channel blockers [25]. Physicians must bear this fact in mind when the hypertensive patient also needs NSAID for a long time period.

Peripheral arterial disease is also very common. The ankle/brachial index (ABI) is obtained dividing the systolic pressure of each of the ankles (measured using a Doppler device) by the highest brachial pressure of either arm. A resting ABI value 0.90 not only defines the presence of peripheral arterial disease. The level of ABI also correlates with peripheral arterial disease severity (Table 1) [26, 27]. A low ABI has been also identified as an independent predictor of coronary heart disease, stroke and mortality. A very high ABI (1.40) in relation to stiffened arteries is associated with increased mortality too. In fact, there is an increase of 10.2% in the relative risk for a cardiovascular event by each reduction of 0.1 in the ABI [27]. The TASC II guidelines recommend that ABI should be measured in all patients 70 years or older, regardless of risk factor status, and in all patients between 50 and 69 years of age with at least one cardiovascular risk factor (particularly diabetes or smoking) [28].

Table 1. Level of ankle/brachial index and peripheral arterial disease severity.

Resting ABI Peripheral Arterial Disease Severity

1.4 Increased risk for a cardiovascular event (RR 1.78)

> 1.3 Calcification of arterial wall

0.9 a 1.3 Normal

0.41-0.9 Peripheral Arterial Disease Mild to moderate

< 0.4 Peripheral Arterial Disease Severe. High risk of Amputation

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POLYPHARMACY

Several drugs that are usually been taken by elderly patients may interfere with blood pressure control, and are shown on Table 2 [29].

Even in hypertensive patients taking multiple anti- hypertensive drugs, Phosphodiesterase 5 inhibitors (PDE5) did not cause any important effects on blood pressure. PDE5 are effective, safe and well tolerated in hypertensive patients, and can be safely administered to elderly hypertensive patients receiving antihypertensive agents. However, PDE5 are contraindicated in patients receiving nitrates because coadministration of both drugs may cause severe hypo- tension and death [30].

TREATMENT OF ELDERLY HYPERTENSIVE PATIENTS

As in all hypertensive patients, in the elderly patient treatment must begin with life-style changes such are reduced salt intake and increased physical exercise [11].

The NICE guidelines for clinical management of hypertension in adults [31], recommends pharmacologic treatment for patients < 80 years old with stage 1 hypertension (BP 140-159/90-99 mm Hg) and the presence of target organ damage, history of coronary heart disease, chronic kidney disease diabetes or a 10 years CVD 20%, and also pharmacologic treatment in patients with stage 2 hypertension (BP 160/90mmHg) at any age. In this point, its important to remember the possible existence of peripheral arterial disease, then, the measurement of ankle brachial index may modified the cardiovascular risk and be determinant in the initiation of antihypertensive agents [27].

According to the 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension, in elderly hypertensive patients, drug treatment is recommended when SBP is 160 mmHg. Pharmacologic treatment may also be considered in the elderly (at least when younger than 80 years) when SBP is in the 140159 mmHg range, provided that antihypertensive treatment is well tolerated. (11) JNC8 suggest that patients aged 60 years or older, to initiate pharmacologic treatment at SBP 150 mmHg or DBP 90mmHg.

WHICH ANTIHYPERTENSIVE DRUG OR COMBINATION SHOULD BE USED?

The choice of an antihypertensive drug is influenced by the presence of medical history, comorbidities, adverse

events to medication, intake of other drugs, cost and patient preferences [3]. The principal benefits of treatment derives from blood pressure reduction, and most guidelines do not shown preference for any specific drug family on the basis of age [11, 12], although beta blockers are not recommended in elderly patients as first choice drugs [12, 32].

NICE guidelines recommend that calcium channel blockers or thiazide-like diuretics (in patients intolerant to calcium channel blockers) should be preferred in patients > 55 years, and that indapamida and chlorthalidone should be used instead of hydrochlorothiazide, and that beta blockers not be used as a first-line option [31].

Most of the patients will need two or more anti- hypertensive agents to reach the therapeutic goals. The use of combinations with drugs with complementary mechanisms of action allows utilizing lower doses, with more effective and more prompt BP lowering, less adverse effects and a greater reduction of cardiovascular risk than monotherapy. It is desirable that both drugs be administered in the same pill (fixed-dose), because this formulation improves adherence and potentially reduces costs [33].

Acceptable combinations in the elderly hypertensive patient include a renin angiotensin inhibitor plus a diuretic or a calcium channel blocker. In the SYST-EUR study (17), 80% of patients were in combination therapy with nitrendipine plus enalapril and hydrochlorothiazide. The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial [34], demonstrated that the fixed-dose combination benazepril-amlodipine was superior to the combination benazepril hydrochlorothiazide in reducing cardiovascular death, stroke, myocardial infarction and chronic kidney disease, in spite of a similar blood pressure reduction. Although the ACCOMPLISH trial did not involve solely elderly patients, included predominantly patients with a mean age of 68 years, and the results were independent of age. The results of the ACCOMPLISH study suggest that cardiovascular risk reduction not only depends on blood pressure reduction.

The HYVET trial shown the advantages of the combination of the angiotensin converting enzyme inhibitor (ACEI) perindopril, plus indapamide in old and very old patients [21].

LACK OF RESPONSE TO TREATMENT

This is a relatively common problem in elderly hypertensive patients. The first issue to asses in these patients is adherence to therapy. If this is the case, fixed dose combinations and to ask a relative or to the patients career for support may help to solve the problem. It is also necessary to asses that the patient is not receiving any of the drugs listed on Table 2 [29].

In elderly hypertensive patients, the amplitude of the reflected wave component of the pulse wave is increased, perhaps as a result of the arterial stiffness and endothelial dysfunction. Although calcium channel blockers, inhibitors of the renin-angiotensin system and diuretics reduce pulse wave reflection, their effect is usually not enough to reach an adequate blood pressure control [35].

Table 2. drugs that may interfere with blood pressure control.

Nasal decongestants Notriptyline, Desipramine

Monoamine-oxidase inhibitors Amphetamines

Adrenal steroids Sympathomimetics

Erythropoietin Cyclosporine and tacrolimus

Non-steroidal antiinflammatory drugs Specially Cox-2 inhibitors Estrongens and progestins

Ginseng

Alcohol

Venfalaxine Sibutramine

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Nitric oxide donors, as isosorbide mononitrate, may reduce wave reflection by 40% or more, which results in reduction on systolic and pulse pressure without change in the diastolic values [36]. In patients with systolic values > 150 mm Hg, and/or pulse pressure > 60 mm Hg in spite of an adequate antihypertensive regimen, the addition of 60-120 mg of extended-release isosorbide mononitrate once a day, (starting with 30 mg in the morning, and increasing the dose until 120 mg daily), without changes in the previous therapy, is accompanied by a reduction in systolic blood pressure that usually is enough to achieve therapeutic goal in most patients [36]. The only contraindication to the use of isosorbide mononitrateis in patients receiving PDE5 for erectile dysfunction [30].

RESISTANT HYPERTENSION

Truly resistant hypertension is defined as the lack of response to a triple drug regimen that includes a diuretic. In patients with a good adherence to therapy, in whom pseudohypertension and white coat hypertension were excluded, about 2% to 5% of hypertensive patients suffer resistant hypertension [29].

The main causes of resistant hypertension in the elderly are obstructive sleep apnea, renal artery stenosis, pheochromocytoma, and nephropathy [29], these conditions should be assessed, and, if is the case, treated, in these patients.

Treatment includes (when apply), the recommendations shown in Table 3 [29].

Although mineralocorticoid receptor antagonistsare nor recommended as a first choice option in elderly hypertensive patients, may be an effective therapy when added to antihypertensive regimens in elderly patients with resistant hypertension and normal renal function [35]. The addition of spironolactone (12.5-50 mg daily) to the therapeutic antihypertensive regimen reduces blood pressure with an average of 25 mm Hg in systolic and 10 mm Hg on diastolic blood pressure. The use of amiloride is accompanied by greater reductions of blood pressure than spironolactone, both drugs are safe and well tolerated, however, monitoring potassium levels is recommended in elderly patients [29, 35].

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Table 3. Recommendations for the treatment of resistant hypertension.

Improve adherence.

Withdrawal of interfering medication.

Perform Ambulatory Blood Pressure Monitoring

Administering one of the agents at night.

If the diuretic that the patient receives is hydrochlorothiazide, change it to chlorthalidone.

Use of antagonist of mineralocorticoids,

Addition of other drugs. (Direct vasodilators, Centrally acting agents)

Refer to a hypertension specialist.

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Received: July 23, 2014 Revised: September 25, 2014 Accepted: December 11, 2014