Cardiovascular Drugs and Therapy 15 269–273 2001

C© Kluwer Academic Publishers. Printed in The Netherlands

Antihypertensive Drugs in the Elderly—the Evidenceof Benefit

Tony Stanton and John L. ReidDepartment of Medicine and Therapeutics,University of Glasgow, Glasgow, Scotland, UK

Summary. Hypertension is a major cardiovascular risk

factor. The commonest mode of death in the elderly is a

cardiovascular one and so the treatment of hypertension

in the elderly population is an important clinical objective.

The choice of which antihypertensive drug to prescribe is

expanding and an evidence-based approach should be ap-

plied. In recent years more studies have been carried out

into the efficacy of the various antihypertensive drugs in

the elderly. This review looks at the “hard” outcome data for

each major drug class and their suitability for prescribing in

the elderly. The differing drug classes are divided into 3 cat-

egories based on the weight of evidence supporting them—

established, emerging, and add-on therapies. Currently, and

until the publication of ongoing trials into newer therapies

such as ACE inhibitors and calcium-channel blockers, out-

come data suggests that thiazides remain the drug of first

choice except where other therapies are indicated for co-

existant conditions or more than one drug is required to

achieve the desired response.

Key Words. hypertension, elderly, antihypertensives drugs,

cardiovascular

Introduction

The population of the developed world is progressivelyageing. In the UK alone the life expectancy in men nowstands at 72.5 years and 78.5 years in women comparedto 66.4 and 71.5 respectively in 1950 [1]. The treat-ment of elderly patients is becoming a larger part ofthe clinician’s routine work. The choice of drug usedfor the treatment of this ever-increasing group was,in the past, often extrapolated from studies done onmuch younger subjects. However doctors have recog-nised the importance of treating the elderly populationusing an evidence based approach. Over the past 20years more studies have been carried out in this “atrisk” population.

The importance of treating hypertension in the gen-eral population has been known for many years. Doesthe same hold true for the elderly? This is an importantquestion as the estimated prevalence of hypertension(blood pressure >140/90 mmHg) in the over 65’s is 50%in industrialised countries, and 20% have isolated sys-tolic hypertension (diastolic blood pressure <90 mmHgwith systolic blood pressure >140 mmHg) [2]. This isnot suprising as systolic blood pressure continues to

rise until the age of 80 although diastolic blood pressureplateau’s or even falls slightly after the 6th decade.

Hypertension is a major cardiovascular risk fac-tor and people who have high blood pressure oftenalso have other co-existent cardiovascular risk fac-tors such as diabetes mellitus, hypercholesterolaemiaor cigarette-smoking. Age in itself is a major (but nottreatable or reversible) risk factor for cardiovasculardisease ! In this at risk population drug treatment of hy-pertension reduces cardiovascular morbidity and mor-tality. As cardiovascular death is the commonest causeof death in the over 65’s, accounting for approximately50% of all deaths in this age group [3], there is a soundrationale for the effective treatment of hypertension inthe elderly population.

Although the need to treat hypertension in the el-derly can be justified, there are many issues which mustbe borne in mind when selecting a drug regimen. Someof these considerations are generic. It is desirable tohave a once daily dosing schedule to aid complianceand to start each chosen medication at a low, safe doseto avoid lowering the blood pressure by too much orcausing unwanted side effects. The use of medicationsto treat hypertension which would also aid the treat-ment of other co-existent conditions (e.g. β-blockers inangina, ACE inhibitors in those with a past history ofmyocardial infarction) would also seem judicious. Co-existent conditions are more prevalent in the elderlyand these may also provide contra-indications (e.g. β-blockers in peripheral vascular disease and some cal-cium channel blockers in congestive heart failure).

As well as drug therapy another important partof the treatment of hypertension has involved non-pharmacological methods such as taking exercise,weight reduction, lowering alcohol and salt intake, andstopping smoking. However there is no more “hard”outcome evidence of benefit of these interventions doc-umented in the elderly than in younger populations.

Tony Stanton is a Wellcome Trust entry level training fellow

Address for correspondence: Dr. T. Stanton, Department ofMedicine and Therapeutics, Gardiner Institute, Western Infir-mary, Glasgow, G11 6NT Scotland, UK. Tel.: 0141 211 2320; Fax:0141 339 2800; E-mail: ts39u@clinmed.gla.ac.uk

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There remains controversy whether drug therapy inthe treatment of hypertension is beneficial primarily bythe lowering of blood pressure or whether the specificmechanism of each drug class conveys the particularbenefit (or even harm). Full consideration of this matteris beyond the scope of this review. We discuss here theevidence for and against each of the major drug classesused in the treatment of hypertension. We have identi-fied 3 categories—established first line drugs, emergingchoices, and add-on or back-up therapy.

Established/“First Line”Therapeutic Strategies

Thiazides

The class with the most evidence, are thiazide diuretics.Numerous clinical trials specifically targeting the treat-ment of hypertension with thiazide diuretics in the el-derly have been carried out and the evidence for theiruse is strong. One of the first trials to suggest bene-fit was the European Working Party On High BloodPressure In The Elderly (EWPHE) trial published in1985 [4]. This compared hydrochlorothiazide, plus thepotassium sparing diuretic triamterene, with placeboin a population over the age of 60 with a mean BP of183/101. The results showed that, as well as reducingblood pressure, there was a significant reduction in car-diovascular mortality when the treated group was com-pared to the non-treated group. There was also a non-significant reduction in cerebrovascular mortality andit was noted that there was a reduction in severe, butnot mild, congestive heart failure. The total numberof patients in the EWPHE study was however only840. In subsequent years larger trials have strength-ened the case for thiazides in the elderly. Three of themost important are the SHEP trial (4736 patients) [5],the STOP trial (1627 patients) [6], and the MRC trial(4396 patients) [7]. Each of these trials compared athiazide (hydrochlorothiazide or chlorthalidone), plusor minus a potassium sparing diuretic, against placebo.The results were impressive showing a reduction instroke and total cardiovascular events in all threetrials.

Thiazides, as a class, have now been around for over40 years and over that time they have proved effec-tive and safe in the elderly population lowering bloodpressure and cardiovascular events. They are inexpen-sive and most doctors are comfortable with their useespecially with newer, lower doses. Most are once dailypreparations which makes them useful in the elderly.Diuretics are also useful in congestive heart failure(CHF) with ACE inhibitors and AII blockers. Side ef-fects are mainly metabolic including hyperuricaemia,impaired glucose tolerance and an adverse effect onplasma lipid profile—these are dose related and rela-tively rare at low doses used nowadays. There is a po-tential for cardiac arrhythmia as a consequence of thehypokalaemia or hypomagnesaemia which thiazides can

cause. These risks and others such as reduced plasmavolume, an increased risk of postural hypotension anddecreased end-organ perfusion remain concerns notsubstantiated by outcome trial evidence.

Thiazides should remain one of the first drugsused when treating the elderly hypertensive. Theyhave proven themselves safe and effective over manyyears with sustained reductions in blood pressure andcardiovascular events. Treatment should usually bewith a once daily low dosage regimen. Many patientsmay require a combination of low dose diuretic withother drugs.

β-adrenoceptor blockers

β blockers are also a well established drug class. In boththe MRC and STOP trials β-blockers were comparedto both thiazides and placebo. They were found to notonly reduce blood pressure by a similar amount to thi-azides but, with the exception of the MRC trial, theyalso conferred similar reductions in stroke and cardio-vascular events. Further evidence for their efficacy wasprovided in 1999 by the STOP-2 (Ref. 8) trial, whichcompared β-blockers against thiazides, calcium chan-nel blockers, and ACE inhibitors but not placebo. Thistrial showed that β-blockers were as effective at lower-ing cardiovascular events and mortality as each of theother 3 therapies in an elderly hypertensive population.

The main action of β-blockers is to reduce heart rateand the force of contraction. Higher doses may be re-quired in the elderly due to the change in β-receptorsensitivity which accompanies ageing. They are of-ten indicated because of coexistent conditions such asangina, heart failure, and post-MI.

Even the cardioselective β-blockers have un-wanted side effects from the partial blockade of β2-adrenoreceptors. While they benefit myocardial is-chaemia they worsen peripheral vascular disease symp-toms. Bronchial constriction, another unwanted β2-blockade side-effect, also limits their use in asthmaand chronic obstructive pulmonary disease—a condi-tion which often goes hand in hand with ischaemic heartdisease in elderly smokers. β-blockers should be usedcautiously in insulin-dependent diabetics were thesedrugs can mask the sympathetic response to hypogly-caemia. As the elderly are more likely to suffer fromsino-atrial node disease they may be more prone tosymptomatic bradycardia or heart block when startedon β-blockers.

Currently, β-blockers remain a well established firstline therapeutic option especially in elderly hyperten-sive patients who have coincidental conditions indicat-ing their use.

Emerging Therapeutic Approaches

Calcium-channel blockers (C.C.B’s)

There is increasing evidence for newer classes of drugsto be used in this treatment field. In recent years more

Antihypertensive Drugs in the Elderly 271

information from prospective outcome trials withcalcium antagonists has become available.

The STONE trial [9], published in 1996, comparednifedipine to placebo. The treated cohort experiencedblood pressure reductions similar to treated patientsin trials using thiazides or β-blockers and overall thistrial showed a reduction in stroke incidence and over-all cardiovascular events. Since then these benefitshave been confirmed in the Syst-Eur [10] and Syst-China [11] trials showing that the CCB nitrendipinelowered both stroke and cardiovascular events in twoethnically different populations. A further claim to beconsidered a first line choice is exhibited in evidencefrom the class comparative STOP-2 trial where onearm of the study design was patients treated withthe CCB’s felodipine and isradipine. This showed thatCCB’s were as effective at lowering blood pressureand decreasing the risk of cardiovascular events as themore established therapies of thiazides and β-blockers.However in this trial ACE inhibitors had significantlylower frequencies of MI and CHF than CCB’s. TheINSIGHT trial [12] published in 2000 showed thattreatment with nifedipine provided the same cardio-vascular event reduction as the diuretic combination co-amilozide.

All the above trials used dihydropyridine calcium-channel blockers. However the recent NORDILtrial [13] compared the non-dihydropyridine diltiazemagainst a thiazide, β-blocker, or a combination of thetwo. It showed that diltiazem reduced cardiovasculardeath as well as conventional treatment but was betterat preventing fatal and non-fatal stroke. This findingrequires further investigation and confirmation.

The side effects of CCB’s are often viewed as an-noying rather than life threatening. They include flush-ing, headache, ankle oedema, and constipation. Theydo impact on the quality of life of older people and socould reduce their compliance. Diltiazem which has alower incidence of these side effects than dihydropy-ridine calcium-channel blockers appears to be betterthan placebo and similar to established drugs in reduc-ing stroke risk in older patients.

ACE inhibitors

The other major class of drugs for the treatmentof hypertension in the elderly are the Angiotensin-Converting Enzyme (ACE) Inhibitors. There is stillrelatively little published evidence from prospectiverandomised trials of ACE inhibitors in hypertension.Two large studies using the ACE inhibitor lisinoprilas a blood pressure lowering agent are in progress.The HYVET trial [15] will compare lisinopril againstplacebo and a thiazide in patients over the age of 80.This will not only answer the question of the efficacyof ACE inhibitors but also the value of blood pres-sure reduction in the very elderly over 80 years. Thesecond ongoing trial, ALLHAT [16], has four arms com-paring lisinopril, a CCB (amlodipine) and an α-blocker

(doxazosin). The final results of this trial are expectedin full in early 2002.

ACE inhibitors are being increasingly used. Theyare effective and generally well tolerated. In the treat-ment of the elderly with hypertension they can use-fully be combined with thiazides. They are also use-ful in the treatment of CHF. ACE inhibitors causeLVH regression and lower proteinuria in diabetic pa-tients with nephropathy. The HOPE study [17] whichincluded older patients with risk factors for cardiovas-cular disease showed that an ACE inhibitor, ramipril,improved cardiovascular outcome in the absence of amarked change in blood pressure. These drugs are use-ful in patients with heart failure, ischaemic heart dis-ease, diabetes, and hypertension—all conditions preva-lent in the elderly.

Are there any problems with ACE inhibitors? Thereis a risk of first does hypotension especially in those al-ready taking loop diuretics or with heart failure. Anyhistory of angioedema, aortic stenosis, or renovasculardisease contra-indicates their use. A less life threaten-ing but annoying and disturbing side effect is that of drycough probably caused by the inhibition of bradykinindegradation as a consequence of the ACE inhibition inup to 10–20% of patients.

The publication of ongoing trials if positive maymake ACE inhibitors an even more appropriate choicein the future.

Angiotensin II receptor antagonists

The success of ACE inhibitors has prompted the inves-tigation of other ways to block the renin-angiotensinsystem. The cardiovascular benefits of ACE inhibitorsappear to be due to the inhibition of angiotensin II for-mation. Angiotensin II receptor blocking drugs, specif-ically the AT1 subtype, work by antagonizing the AIIreceptor itself. The first of these drugs, losartan, wasregistered in 1994. There are only limited studies inthe elderly and no published outcome trials in hyper-tensives. One small study [18] in elderly hypertensivesshowed that the AII blocker eprosartan lowered bloodpressure as effectively as enalapril and when given witha thiazide produced a further BP reduction. The on-going LIFE study [19], which has over 8000 patientsbetween the ages of 55 and 80 enrolled, will comparethe effects of losartan against those of the β-blockeratenolol with respect to BP, LVH regression, and car-diovascular morbidity and mortality. This should pro-vide more information with which to evaluate the placeof these drugs.

This group of drugs has a similar profile and list ofcontra-indications to ACE inhibitors. They do not, how-ever, inhibit bradykinin breakdown and do not producethe persistent dry cough which can cause patients todiscontinue ACE inhibitors. Other possible advantagesover ACE inhibitors are that AII blockers appear lesslikely to cause either first does hypotension or renal im-pairment. Their role at present is as an alternative to

272 Stanton and Reid

or as a replacement for ACE inhibitors when the latterare inappropriate or cause adverse effects.

Add-on/“Second Line”Therapeutic Options

α-adrenoceptor blockers

α-blocking drugs as a treatment for hypertension havebeen marginalised somewhat in recent times. Theywere previously viewed as an alternative first choicefor monotherapy when treating hypertension in the el-derly. The TOHMS trial [20] showed that doxazosin waseffective in lowering blood pressure and as well toler-ated as other drug classes. However in 2000 the doxa-zosin arm of the ALLHAT trial was discontinued afteran interim analysis comparing it to the thiazide armof the trial. The analysis showed that doxazosin had ahigher risk of stroke, CHF, and cardiovascular diseasecompared to chlorthalidone. There was a difference insystolic BP which was 2–3 mmHg higher with doxa-zosin. The interpretation of these findings is controver-sial. However, it has set back the case for α-blockers asa first line drug. Many now view their place as an add-ontherapy in those with resistant hypertension and menwith prostatic symptoms.

Centrally acting antihypertensive drugs

This group includes older agents such as methyldopa,clonidine, reserpine, and newer imidazolines such asmoxonidine and rilmenidine. The early agents reducedblood pressure but with a considerable side effect bur-den (dry mouth, sedation). The newer centrally actingagents such as moxonidine and rilmenidine are muchbetter tolerated while retaining BP lowering efficacycompared to other classes. There is no outcome datafrom prospective trials with these drugs and their roleat present is as second line or add-on to other classes.

Conclusion

The benefits and safety of aggressive blood pressurecontrol was evident in the HOT trial [21]. This trialshowed that when reducing blood pressure even seem-ingly small differences can have an important effecton the incidence of major cardiovascular events. Theseconclusions can be extrapolated to the elderly popula-tion. Where once high blood pressure was, in the past,thought to be a protective mechanism in essential hy-pertension it is now recognised to be pathological andrequires treatment.

In many patients more than one drug will be re-quired. Therapy should be tailored to combine medica-tions which are also indicated in other coexistent con-ditions. At present the evidence still supports thiazidediuretics as the first choice. They have been provensafe, well tolerated, and effective in the long-term tri-als in the elderly. β-blockers are another option. ACE

inhibitors and calcium channel blockers are alternativeswhich at present are less well supported by outcometrial evidence.

The effective treatment of hypertension in the el-derly is important and should be vigorously pursued.The choice of therapy should take into account the in-dividual patient’s coexistent conditions. Good medicalpractice necessitates that the medications chosen havea sound evidence base. The purpose of this review is tooutline the current evidence concerning each of the ma-jor classes of antihypertensive drugs so enabling clini-cians to choose wisely when prescribing for the elderlypopulation.

References

1. Rajkumar C. Hypertension in the elderly. In: BirkenhagerWH, Reid JL, Bulpitt CJ, eds. Handbook of Hypertension.Elsevier Science, 2000;106–114, Vol. 20, ch. 7.

2. Shammas E, Dickstein K. Drug selection for optimal treat-ment of hypertension in the elderly. Drugs & Aging1997;11(1):19–26.

3. Rajkumar C. Hypertension in the elderly. In: BirkenhagerWH, Reid JL, Bulpitt CJ, eds. Handbook of Hypertension.Elsevier Science, 2000;106–114, Vol. 20, ch. 7.

4. European Working Party on High Blood Pressure in theElderly. Mortality and morbidity results from the Europeanworking party on high blood pressure in the elderly trial.Lancet 1985;15(1):1349–1355.

5. SHEP Cooperative Research Group. Prevention of strokeby antihypertensive drug treatment in older persons withisolated systolic hypertension. JAMA 1991;265(24):3255–3264.

6. Dahlof B, Lindholm LH, Hansson L, et al. Morbidity andmortality in the Swedish trial in old patients with hyperten-sion (STOP-hypertension). Lancet 1991;338:1281–1285.

7. MRC Working Party. Medical Research Council trial oftreatment of hypertension in older adults: Principal results.BMJ 1992;15(304):405–412.

8. Hansson L, Lindholm LH, Ekbom T, et al. Randomisedtrial of old and new antihypertensive drugs in elderlypatients: Cardiovascular mortality and morbidity in theSwedish trial in old patients with hypertension-2 study.Lancet 1999;20(354):1751–1756.

9. Gong L, Zhang W, Zhu Y, et al. Shanghai trial of nifedipnein the elderly (STONE). J Hypertens 1996;14:1237–1245.

10. Staessen JA, Thijs L, Gasowski J, Celis H, Fagard RH.Treatment of isolated systolic hypertension in the elderly:Further evidence from the systolic hypertension in Europe(Syst-Eur) trial. Am J Cardiol 1998;82:20R–22R.

11. Lisheng L, Ji Guang W, Lansheng G, Guozhang L, StaessenJA for the Systolic Hypertension in China (Syst-China)Collaborative Group. Comparison of active treatment andplacebo in older Chinese patients with isolated systolic hy-pertension. J Hypertens 1998;16:1823–1829.

12. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity andmortality in patients randomised to double-blind treat-ment with a long-acting calcium channel blocker or diureticin the international nifedipine GITS study: Interventionas a goal in hypertension treatment (INSIGHT). Lancet2000;29(356):366–372.

13. Hansson L, Hedner T, Lund-Johansen P, et al. Randomisedtrial of effects of calcium antagonists compared with

Antihypertensive Drugs in the Elderly 273

diuretics and β-blockers on cardiovascular morbidity andmortality in hypertension: The Nordic Diltiazem (NORDIL)study. Lancet 2000;29(356):359–365.

14. Stahl M, Bulpitt CJ, Palmer AJ, et al. Calcium channel block-ers, ACE inhibitors, and the risk of cancer in hypertensivepatients: A report from the department of Health Hyper-tension Care Computing Project (DHCCP). J Human Hy-pertens 2000;14:299–304.

15. Bulpitt CJ, Fletcher AE, Amery A, et al. The hypertension inthe very elderly trial (HYVET). Rationale, methodology andcomparison with previous trials. Drugs & Aging 1994;5:171–183.

16. The ALLHAT Officers and Coordinators for the ALL-HAT Collaborative Research Group. Major cardiovascularevents in hypertensive patients randomised to doxazosinvs. chlorthalidone: The antihypertensive and lipid-loweringtreatment to prevent heart attack trial (ALLHAT). JAMA2000;283:1967–1975.

17. The Heart Outcomes Prevention Evaluation (HOPE) StudyInvestigators. Effects of an angiotensin-converting-enzyme

inhibitor, ramipril, on cardiovascular events in high-risk pa-tients. NEJM 2000;342:145–153.

18. Argenziano L, Trimarco B. Effect of eprosartan andenalapril in the treatment of elderly hypertensive patients:Subgroup analysis of a 26-week, double-blind, multicentrestudy. Current Medical Research and Opinion 1999;15:9–14.

19. Dahlof B, Devereux R, de Faire U, et al. The losartan in-tervention for endpoint reduction (LIFE) in hypertensionstudy: Rationale, design, and methods. The LIFE studygroup. Am J of Hypertens 1997;10(7):705–713.

20. Grimm RH, Grandits GA, et al. for the TOHMS group. Rela-tionships of the quality of life measures to long term life styleand drug treatment in the treatment of mild hypertensionstudy. Arch Intern Med 1997;157:638–648.

21. Hansson L, Zanchetti A, Carruthers SG, et al. Effects ofintensive blood-pressure lowering and low-dose aspirin inpatients with hypertension: Principal results of the hyper-tension optimal treatment (HOT) randomised trial. Lancet1998;13(351):1755–1762.