DRUG THERAPY Drugs & Aging 6 (6): 436<144.1995 117D-229XJ95/0006-ll436/S04.50/0

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Withdrawal of Antihypertensive Therapy in the Elderly The Issues

Martin D. Fotherby Division of Medicine for the Elderly, Department of Medicine, University of Leicester, The Glenfield Hospital, Leicester, England

Contents Summary .................... . · 436 1. Studies of Antihypertensive Drug Withdrawal · 437

1. 1 Studies in Elderly Patients ........ . · 437 .439 .439

2. Factors Influencing Return to Hypertension . . 3. Antihypertensive Treatment Withdrawal in the Elderly 4. Mechanisms Involved in Maintenance of Normotension

4.1 Regression of Vascular Changes . . . . . . . . . . . 4.2 Baroreceptor Reset. . . . . . . . . . . . . . . . . . .

439 440 440 440 441 442 442 442 442

5. Which Older Patients Should be Considered for Treatment Withdrawal? 6. How Should Treatment be Withdrawn? . . . . . . . . . . . . 7. Advantages and Disadvantages of Treatment Withdrawal

7.1 Advantages .. 7.2 Disadvantages

8. Conclusions . . . . .

Summary Studies of antihypertensive drug withdrawal suggest that at least 20% of se­lected older patients with hypertension can remain normotensive without drug treatment for periods of up to 5 years. Success of drug withdrawal is greater in those patients controlled on low dose monotherapy who have low on-treatment blood pressure (BP), are not overweight and who have no ECG evidence of left ventricular hypertrophy. Compliance with lifestyle advice may increase the chance of successful drug withdrawal. Unfortunately, many older hypertensive patients have poorly controlled BPdespite treatment with antihypertensive drugs, and are overweight. These factors limit opportunities for drug withdrawal al­though they may not be so much of a problem in the very elderly. Patients who could be considered for a trial of antihypertensive drug withdrawal are those unhappy with such therapy who also: (a) have well controlled BPon monotherapy with no significant target organ damage, (b) have 'white-coat' hypertension, or (c) are very elderly (>80 years). The withdrawal of antihypertensive drugs can improve drug-induced metabolic abnormalities and symptoms, and appears safe providing there is a gradual reduction in drug dosages and close follow-up to detect a return to hypertension.

Withdrawal of Antihypertensive Therapy in the Elderly

Elevated blood pressure (BP) continues to be associated with a greater risk of cardiovascular dis­ease in older people,Dl although the strength of this association in the very elderly is less clear.!2,3l Accordingly, studies have shown that pharmaco­logical treatment of hypertension is of benefit in reducing these risks in people up to the age of 80 years and perhaps beyond.[4.6l Achieving and main­taining 'normotension' in individuals diagnosed as hypertensive is therefore desirable but, as the prev­alence of hypertension has been estimated at >40% in people aged 60 to 79 years, the potential number of older individuals eligible for treatment is enor­mous.!?l Essential hypertension is considered incurable but treatable. Therefore, the concept of lifelong antihypertensive drug therapy has been established and widely accepted.

So why consider antihypertensive treatment withdrawal? Clearly, it is important to maintain normotension and hence reduce the risk of cardio­vascular events. If normotension is maintained af­ter drug withdrawal, the cost, adverse effects and any detrimental effects on quality of life incurred by drug treatment will be removed. This may be of particular relevance in patients who have contin­ued on treatment well into their 80s, an age at which the benefits of treatment are less clearly es­tablished.l8l Also, drug withdrawal may shift the focus of concern in patients with hypertension from purely drug-based therapy to a broader con­sideration of reduction in overall cardiovascular risk. National and international guidelines on the management of hypertension now recognise that, in patients with well-controlled BP, a reduction in the dose and number of antihypertensive drugs, or cessation of drug therapy, is indicated.[9.11l

1. Studies of Antihypertensive Drug Withdrawal

Reduction or complete withdrawal of antihyper­tensive drug therapy has been considered since soon after the widespread introduction of such therapy. The first report of a drug withdrawal study was in 1956 by Perry and Schroeder.[l2l In a later study,D3l these same authors observed prolonged

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437

remission of hypertension in 5% of 316 patients after discontinuation of drug treatment. In 1962, Page and Dustan[l4l withdrew all treatment from 27 patients with previously severe hypertension; in 18 the BP increased, requiring reinstitution of treat­ment, but in the other 9 (33%) BP levels remained satisfactory without treatment for between 6 months and 5 years. Since this time, there have been many such studies, most uncontrolled and carried out in middle-aged patients. Comparison between studies and interpreting their relevance to clinical practice can be difficult as the degree of patient selection and BP criteria for withdrawal and reinstitution of therapy vary.

Table I summarises some of the studies carried out in middle-aged people which, on average, sug­gest that one-third of selected patients can be suc­cessfully withdrawn from treatment for periods of 1 to 4 years. Substitution of nonpharmacological therapy, such as body weight loss and sodium re­striction, may more than double the probability of successful drug withdrawaU22,2?l

1,1 Studies in Elderly Patients

There have been relatively few studies of anti­hypertensive treatment withdrawal in the elderly, and only one where nonpharmacological methods have been substituted for drug therapy over a pro­longed period, despite increasing evidence of the efficacy of such methods in this age group.[30.32l Early studies used criteria for defining hyperten­sion at BP levels greater than those accepted today, making interpretation of results for today's practice unclear. Hansen and colleagues[33l withdrew anti­hypertensive therapy in 169 patients aged over 50 years; 51 (30%) rapidly became hypertensive. Of the remaining 118, 105 were over 60 years of age (mean age 75 years) and had diastolic BP (DBP) <110mm Hg three weeks after withdrawal. Af­ter 1 year, 43 (41 %) of these patients had DBP <llOmm Hg and remained untreated, while 15% developed hypertension (DBP > IIOmm Hg) and were treated. In 32% of patients, although DBP did not exceed 100mm Hg, treatment was restarted be­cause of angina or congestive cardiac failure.

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438 Fotherby

Table I. Results of antihypertensive withdrawal studies in middle-aged patients.

Study No. of patients Age (mean or range) BP criteria for Follow-up Patients [years] normotension (months) normotensive off

(mmHg) drugs (%) Alderman et al.[15] 66 56 <160/95 36 23 Aylett & Ketchin[16] 9 54 <100 24 89 Boyle et al. [17] 20 51 <100 31 10 Dannenberg & Kannel[18] 95 60 <160/95 48 12 Fagerberg et al. [19] 32 49 <170/105 33 0 Fernandez et al. [20] 24 42 <140/95 11 75 Finnerty[21] 59 50 <85 57 61 Langford et al. [22]a 415 56 <95 13 35-60 Levinson et al. [23] 24 NA <90 12 21 Maland et al. [24]a 62 30-70+ <90 12 74 Mitchell et al. [25] 103 52 <90 12 37 MRc[26]a 650 35-64 <90 24 45-55 Stamler et al. [27]a 136 55 <90 48 5-39 Thurm & Smith[28] 69 57 <90 10-42 23 VA[29]a 60 52 <95 18 15 a Controlled studies.

Abbreviation: BP = blood pressure; MRC = Medical Research Council Working Party on Mild Hypertension; NA= not avai[able; VA= Veterans Administration Co-operative Study Group on Anti-hypertensive Agents.

Lernfelt and colleagues[341 found that 8 (32%) of 25 hypertensive 70-year-olds remained normotensive 4 years after drug withdrawal.

The largest study of antihypertensive treatment withdrawal in the elderly was carried out by Ekbom and colleagues.l351 333 patients aged 70 to 84 years were withdrawn from treatment for possible inclu­sion in the Swedish Trial in Old Persons (STOP). The majority of patients had been receiving low dose diuretic monotherapy, had a mean BP during treatment of approximately l70/90mm Hg and were relatively healthy. Criteria for return to hyper­tension and randomisation into STOP-Hyper­tension were systolic BP (SBP) readings of 180 to 230mm Hg on 3 consecutive occasions, and DBP >90mm Hg or DBP between 105 and l20mm Hg. Those patients not meeting the criteria were ob­served for a period of up to 5 years. During the first year, 60% of patients had their medication restart­ed; after 5 years, there was a 20% chance of remain­ing without antihypertensive therapy. However, 37% of patients who returned to treatment did so for reasons other than hypertension, i.e. oedema, heart failure, anxiety, headache, angina, and many

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were simply unwilling to continue without anti­hypertensive therapy. Factors predicting successful treatment withdrawal were initial monotherapy and low BP prior to treatment withdrawal. There was a significantly lower risk of cardiovascular events in patients without treatment in comparison with those who entered the STOP-Hypertension trial (some of whom were given placebo) and those who were treated for reasons other than hyperten­sion (e.g. angina, palpitations, oedema or cardiac failure).

In a recent British study, of 105 hypertensive patients (aged 65 to 84 years) treated with anti­hypertensives for >1 year, 78 (74%) with SBP <175mm Hg and DBP <100mm Hg had antihyper­tensive drug therapy withdrawn and nonpharmaco­logical therapy instituted.[361 Of these, 74 patients were followed up for 12 months and 64 for 2 years. In overweight patients, body weight was reduced by 2.6kg and, although there was no significant change in sodium excretion, there was an increase in the potassium to creatinine ratio. After 1 year, 20 (25%) patients who were withdrawn from treat­ment remained normotensive (SBP <160 and/or

Drugs & Aging 6 (6) 1995

Withdrawal of Antihypertensive Therapy in the Elderly

DBP <90mm Hg) whilst continuing with non­pharmacological therapy. Of the 64 patients fol­lowed up for 2 years, 13 (20%) who were normo­tensive at 18 months remained so at 2 years. The majority (75%) of patients restarting therapy did so within the first 3 months. There was no signifi­cant difference in baseline characteristics between those restarting therapy and those remaining off therapy at 1 year with respect to age; sex, number of antihypertensive agents taken, history of vascu­lar disease, treatment duration, left ventricular mass index or mean DBP. However, a higher on­treatment SBP, a higher body mass index (BMI) and a higher ECG (sVl + rV6) voltage was asso­ciated with return to hypertension. Three patients restarted diuretic treatment for reasons other than hypertension: 2 had diuretic-dependent ankle oedema, and 1 had mild left ventricular failure.

2. Factors Influencing Return to Hypertension

When considering results from studies con­ducted in middle-aged and older patients, certain conclusions emerge.

Neither age nor gender has a consistent effect on the success of treatment withdrawal. This sug­gests that older individuals with a less compliant vascular system are as likely to remain normotens­ive off treatment as younger patients.

Many studies have reported that lower pretreat­ment BP is associated with a longer period of normotension,£22,24,27,291 However, in Ekbom's study of older people, pretreatment BP was not as­sociated with maintenance of normotension,l351

In younger and older people, studies have found that lower on-treatment BP levels were associated with the maintenance of normotension.[23,35,361

Most studies require antihypertensive therapy to have been regularly taken for> 1 year prior to withdrawal. No consistent effect of the duration of drug treatment prior to withdrawal on the mainte­nance of normotension has been reported in young or older patients. However, monotherapy and low doses may be associated with a greater chance of successful treatment withdrawal.[351

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Fotherby and colleagues[361 found that being overweight at the time of drug withdrawal was an independent predictor of return to hypertension in older patients. This association had been pre­viously reported in younger patients,£271

Fagerberg and colleagues[191 found larger pre­withdrawal left ventricular mass (LVM) in patients who rapidly returned to hypertension compared with those whose BP increased more slowly. How­ever, in older patients, although echocardiograph­ically determined LVM was not predictive of re­turn to hypertension, a lower ECG (sVl + rV6) voltage was associated with maintenance of nor­motension.[361 A similar finding was reported in younger patients by Imataka and colleagues, [371 but not by Levinson and colleagues,l231

In summary, it appears that older patients are as likely as younger patients to be successfully with­drawn from treatment. Those patients receiving low dose monotherapy with low on-treatment BP, ideal bodyweight and no evidence ofleft ventricu­lar hypertrophy on ECG will have the greatest chance of remaining normotensive off treatment.

3. Antihypertensive Treatment Withdrawal in the Elderly

In an unselected group of 130 patients aged 65 to 92 years receiving antihypertensive treatment for more than 1 year, 46% of those aged 65 to 79 years had poorly controlled hypertension (SBP >160mm Hg) and almost one-half were over­weight. [381 The older patients (>80 years) tended to have better controlled blood pressure, lower BMI and lower ECG (sVI + rV6) voltage, suggesting a greater potential for successful treatment with­drawal in this group.

4. Mechanisms Involved in Maintenance of Normotension

It is likely that some persons diagnosed as hy­pertensive on the basis of only 2 or 3 BP readings (the practice of up to 70% of doctors[391) do not have sustained hypertension. High BP levels tend to fall on successive occasions,[401 particularly el­evated SBP levels in older people,l411 Conse-

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quently, with time, BP readings may fall into the normotensive range whether or not antihyperten­sive therapy is administered. This observation has been made in the placebo arm of various interven­tion studies.l42)

4,1 Regression of Vascular Changes

Hypertension is implicated in vascular wall thickening and left ventricular hypertrophy, and these in tum may contribute to the maintenance of hypertension.l43) A period of normotension in­duced by drugs can lead to a regression of these changes, at least partially. [44) Following drug with­drawal, it is hypothesised that normotension will persist because of normalisation of the structural changes. However, the initial stimulus to hyperten­sion may persist, leading to elevated BP and the recurrence of vascular and ventricular hypertrophy. Indeed, it has been reported that lower LVM is cor­related with a longer period of normotension fol­lowing treatment withdrawal; however, all patients eventually returned to hypertension.l 19)

4,2 Baroreceptor Reset

It has been suggested that after a period of normo­tension the carotid baroreceptor could be reset at a lower leveI.l28) However, there is little experimen­tal evidence of this.l45)

5. Which Older Patients Should be Considered for Treatment Withdrawal?

There are no detailed published guidelines dis­cussing which patient groups should be considered for a trial of antihypertensive drug withdrawal. However, some reports suggest that it may be pos­sible to attempt a careful progressive reduction in dose and number of drugs used in patients with BP which is well controlled on prolonged treatment, with cautions against complete cessation in pa­tients correctly diagnosed as hypertensive.[IO,II) In a discussion involving representatives of national hypertension guidelines from the USA, Canada, United Kingdom, New Zealand and the World Health OrganisationlInternational Society of Hyper-

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Fotherby

tension (WHO/lSH), all agreed that antihyperten­sive therapy could be decreased or withdrawn in selected patients because (a) there may be uncer­tainty about the initial diagnosis, (b) the disease process may have changed, e.g. because of life sty Ie changes, and (c) unnecessary therapy should be eliminated.l46) The British Hypertension Society guidelines suggest that treatment may be with­drawn in some patients with well-controlled BP and no evidence of target organ damage.£9) The US Joint National Committee V recommendations state that in general complete cessation of anti­hypertensive drug therapy is not indicated, but if BP has been controlled for one year on at least 4 visits then it may be possible to reduce drug ther­apy, particularly if lifestyle treatment is contin­ued'£") WHO/ISH guidelines suggest that after prolonged BP control it may be possible to attempt a reduction in dosage or number of drugs used, especially in patients complying with non-drug therapy.£IO)

More specifically, in the elderly, groups which could be considered for antihypertensive drug therapy reduction and withdrawal, followed by substitution of nonpharmacological methods, are as follows. • Well-controlled hypertensive patients: individ­

uals who have been receiving monotherapy for more than 1 year with well controlled BP levels (e.g. <150/90mm Hg), who have no evidence of significant target organ damage, and who are unhappy taking tablets and request a trial of treatment withdrawal.

• ?Never truly hypertensive: patients with well­controlled BP levels (e.g. <150/90mm Hg) in whom treatment was started after only 2 or 3 BP readings and who may have been wrongly diag­nosed as hypertensive. Such patients are less likely to have evidence of hypertensive target or­gan damage compared with truly hypertensive patients.

• Patients with 'white coat' hypertension: al­though high clinic BP levels tend to fallon re­peated measurements, levels taken repeatedly in the clinic, especially by a doctor, may be signif-

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Withdrawal of Antihypertensive Therapy in the Elderly

icantly higher than levels taken at home by the patient or an automatic BP monitor.l41,47] This 'white coat' hypertension may affect 20% of younger patients and an even greater percentage of the elderly.l48-50] The condition may not be benign but probably has a lower cardiovascular risk than sustained hypertension.[5I,52] The con­dition can be suspected in people with elevated clinic BPs, but no risk factors for hypertension nor any evidence of target organ damage or left ventricular hypertrophy. In such patients, par­ticularly those who complain of hypotensive symptoms on treatment or who are even mildly intolerant of drug therapy, a trial of treatment withdrawal is appropriate.

• Patients with orthostatic hypertension: in pa­tients with an SBP fall ~20mm Hg on standing

.. from a lying position, the prevalence of ortho­static hypotension has been reduced by with­drawal of antihypertensive drugs and institution of nonpharmacological methods.[53] For patients who have symptomatic orthostatic hypotension, a trial of antihypertensive drug reduction or with­drawal would be appropriate.

• Removal of stimulus for hypertension: despite being correctly diagnosed as having sustained hypertension, if lifestyle changes (e.g. reduc­tion in weight or alcohol intake) have been ini­tiated, antihypertensive treatment may no longer be required provided the lifestyle changes are continued.

• The very elderly: in people over 80 years of age, the benefits of antihypertensive treatment are unclear. [8] Higher BP levels and evidence of cardio­vascular disease may be factors favouring treat­ment. For patients entering this age range and receiving antihypertensive drugs who have con­ditions that can be symptomatically helped by such treatment (e.g. angina and congestive car­diac failure), treatment should be continued. In general, if patients are happy to remain on treat­ment and experience no adverse effects, it is reasonable to continue. For those without overt cardiovascular disease who do not want to take medications daily, there may be less need for

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continuing treatment even with BP levels up to 160/90mm Hg. A trial of treatment withdrawal can be offered; if quality of life deteriorates or, for example, dyspnoea or oedema occur or BP rises to very high levels (>1801l05mm Hg), treatment can be reinstituted.

6. How Should Treatment be Withdrawn?

The first consideration is to establish that BP is well controlled with treatment by taking multiple measurements over a prolonged period; standing measurements should be taken into consideration if they are significantly lower than sitting or supine measurements.

Ideally, patients should have been advised re­garding nonpharmacological methods of BP low­ering on first diagnosis, although this is often not the caseP9] Prior to treatment withdrawal, where appropriate, patients should be given individual­ised advice on reducing sodium intake, reducing alcohol intake, participating in more aerobic exer­cise, increasing dietary potassium intake and losing weight.

The patient should be involved in the decision to withdraw treatment and should be aware that it is a trial, i.e. treatment may need to be restarted and hence the need for continued follow-up. There are 2 main concerns: the possible rebound effect on stopping treatment (an infrequent problem) and, more commonly, return of elevated BP.

If possible, drug therapy should be withdrawn in a stepwise manner. Although the drug is rarely used nowadays, sudden withdrawal of clonidine can lead to rebound hypertension and a hyperten­sive crisis.l54] It is also suggested that ~-blockers should be reduced in a gradual manner over 1 to 3 weeks as sudden cessation may exacerbate pre­existing angina or provoke myocardial infarction in patients with ischaemic heart disease.[55,56] How­ever, this is rarely a problem in hypertensive pa­tients,[57] and if patients are intolerant of ~-block­ers, e.g. they develop dyspnoea, these drugs should be stopped immediately. The withdrawal of diuret­ics may lead to rebound oedema or may unmask

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mild congestive cardiac failure.l581 In older pa­tients, reducing the dose or taking diuretics on al­ternate days, then every third or fourth day over several weeks may reduce the chance of oedema developing.

Studies in older patients have shown that be­tween two-thirds and three-quarters of those who return to hypertension do so within the first 3 to 6 months. Therefore, during the first 3 months after withdrawal of antihypertensive drugs, BP should be measured every 2 to 3 weeks and then every 4 to 8 weeks, depending on the BP level, for the first year. If BP remains in the normotensive range after this, measurements can be taken every 3 to 6 months. However, if BP elevations do occur, more frequent measurements will need to be taken to confirm sustained hypertension.

7. Advantages and Disadvantages of Treatment Withdrawal

7.1 Advantages

Although the clinical significance of metabolic abnormalities secondary to antihypertensive agents is unclear, most return towards pretreatment levels on drug withdrawal. Rises in mean serum potassium levels of 0.6 mmollL,[27] decreases in the preva­lence of hypokalaemia of approximately 25%, and falls in serum urate level of 11 to 40% have been found on withdrawal of mainly diuretic-based treatment. [56.2 1] Other adverse effects attributed to treatment should improve. Cooper and col­leagues[591 found that most symptoms, except headache, significantly improved within 2 weeks following drug withdrawal.

There may be some financial savings from re­duced drug use, but these will be limited because only a minority of treated hypertensive patients will be suitable for drug withdrawal, and savings may be offset by the need for continued and ini­tially closer follow-up.

7.2 Disadvantages

As noted above, withdrawal of certain drugs may unmask or exacerbate underlying conditions

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Fotherby

such as angina, oedema or cardiac failureP9,581 However, in terms of total mortality, drug with­drawal in selected elderly patients has been found to be 'safe' p 51 Loss to follow-up is a potential problem requiring effective call-back procedures. A cardiovascular event may occur following treat­ment withdrawal despite maintenance of normo­tension, and it should be explained to patients at the outset that such events can occur on or off treat­ment. Documentation of BP readings is essential.

8. Conclusions

Some older treated hypertensive patients with well controlled hypertension and no significant cardiovascular disease can be considered for a trial of drug withdrawal in a gradual, stepwise manner. This may be of particular relevance to individuals over 80 years of age where the risks and benefits of treatment are less clear. Relevant lifestyle advice should be given prior to drug withdrawal. Contin­ued and close follow-up is necessary to monitor BP levels and adherence to the lifestyle advice.

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Correspondence and reprints: Dr Martin D. Fotherby, Divi­sion of Medicine for the Elderly, Department of Medicine, University of Leicester, The Glenfield Hospital, Groby Road, Leicester LE3 9QP, England.

Drugs & Aging 6 (6) 1995