WITHDRAWAL OF ANTIHYPERTENSIVE DRUGS I N MILD HYPERTENSION

Mats Danielson, M.D.,

Department o f Medicine I, Sodersjukhuset, 100 64 Stockholm,Sweden.

Marianne Lundback M.D.

High b lood pressure almost w i thou t except ion has t o be t r e a t e d by means of a n t i -

hypertensive drugs. I n t h e m a j o r i t y o f cases t h e t rea tment w i l l be o f l i f e - l o n g

dura t ion . Therefore, i n newly discovered hypertension, t h e ques t i on o f t e n a r i s e s

whether the t reatment i n i t i a t e d has t o be kept up i n d e f i n i t e l y .

This problem has i t s relevancy n o t on l y f o r t h e p a t i e n t , b u t a l s o for doctors

engaged i n c l i n i c a l research: Is i t e t h i c a l t o d i scon t inue an an t i hype r tens i ve

t reatment once i n i t i a t e d ? And - i f cross-over technique i s a p p l i e d - f o r how long

a pe r iod has t h e p a t i e n t t o be depr ived o f t he a c t i v e substance i n order fo r t he

r e s u l t no t t o be a f f e c t e d by a carry-over e f f e c t ?

The e f f e c t o f d i scon t inu ing treatment i n hyper tens ive p a t i e n t s has been prev ious-

l y analyzed i n a couple o f s tud ies . The r e s u l t s have been varying. Page and Dustan

(1962) i n i t i a l l y repo r ted t h a t 9 of 27 (33%) p a t i e n t s i n whom t rea tment had been

discont inued remained e s s e n t i a l l y normotensive w i thou t drug therapy f o r pe r iods

vary ing from s i x months t o f i v e years o f observat ion. I n a l a t e r rev iew o f 65

pa t i en ts , however, t he same authors found t h a t d i a s t o l i c hyper tens ion reappearedin

a l l bu t two p a t i e n t s (3%), (Dustan e t a 1 1968).

Perry e t a1 (1966) s tud ied 316 p a t i e n t s wi th an i n i t i a l d i a s t o l i c p ressure o f

>/ 110 mm Hg a t r e s t i n h o s p i t a l , a l l o f whom had been t r e a t e d fo r more than 6

years. S ix teen o f those ( 5 % ) cou ld a b s t a i n from an t ihyper tens i ve t reatment during

a mean observa t ion t ime o f 6 years.

Thurm and S m i t h (1967) d iscont inued an t i hyper tens i ve drugs i n 69 p a t i e n t s . They

found t h a t 16 (231) remained normotensive f o r pe r iods o f 10 t o 42 months a f t e r

d i scon t inu ing treatment.

The VA Cooperative Study Group (1975) i n t h e i r research, i n c l u d i n g t h e use o f

placebo, found t h a t 9 p a t i e n t s (15%) remained normotensive d u r i n g an observat ion

t ime o f 72 weeks a f t e r d i sbon t inu ing a c t i v e t reatment, t h e p o p u l a t i o n be ing 60

p a t i e n t s o f 53 years age (mean), a l l o f whom had been t r e a t e d fo r two years or

more with hydroch lo ro th iaz ide , rese rp ine and hydra laz ine .

Boyle e t a1 (1979) i n v e s t i g a t e d the e f f e c t o f w i thho ld ing t rea tment from a group

o f p a t i e n t s w i t h m i l d hypertension i n a l l o f whom t h e hyper tens ion had been w e l l

c o n t r o l l e d by t h i a z i d e d i u r e t i c s only. They found t h a t e igh teen o f twenty pat ients

were re tu rned t o t reatment a f t e r 1 t o 132 weeks (mean 31 weeks).

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Totterman and E i s a l o (1980) repor ted , i n a p r e l i m i n a r y account, t h a t 11,5L o f 122

p a t i e n t s aged 50 were a b l e t o manage w i thou t t reatment, and so d i d 24,676 o f s i x t y -

n ine , 65 years o l d p a t i e n t s (observa t ion t i m e 9 months).

Our purpose i s t o study t h e e f f e c t o f d i s c o n t i n u i n g t rea tment i n a f a i r l y homo-

genous popu la t i on o f p a t i e n t s s u f f e r i n g from es tab l i shed, m i l d and w e l l t r e a t e d

hypertension. Th is r e p o r t accounts f o r t h e r e s u l t s a f t e r a n obse rva t i on t ime o f

3 - 24 months.

M a t e r i a l and methods

The study i nc ludes 47 p a t i e n t s (21 men, 26 women), mean age 42 2 11 YearS,suffer-

i n g from e s s e n t i a l hyper tens ion stage WHO I. T h i r t y t h r e e p a t i e n t s conf i rmed t h e

prevalence o f hyper tens ion i n a t l e a s t one o f t h e i r paren ts . The i n i t i a l blood-

p ressure was 178/118 (aye-group < 40 years, n=20'), 187/115 (40 - 60 years, n=25)

and 188/110 mm Hg (> 60 years, n=2) r e s p e c t i v e l y . The known mean d u r a t i o n o f

hypertension was 4,4 years (range 1 - 20 years). Twentythree p a t i e n t s had another

r i s k f a c t o r besides hypertension: 20 were smokers, 2 had hyper l i p idemia and one

had diabetes m e l l i t u s t r e a t e d with i n s u l i n e .

The c r i t e r i a f o r i n c l u s i o n i n the s tudy were:

1) es tab l i shed hyper tens ion (repeated pressure r e g i s t r a t i o n s be fo re t rea tment ) .

2 ) d u r a t i o n o f hyper tens ion n o t l e s s than 1 year, and 3 ) w e l l c o n t r o l l e d hyper-

t ens ion f o r a t l e a s t 6 months.

Before t h e study the p a t i e n t s were t r e a t e d with s a l u r e t i c s (hyd roch lo ro th iaz ide

50 mg every second day up t o 50 mg d a i l y ) n=9,beta-blockers ( p i n d o l o l 5 - 15 mg

d a i l y or a t e n o l o l 50 - 100 mg d a i l y ) n=33, s a l u r e t i c s p l u s a beta-blocker n = 4 , o r a beta-blocker p l u s hyd ra laz in n=l. The mean l e v e l o f s y s t o l i c and d i a s t o l i c

pressure a t t h e two l a s t r e g i s t r a t i o n s be fo re t h e beg inn ing o f t h e s tudy was

131/84 ( < 40 years), 137/88 (40 - 60 years) and 145/90 (> 60 years) mm Hg.

The treatment was d iscont inued prompt ly and t h e p a t i e n t s were fo l l owed upp every

t h i r d month du r ing t h e f i r s t year, and every f o r t h month d u r i n g t h e second.

Whenever an occasional s y s t o l i c or d i a s t o l i c hyper tens ion was r e g i s t e r e d a con-

t r o l measurement was performed a f t e r one month. The l i m i t values f o r hyperten-

s i o n were de f i ned w i t h due cons ide ra t i on t o age and prevalence o f a d d i t i o n a l

r i s k f a c t o r s (Table I ) .

A l l r e g i s t r a t i o n s were made with a mercury sphygmo-manometer , t h e p a t i e n t s

having been a t r e s t i n sup ine p o s i t i o n f o r 10 minutes.

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Table I. D e f i n i t i o n s o f hypertension.

Age 9 Number o f Without o ther With o the r

years pa t i ents r i s k f a c t o r r i s k f a c t o r

~~

< 40 20 160/100 155/95

40 - 60 25 170/105 165/100

> 60 2 180/110 175/105

Resul ts

The number o f p a t i e n t s observed du r ing 0 - 2 years i s represented i n F ig . 1. Out

o f 47 p a t i e n t s 18 have so f a r resumed ant i -hyper tens ive t reatment. One p a t i e n t

d iscont inued t h e fol low-up due t o headache, appear ing on d i s c o n t i n u i n g treatment

with a beta-blocker. Another p a t i e n t had t o resume t rea tment with s a l u r e t i c s due

t o reappearence of oedema. I n the o ther 16 p a t i e n t s s y s t o l i c (n=3), d i a s t o l i c

(n=6) or s y s t o - d i a s t o l i c (n=7) hypertension was reg i s te red . I n 5 o f t h e p a t i e n t s

t h e e leva t i on appeared a f t e r 3 months, i n another 6 p a t i e n t s a f t e r 6 months and

i n the remaining cases a f t e r 9 months. None o f t h e p a t i e n t s fo l l owed f o r 1 year

or more has recovered h i s hypertension.

n

w-

.w -

20 -

10 -

0 N I HT

LL 2 years

Figure 1. Number o f normotensive (NT) and hyper tens ive (HT) p a t i e n t s .

With due r e s e r v a t i o n f o r t h e f a c t t h a t t h e number o f p a t i e n t s under observa t ion decreases as t h e t ime o f observa t ion increases i t appears t h a t t h e s y s t o l i c and d i a s t o l i c reduc t i on o f p ressure i s f a i r l y constant du r ing t h e f i r s t 2 years. (Fig. 2 ) . I n a comparision a f t e r one year between the p a t i e n t s who recovered t h e i r hyper- tens ion (n=16) and t h o s e e s t i l l be ing normotensive (n=22) no d i f f e r e n c e was esta- b l i shed as t o t h e prevalence o f hypertension i n any o f t he parents , age, sex, du ra t i on o f hypertension, c o e x i s t i n g r i s k f a c t o r s or e f f e c t o f t reatment. There was, however, among t h e p a t i e n t s recover ing t h e i r hyper tens ion a h igher i n i t i a l (un t rea ted) d i a s t o l i c b lood pressure, as compared t o the normotensive ones, 1 8 6 / E and 179/= mm Hq, respec t i ve l y .

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0 i i years n=47 39 31 23 22 17 15 I0

Figure 2. Sys to l i c (-1 and d i a s t o l i c ( - - -1 blood pressure reduct ion as compared t o the i n d i v i d u a l d e f i n i t i o n s o f hypertension i n normotensive pat ients . M 2 S.D., n number o f pat ients .

Discussion

These p re l im ia ry r e s u l t s from an on-going study suggest t h a t i t i s poss ib le t o

discont inue the treatment o f hypertension.

A l l o f t he pa t i en ts had a m i l d hypertension. On t h e other hand they i n i t i a l l y

suf fered from a marked e levat ion o f t h e blood pressure. As could be seen from

the r e s u l t s the resumption o f treatment was caused not on ly by the e levat ion of

pressure, but by other symptoms as headache and oedema as wel l . The m a j o r i t y o f

pa t i en ts discont inuing the follow-up, however, became hypertensive. The re- occurrences were evenly d i s t r i b u t e d dur ing t h e f i r s t 9 months. A f te r t h a t none

of the pa t i en ts so f a r observed recovered t h e i r hypertension.

The d e f i n i t i o n s o f hypertension used are founded on the p r e v a i l i n g opin ion i n

Sweden. However, the c r i t e r i a o f hypertension are subject t o discussion and t h e

p o s s i b i l i t y ex i s t s t h a t the l i m i t values should be set- lower. This i s why i t has

t o be stressed, i n studies l i k e t h i s , t h a t you only r e g i s t e r whether t h e p a t i e n t

has surpassed a c e r t a i n l i m i t of pressure or not. Thus there are pa t i en ts who

have a very low pressure dur ing treatment, regain ing a l i m i t - v a l u e or j u s t under-

neath when l e f t untreated, These pa t i en ts would no t be c l a s s i f i e d as hypertensivs

according t o the present d e f i n i t i o n . The e levat ion o f pressure a f t e r d iscont inu ing

treatment could, however, be considerable, e n t a i l i n g an increased r i s k o f cardio-

vascular disease.

It has been reported t h a t a h igh i n i t i a l blood pressure i s co r re la ted t o re lapse

o f hypertension a f t e r an attempt t o d iscont inue ant ihypertensive treatment ( T h w

and Smith 1967, Dustan e t a1 1968). Young pa t ien ts seem t o recover t h e i r hyper-

tension more r a p i d l y as compared t o o lder ones. ( V A Cooperative Study Group,1975).

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This study a l s o suggests the s i g n i f i c a n c e o f t h e i n i t i a l p ressure when judq in r j

t h e p o s s i b i l i t y o f d i scon t inu ing an t i hype r tens i ve t reatment. Other f a c t o r s l i k e

age, sex, du ra t i on o f hypertension seem t o have no importance.

To conclude: Our p r e l i m i n a r y f i nd ings i n t h i s ongoing s tudy suggest t he p o s s i b i -

l i t y o f making i n t e r r u p t i o n s i n or even, i n some cases, t he d i s c o n t i n u a t i o n o f

t h e an t ihyper tens ive therapy i n es tab l i shed b u t w e l l t r e a t e d m i l d hypertension.

References

Boyle R.M., P r i c e M.L., Hamil ton M.: Thiazide withdrawal i n hypertension. J Royal C o l l Phys. 13: 172-173, 1979

Dustan H.P., Page I.H., Taraz i R.C., F r o h l i c h E.D.: A r t e r i a l pressure responses t o d i scon t iun ing an t i hype r tens i ve drugs. C i r c u l a t i o n 37: 370-379. 1968.

Page I.H., Dustan H.P.: Persistence o f normal b lood pressure a f t e r d i scon t inu ing t rea tment i n hyperterisj.vc, p a t i e n t s . C i r c u l a t i o n 25: 433-436, 1962.

Perry H.M., Schroeder H.A., Catanzaro F.J., Moore-Jones D., Camel G.: Studies on the c o n t r o l o f hypertension. VIII. M o r t a l i t y , m o r b i d i t y and remissions du r ing t e l v e years o f i n t e n s i v e therapy. C i r c u l a t i o n 33: 950-972, 1966.

Thurm R.H., Smith W.M.: On r e s e t t i n g o f "barostats" i n hyper tens ive p a t i e n t s . JAMA 201: 301-304, 1967.

Totterman K.J., E i sa lo A.: P o s s i b i l i t y o f reduc t i on o f an t i hype r tens i ve therapy i n hypertension. Abs t rac t , Seventh s c i e n t i f i c meeting o f t h e I n t e r n a t i o n a l Soc ie ty o f Hypertension, New Orleans 1980, p. 136.

Veterans Admin i s t ra t i on Cooperative Study Group on Ant ihyper tens ive Agents: Return o f e levated b lood pressure a f t e r wi thdrawal o f an t i hype r tens i ve drugs. C i r c u l a t i o n 51: 1107-1113, 1975.

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