beta-blockers versus thiazide diuretics in the first line drug treatment of hypertension

75

BETA-BLOCKERS VERSUS T H I A Z I D E DIURETICS I N THE FIRST

L I N E DRUG TREATMENT OF HYPERTENSION

D G Beevers and P Davies Departments o f Medicine and S t a t i s t i c s , U n i v e r s i t y o f Birmingham, England

I n t r o d u c t i o n

There seems l i t t l e r e a s o n t o doubt t h a t f o r p a t i e n t s below t h e age o f 7 0 y e a r s , i f t h e d i a s t o l i c blood p r e s s u r e i s g r e a t e r t h a n 100 mmHg, t h e n b lood p r e s s u r e r e d u c t i o n i s e f f e c t i v e i n p r e v e n t i n g v a s c u l a r c o m p l i c a t i o n s . T h i s means t h a t t h e r e a r e many m i l l i o n s o f p e o p l e i n t h e p o p u l a t i o n who need a c t i v e i n t e r v e n t i o n and t h e i r d e t e c t i o n and f o l l o w up needs i s t o be o r g a n i s e d .

The n e x t problem however i s "does i t m a t t e r how we reduce blood p r e s s u r e ? " . The answer t o t h i s q u e s t i o n i s n o t as y e t a v a i l a b l e and t h i s review d i s c u s s e s t h e i s s u e s i n v o l v e d . I n a d d i t i o n , some d a t a i s p r e s e n t e d which s u g g e s t s t h a t t h e b e t a r e c e p t o r b l o c k i n g d rugs may have added advan tages o v e r o t h e r a g e n t s by p r e v e n t i n g more v a s c u l a r c o m p l i c a t i o n s .

Cost - Although b e t a r e c e p t o r b l o c k e r s have been a v a i l a b l e

s i n c e 1 9 6 5 , t h e y remain r e l a t i v e l y e x p e n s i v e . One month 's t r e a t m e n t w i t h a s i n g l e d a i l y dose o f a h y d r o p h i l i c c a r d i o - s e l e c t i v e d rug c o s t s abou t 17 .00 , whereas a s imilar c o u r s e of a t h i a z i d e d i u r e t i c i s a b o u t 30p. T h i s twenty t o t h i r t y - f o l d d i f f e r e n c e i n c o s t i s v e r y i m p o r t a n t , when c o n s i d e r i n g t h e m i l l i o n s o f p a t i e n t s who a r e a f f e c t e d . The more expens ive a g e n t s must have d e f i n a b l e advan tages i f t h e y a r e t o be advoca ted a s f i r s t l i n e t h e r a p y . T h i s i s s u e i s i m p o r t a n t when c o n s i d e r i n g t h e problem o f h y p e r t e n s i o n i n t h i r d world c o u n t r i e s .

76

C o n t r a - i n d i c a t i o n s

B e t a - r e c e p t o r b l o c k i n g a g e n t s a r e s p e c i f i c a l l y c o n t r a - i n d i c a t e d i n p a t i e n t s who have h e a r t f a i l u r e o r a i rways o b s t r u c t i o n . Whi l s t t h e c a r d i o - s e l e c t i v e b e t a - b l o c k e r s may have l e s s e f f e c t on a i r w a y s , t h e y a r e s t i l l n o t s a f e i n p a t i e n t s w i t h asthma. Whi l s t b e t a - b l o c k e r s have l i t t l e e f f e c t on g l u c o s e metabol ism i n u n t r e a t e d d i a b e t i c s , t h e y do i m p a i r b o t h t h e autonomic and m e t a b o l i c r e sponse t o hypoglycaemia. There i s some ev idence t h a t c a r d i o - s e l e c t i v e d rugs are less haza rdous , b u t b e t a b l o c k e r s a r e c o n t r a - i n d i c a t e d i n p a t i e n t s w i t h " b r i t t l e " d i a b e t e s . B e t a - b l o c k e r s may a l s o induce s e v e r e Raynaud's syndrome and may c a u s e o r a g g r a v a t e i n t e r m i t t e n t c l a u d i c a t i o n i n peop le w i t h p e r i p h e r a l v a s c u l a r d i s e a s e .

T h i a z i d e d i u r e t i c s c a u s e p r o g r e s s i v e d e t e r i o r a t i o n i n g l u c o s e t o l e r a n c e . I t i s p o s s i b l e t h a t i n p a t i e n t s r e c e i v i n g i n s u l i n t h e r a p y , o n l y a s m a l l ad jus tmen t o f i n s u l i n dosage i s r e q u i r e d bu t t h e s e d rugs a r e b e s t n o t used i n m a t u r i t y o n s e t d i a b e t e s .

S i d e e f f e c t s

I t i s u s u a l l y c o n s i d e r e d t h a t t h i a z i d e d i u r e t i c s have few c l i n i c a l s i d e e f f e c t s . However, some p a t i e n t s f e e l g e n e r a l l y t i r e d when t a k i n g t h e s e d rugs and t h a t t h i s e f f e c t i s u n r e l a t e d t o m e t a b o l i c e f f e c t s . R e c e n t l y , t h e MRC t r i a l o f m i l d h y p e r t e n s i o n (1) has demons t r a t ed t h a t impotence i n i n men i s more common i n t h i a z i d e t r e a t e d h y p e r t e n s i v e s t h a n i n p a t i e n t s r e c e i v i n g b e t a - b l o c k e r s o r p l a c e b o .

B e t a - r e c e p t o r b l o c k e r s a r e known t o c a u s e s l e e p d i s t u r b a n c e , c o l d e x t r e m i t i e s and v i v i d dreams. I t i s p r o b a b l e t h a t t h e h y d r o p h i l i c b e t a - b l o c k e r s c a u s e fewer s i d e e f f e c t s . However, many p a t i e n t s n o t i c e a r e d u c t i o n i n e f f o r t t o l e r a n c e . Whi l s t t h e s e s i d e e f f e c t s a r e low g r a d e i t s h o u l d be remembered t h a t t h e r e may be i n t o l e r a b l e f o r p a t i e n t s on a long-term b a s i s and r e g a r d e d a s an i n t r u s i o n i n t o t h e i r 1 i f e - s t y l el* .

77

E f f e c t i v e n e s s

Be ta -b lock ing a g e n t s and t h i a z i d e d i u r e t i c s a r e rough ly e q u a l l y e f f e c t i v e i n r e d u c i n g blood p r e s s u r e . There i s however, ev idence t h a t b e t a b l o c k e r s a r e l ess e f f e c t i v e i n o l d e r p a t i e n t s and i n b l a c k h y p e r t e n s i v e s ( 2 ) .

Metabo l i c s i d e e f f e c t s

B e t a - r e c e p t o r - b l o c k e r s c a u s e a s l i g h t impairment i n l i p i d metabol ism. I t i s g e n e r a l l y c o n s i d e r e d t h a t t h i s a d v e r s e e f f e c t on c o r o n a r y r i s k i s amply o f f s e t by t h e b e n e f i c i a l e f f e c t s o f blood p r e s s u r e r e d u c t i o n .

T h i a z i d e d i u r e t i c s have m u l t i p l e m e t a b o l i c e f f e c t s . They c a u s e a p r o g r e s s i v e d e t e r i o r a t i o n i n g l u c o s e t o l e r a n c e and may induce d i a b e t e s m e l l i t u s . About 60 p e r c e n t o f p a t i e n t s r e c e i v i n g t h i a z i d e d i u r e t i c s deve lop h y p e r u r i c a e m i a , a l t h o u g h o n l y abou t 2 p e r c e n t develop g o u t . I t i s n o t known whether hype ru r i caemia i s an independen t co rona ry r i s k f a c t o r as it i s i t s e l f a s s o c i a t e d w i t h h y p e r t e n s i o n , hype r - l i p i d a e n i i a and o b e s i t y .

The t h i a z i d e group o f d i u r e t i c s have an a d v e r s e e f f e c t on l i p i d s which i s s l i g h t l y g r e a t e r t han t h e e f f e c t s e e n w i t h b e t a b l o c k e r s . I t shou ld be s t r e s s e d however, t h a t t h i s e f f e c t i s s t i l l r e l a t i v e l y small when looked a t i n r e l a t i o n t o c o r o n a r y r i s k .

P a t i e n t s who r e c e i v e t h i a z i d e d i u r e t i c s f r e q u e n t l y deve lop hypolialaemia. There i s no e v i d e n c e t h a t hypokalaemia i s an independen t c o r o n a r y r i s k f a c t o r , b u t t h e r e a r e s e v e r a l s t u d i e s which s u g g e s t t h a t p a t i e n t s w i t h hypokalaemia who s u s t a i n a myoca rd ia l i n f a r c t i o n do have a worse p r o g n o s i s t h a n c a s e s w i t h normal serum p o t a s s i u m l e v e l s . A s h y p e r t e n - s i v e p a t i e n t s a r e prone t o deve lop c o r o n a r y h e a r t d i s e a s e anyway, t h i s i s a s e r i o u s problem.

78

T h i a z i d e d i u r e t i c s e l e v a t e plasma r e n i n a c t i v i t y . Although a r a i s e d plasma r e n i n was once c o n s i d e r e d t o be a p o s s i b l e r i s k f a c t o r , t h e ev idence i n f avour o f t h i s h y p o t h e s i s i s u n a c c e p t a b l e . I n a d d i t i o n t h e y c a u s e a s m a l l r i s e i n serum u r e a and c r e a t i n i n e a s w e l l as t h e packed c e l l volume. A l l t h e s e b iochemica l e f f e c t s might be c o n s i d e r e d t o be adve r se a l t h o u g h t h e y a r e p r o b a b l y n o t s p e c i f i c a l l y dange rous . T h i a z i d e d i u r e t i c s do t h e r e f o r e , have s e v e r a l b iochemica l e f f e c t s which must be a c a u s e f o r conce rn . I t i s p o s s i b l e t h a t t h e b e n e f i c i a l e f f e c t s o f blood p r e s s u r e r e d u c t i o n might i n some c a s e s be o f f - s e t by an i n c r e a s e i n co rona ry r i s k s c o r e due t o r i s e s i n b lood l i p i d s and b lood s u g a r .

Are b e t a - b l o c k e r s c a r d i o - p r o t e c t i v e ?

The m a j o r i t y o f d rug t r i a l s on t h e t r e a t m e n t o f h y p e r t e n s i o n have f a i l e d t o show c o n v i n c i n g e v i d e n c e t h a t a n t i h y p e r t e n s i v e d rugs p r e v e n t c o r o n a r y h e a r t d i s e a s e . T h i s might i n p a r t be due t o t h e f r e q u e n t u s e o f t h i a z i d e d i u r e t i c s . B e t a - b l o c k e r s however, might be c a r d i o - p r o t e c t i v e . These d r u g s were o r i g i n a l l y i n t r o d u c e d f o r t h e t r e a t m e n t o f e s t a b l i s h e d i s chaemic h e a r t d i s e a s e and have r e c e n t l y been shown t o be e f f e c t i v e i n t h e secondary p r e v e n t i o n o f myoca rd ia l i n f a r c t i o n . There a r e t h e o r e t i c a l r e a s o n s t o b e l i e v e t h e r e f o r e , t h a t b e t a b l o c k e r s may p r e v e n t h e a r t a t t a c k s where o t h e r d rugs have f a i l e d .

R e t r o s p e c t i v e u n c o n t r o l l e d s t u d i e s have s u g g e s t e d t h a t be t a -b locked h y p e r t e n s i v e p a t i e n t s s u f f e r l e s s h e a r t a t t a c k s t h a n non-be ta -b locked c a s e s . P r o s p e c t i v e t r i a l s a r e underway which s h o u l d answer t h i s p o i n t ( 1 , 3 , 4 ) .

The Glasgow Blood P r e s s u r e C l i n i c Study

W h i l s t t h e r e s u l t s o f p r o s p e c t i v e s t u d i e s a r e a w a i t e d , i t may be worthwhile t o examine t h e r e s u l t s o f t r e a t m e n t o f l a r g e numbers o f h y p e r t e n s i v e p a t i e n t s a t t e n d i n g b lood p r e s s u r e c l i n i c s t o s e e whe the r t h e r e i s any e v i d e n c e t h a t b e t a - b l o c k e d p a t i e n t s f a i r e d b e t t e r , s u s t a i n i n g l e s s v a s c u l a r c o m p l i c a t i o n s .

79

We have conduc ted an a n a l y s i s o f 920 c o n s e c u t i v e h y p e r t e n s i v e p a t i e n t s a t t e n d i n g f o u r b lood p r e s s u r e c l i n i c s i n Glasgow ( 5 ) . Only p a t i e n t s between t h e ages o f 35 and 6 4 y e a r s were i n c l u d e d , and t h e s t u d y was c o n f i n e d t o c a s e s who r e c e i v e d a n t i h y p e r t e n s i v e d r u g s .

L i f e t a b l e a n a l y s i s o f t h e f r e q u e n c y o f f a t a l and n o n - f a t a l v a s c u l a r c o m p l i c a t i o n s o f h y p e r t e n s i o n a r e shown i n t h e f i g u r e .

PRtVlOUS VASCULAR C W L l C A l l D W S 111 PRZVlOllS VASCULAR CWl ICAllONS

19e 15-44 ChI7 1.59. NS ACE 15-44 ChI7 I.U7. NS

I.. . . . . . . . .

m

40 40

L.. L .

L...

P I54

3 40 40 L. I

m

40

I 2 1 4 1 , 1 7 5 4 5 '/cars

F i g . 1 Cumulative r a t e o f c o m p l i c a t i o n s i n b e t a - b l o c k e d ( con t inuous l i n e ) and non-be ta -b locked (broken l i n e ) h y p e r t e n s i v e p a t i e n t s a t t e n d i n g t h e Glasgow Blood P r e s s u r e C l i n i c .

There were s i g n i f i c a n t t r e n d s f o r b e t a - b l o c k e d p a t i e n t s w i t h p r e v i o u s v a s c u l a r c o m p l i c a t i o n s t o deve lop fewer e v e n t s t h a n non-beta-blocked c a s e s . Th i s d i f f e r e n c e i n m o r b i d i t y was

n o t due t o d i f f e r e n c e s i n t h e q u a l i t y o f blood p r e s s u r e c o n t r o l ( 5 ) .

80

There was a non-significant tendency for previously uncomplicated beta-blocker patients to fair better, but numbers o f cases (678) were too few for confident analysis. This study, together with two similar, but smaller, uncontrolled studies, lend support to the idea that beta blockers may indeed be more protective than other drugs. One surprising finding from the present study, was that beta-blocker patients, appeared to develop fewer strokes as well as heart attacks. This tendency was very striking in the sub-set of patients who had already suffered one stroke.

Conclusions

Thiazide diuretics have theoretical disadvantages and beta-blockers have theoretical advantages. There is some uncontrolled evidence to suggest that beta-blockers do prevent more complications than thiazides. If this finding is confirmed by prospective clinical trials then beta- blockers should be used as a routine in all hypertensive patients.

Re f e rence s

1. MRC Working Party on Mild to Moderate hypertension: Adverse reactions to bendrofluazide and propranolol used in the treatment of mild hypertension. Lancet ii:539, 1981.

Antihypertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. J Amer Med Ass 248:1996, 1982.

3. Wilhelmsen, L., Berglund, G., Elmfeldt, 0. & Wedel, H: Beta-blockers versus saluretics in hypertension: comparison of total mortality, myocardial infarction and sudden death: study design and early results on blood pressure reduction. Prev Med 10:38, 1981.

4. I.P.P.P.S.H. Collaborative Group. The International Projective Primary Prevention Study in Hypertension (I.P.P.P.S.H.) : Objectives, design and preliminary data review. Proceedings of International Symposium, Berlin, 1980. Ciba Laboratories, Horsham, Sussex.

5. Beevers, D.G., Johnston, J.H., Larkin, H. & Davies, P. Clinical evidence that B-adrenoceptor blockers prevent more cardiovascular complications than other antihypertensive drugs. Drugs 2 5 (suppl 2):326, 1983.

2. Veterans Administration Cooperative Study Group on