the effect on mortality of long-term antihypertensive therapy

THE EFFECT ON MORTALITY OF LONG-TERM ANTIHYPERTENSIVE THERAPY

Haakon S t o r m - M a t h i s e n , H a l v o r Lprken a n d Knud Landmark

D e p a r t m e n t of M e d i c i n e , L o v i s e n b e r g H o s p i t a l , L o v i s e n b e r g g t . 1 7 ,

0456 O s l o , Norway.

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

M e d i c a l t r e a t m e n t of a r t e r i a l h y p e r t e n s i o n was before 1 9 5 5 more or less b a s e d o n an e x p e r i m e n t a l l e v e l . G a n g l i o n b l o c k i n g d r u g s

i n t r o d u c e d i n 1 9 4 8 were t r i e d by u s i n some s e v e r e c a s e s , b u t were

f o u n d t o possess s e r i o u s a n d t r o u b l e s o m e s ide -e f f ec t s . I n 1 9 5 0 and

1 9 5 2 h y d r a l a z i n e a n d R a u w o l f i a a l k a l o i d s , r e s p e c t i v e l y , were i n t r o d u c e d a s a n t i h y p e r t e n s i v e a g e n t s . We made a p i l o t s t u d y w i t h

t h e s e d r u g s i n 1 9 5 4 , a n d i n 1 0 5 h y p e r t e n s i v e p a t i e n t s , blood

p r e s s u r e was s a t i s f a c t o r y r e d u c e d i n t h e m a j o r i t y , w i t h complete n o r m a l i z a t i o n (b lood p r e s s u r e below 1 6 0 / 9 5 m m Hg) i n many p a t i e n t s .

T h e s e e n c o u r a g i n g and p r o m i z i n g r e s u l t s i n s p i r e d u s t o see i f

a n t i h y p e r t e n s i v e t h e r a p y c o u l d h a v e a b e n e f i c i a l e f f e c t on prog-

n o s i s i n a r t e r i a l h y p e r t e n s i o n , a n d a l o n g - t e r m s t u d y i n a g r e a t e r

number of p a t i e n t s w a s t h e r e f o r e s t a r t e d i n 1 9 5 5 .

M a t e r i a l a n d m e t h o d s

I n t h e p e r i o d f rom J a n u a r y 1st 1 9 5 5 t o December 3 1 s t 1 9 7 9 , 754

h y p e r t e n s i v e p a t i e n t s h a v e b e e n fo l lowed and s t u d i e d r e g u l a r l y by

o n e of u s ( H . S.-M.) from o n e y e a r u p t o 30 y e a r s d u r i n g c o n t i n u o u s

a n t i h y p e r t e n s i v e m e d i c a t i o n . Some p a t i e n t s h a v e d r o p p e d o u t ( T a b l e

T a b l e I . H y p e r t e n s i v e p a t i e n t s i n c l u d e d i n d i f f e r e n t p e r i o d s f r o m

1955-1979 . I n b r a c k e t s number o f . p a t i e n t s who d r o p p e d o u t .

GI- o u p Men Women T o t a l

I 1955-64 2 2 5 ( 3 9 ) 208 ( 8 4 ) 4 3 3 ( 1 2 3 )

I1 1 9 6 5 - 6 9 1 2 4 ( 3 5 ) 68 ( 1 7 ) 1 9 2 ( 5 2 )

I11 1970-74 62 ( 3 ) 29 ( 2 ) 9 1 ( 5 ) I V 1975-79 1 3 2 5 38

T o t a l 424 ( 7 7 ) 330 (103) 754 ( 1 8 0 )

- P 7 I -

T h e p a t i e n t s were below 65 y e a r s of age a t e n t r y , a v e r a g e age f o r men and women was 52 and 53 y e a r s , r e s p e c t i v e l y . Almost a l l p a t i -

e n t s were observed and underwent p h y s i c a l examina t ion and l a b o r a - t o r y t es t s f o r a c e r t a i n p e r i o d of time b e f o r e t h e y were i n c l u d e d

i n t h e s t u d y . The i n c l u s i o n c r i t e r i o n was d i a s t o l i c b lood p r e s s u r e ( B P ) above 105 m m Hg on more t h a n 3 o c c a s i o n s i n t h e s i t t i n g

and/or s t a n d i n g p o s i t i o n .

BP was measured by a s t a n d a r d mercury sphygmomanometer, d i a - s t o l i c v a l u e s be ing t aken a t t h e d i s a p p e a r a n c e of Koro tkof f sounds ( 5 t h p h a s e ) . T h e p a t i e n t s were c l a s s i f i e d i n t o 3 s t a g e s acco rd ing t o t h e c l a s s i f i c a t i o n proposed by World Hea l th O r g a n i z a t i o n (WHO)

( 1 ) . I n g r o u p I ( i n c l u d e d from 1955-1964; T a b l e I) most p a t i e n t s

were i n i t i a l l y t r e a t e d w i t h Rauwolf ia a l k a l o i d s , s i n c e 1958 o f t e n

combined w i t h t h i a z i d e d i u r e t i c . From 1962 , t h e combined admini- s t r a t i o n of a -me thy ldopa and a s m a l l d o s e of h y d r o c h l o r o t h i a z i d e

was t h e c o n v e n t i o n a l r eg ime , b u t from 1970 , - a d r e n e r g i c r e c e p t o r

b l o c k e r s , p r a z o s i n and o t h e r d r u g s , o f t e n i n combina t ion w i t h a t h i a z i d e were a d m i n i s t e r e d . The i n t e n t i o n was t o r e d u c e d i a s t o l i c

BP l e v e l s t o or below 90 m m Hg.

P

The outcome of a l l p a t i e n t s , bo th t h o s e under c o n t i n u o u s medica l

o b s e r v a t i o n by u s ( g r o u p s 5) and d r o p - o u t s ( g r o u p s 12) were , e x c e p t

f o r 3 who went ab road , fo l lowed t o d e a t h o r up t o December 3 1 s t 1981. Death c e r t i f i c a t e s and new a d d r e s s e s were r e c o r d e d from

C e n t r a l Bureau of S t a t i s t i c s of Norway. I n some drop-out p a t i e n t s , t h e c a u s e of d e a t h was i m p o s s i b l e t o o b t a i n .

S t a t i s t i c a l a n a l y s e s were used by means of b inomina l d i s t r i - b u t i o n .

R e s u l t s and d i s c u s s i o n I n an e a r l i e r p a p e r , i t was shown t h a t i n an " u n t r e a t e d sample

of h y p e r t e n s i v e s ; m o r t a l i t y r a t i o (=number of obse rved d e a t h s d i v i d e d by expec ted age-sex s p e c i f i c d e a t h r a t e s f o r t h e whole p o p u l a t i o n m u l t i p l i e d by 100) f o r male and f ema le p a t i e n t s was 985

% and 813 %, r e s p e c t i v e l y ( 2 ) .

T h e p r e s e n t s t u d y d e m o n s t r a t e s t h a t c o n t i n u o u s medica l o b s e r - v a t i o n and t r e a t m e n t of h y p e r t e n s i v e s caused a pronounced r e d u c t i o n i n m o r t a l i t y r a t i o ( T a b l e 11).

- 1 7 2 -

Tab le 11. M o r t a l i t y r a t i o f o r male ( m ) and f ema le p a t i e n t s ( w ) i n

g r o u p s I and I1 a c c o r d i n g t o t h e c l a s s i f i c a t i o n of WHO ( s t a g e s

1-111). I n b r a c k e t s number of observed d e a t h s d i v i d e d by expec ted

age-sex s p e c i f i c d e a t h r a t e s f o r t h e whole p o p u l a t i o n . 5 = p a t i e n t s

under c o n t i n u o u s medica l o b s e r v a t i o n and t r e a t m e n t ; = drop-out

p a t i e n t s .

7 4 ' (-1 (-1

5.1 1.1

WHO: A l l s t a g e s S t a g e I S t a g e I1 I S t a g e 111

1 2 0 5 1 5 4

b

Group I m 2 6 2 * 2 9 9

- a -

I 9 1 0 ~ (- )(-I 1 1 2 . 8 3.6

1 4 3 2 5 ( - 1 ( - 1

5 4 . 5 8.4

1 6 1 1 9 1

Group Iw 2 0 2 * 3 8 5

I 3 3

1 4 .9 1 . 6 (-1 (-)

8 9 5 9 (- 1 (- 1

4 4 . 1 1 5 . 3

Group I I m 1 5 8 * 402

34 2 0 (- (-1

2 1 . 5 5 . 0

Group I I w 1 1 4 2 4 1

5 1 6 (-1 (-1

48 2 . 1

b

1 6 5 382

- a -

4 8 1 8 ( - 1 ( - 1

2 9 . 1 4 . 7

1 4 7 2 3 5

34 2 8 (-I(- ) 2 3 . 1 1 1 . 9

70 2 8 0

b

2 75 8 0

- a -

44 2 ( - 1 ( - 1 1 5 . 7 2.5

200 8 8 1

32 2 0 ( - 1 (-1

1 6 2 . 3

1 3 8 3 8 1

4

0 . 6 5

b

5 3 6 4 3 5

- a -

I 5 2 5 ( - 1 (--) 9 . 7 1 . 2

464 9 8 2

23 11 (-1 (-)

5 . 0 1.1

492 1 7 1 4

1 1 8 6 (-1 (-

3 . 7 0 . 35

1 9 2 7 4 1

) 2 2

[- 1 (- 1 . 0 4 0 . 2 7

* = m o r t a l i t y r a t i o s i g n i f i c a n t l y h i g h e r t h a n i n t h e normal

p o p u l a t i o n (p<O.OOl): c a l c u l a t i o n s only f o r g r o u p s 5 , a l l s t a g e s .

T h u s , w h i l e m o r t a l i t y r a t i o f o r male and f e m a l e p a t i e n t s i n g r o u p

I? was 262 and 202 , r e s p e c t i v e l y , i t f e l l t o 158 and 1 1 4 , r e s p e c - t i v e l y , f o r c o r r e s p o n d i n g p a t i e n t s i n g r o u p 112 ( T a b l e 11). I n g r o u p s 111 & I V , normal d e a t h r a t e s were f o u n d . I n drop-out p a t i -

e n t s ( g r o u p s Ib & I I b ) , m o r t a l i t y r a t i o was c o n s i d e r a b l y h i g h e r

( T a b l e 11). T h e s e r e s u l t s i n d i c a t e : 1) t h e d e c l i n e i n m o r t a l i t y t h r o u g h o u t t h e y e a r s f r o m 1 9 6 5 was p r o b a b l y c a u s e d by t h e i n t r o - d u c t i o n and u s e of bet ter and more e f f i c i e n t a n t i h y p e r t e n s i v e d r u g s w i t h fewer untoward s u b j e c t i v e and o b j e c t i v e s i d e - e f f e c t s ,

and 2 ) t h e c o n t i n u o u s m e d i c a l o b s e r v a t i o n and t r e a t m e n t of hyper -

t e n s i v e s improved p r o g n o s i s . The d e c r e a s e i n m o r t a l i t y f rom g r o u p 12 t o 112 was d u e t o a

d e c l i n e i n d e a t h s from c e r e b r o v a s c u l a r d i s e a s e , c o n g e s t i v e h e a r t f a i l u r e and r e n a l f a i l u r e . On t h e o t h e r h a n d , t r e a t m e n t of hyper -

t e n s i o n had l i t t l e i f any i n f l u e n c e on t h e s e q u e l a e of c o r o n a r y a r t e r y d i s e a s e , an o b s e r v a t i o n i n a c c o r d a n c e w i t h s e v e r a l e a r l i e r

r e p o r t s ( 3 - 6 ) . Thiazj .de d i u r e t i c s were f r e q u e n t l y used s ince 1 9 5 8

i n t h e t h e r a p y of o u r h y p e r t e n s i v e s , and i n some s t u d i e s , t h e u s e

of d i u r e t i c s i n h y p e r t e n s i v e s h a s i n f a c t b e e n a s s o c i a t e d w i t h

more a r r h y t h m i a s , a g r e a t e r m o r t a l i t y and a h i g h e r c o r o n a r y e v e n t

r a t e ( 5 - 7 ) . I n a d d i t i o n , t h i a z i d e s and some - a d r e n e r g i c r e c e p t o r

b l o c k e r s c a n i n i t i a t e m e t a b o l i c s i d e - e f f e c t s which may o f f s e t t h e i r b e n e f i c i a l a n t i h y p e r t e n s i v e a c t i o n i n t h e l o n g r u n ( 8 , 9 ) .

I n o u r p a t i e n t s , h y d r o c h l o r o t h i a z i d e was seldom a d m i n i s t e r e d i n doses h i g h e r t h a n 25 mg p e r d a y , and serum p o t a s s i u m was r e g u l a r l y

measured: most p a t i e n t s r e c e i v e d e x t r a p o t a s s i u m . O t h e r r i s k f a c t o r s f o r d e v e l o p m e n t of c a r d i o v a s c u l a r d i s e a s e s u c h a s t o t a l

c h o l e s t e r o l , a b s e n c e o r p r e s e n c e of d i a b e t e s m e l l i t u s , and c i g a r -

e t t e smoking w e r e , however , n o t t a k e n i n t o a c c o u n t when i n t e r - p r e t i n g t h e e f fec ts of a n t i h y p e r t e n s i v e t h e r a p y i n o u r s t u d y .

P

R e f e r e n c e s 1. World H e a l t h O r g t e c h n Rep S e r : A r t e r i a l h y p e r t e n s i o n and

i s c h a e m i c h e a r t d isease. P r e v e n t i v e a s p e c t s . R e p o r t of an

e x p e r t c o m m i t t e e . No.23l ,p '? ,Geneva 1 9 6 2 . 2 . S torm-Mathisen H , LQken H , Brox D , S t e n b a k @. The p r o g n o s i s i n

l o n g - t e r m t r e a t e d and " u n t r e a t e d " e s s e n t i a l h y p e r t e n s i o n . Acta

Med Scand 1969;158:253-258.

- 174 -

3.

4 .

5.

6.

7.

8 .

9.

F r e i s ED. Medical t r e a t m e n t of c h r o n i c h y p e r t e n s i o n . Mod Con-

c e p t s C a r d i o v a s c D i s 1 9 7 1 :15 :17 -22 .

V e t e r a n s A d m i n i s t r a t i o n C o o p e r a t i v e S t u d y G r o u p on a n t i h y p e r -

t e n s i v e Drugs . E f f e c t s of t r e a t m e n t on m o r b i d i t y i n h y p e r t e n -

s i o n . 111. I n f l u e n c e of a g e , d i a s t o l i c p r e s s u r e , a n d p r i o r

c a r d i o v a s c u l a r d i sease : f u r t h e r a n a l y s i s o f s i d e e f f e c t s .

C i r c u l a t i o n 1 9 7 2 ; 4 5 : 9 9 1 - 1 0 0 4 .

Morgan TO, Adam W R , Hodgson M, G i b b e n d RW. F a i l u r e o f t h e r a p y

t o i m p r o v e p r o g n o s i s i n e l d e r l y m a l e s w i t h h y p e r t e n s i o n . Med J

A U S t 1 9 8 0 ; 2 : 2 7-31.

M u l t i p l e r i s k f a c t o r i n t e r v e n t i o n t r i a l . R i s k f a c t o r c h a n g e s

a n d m o r t a l i t y r e s u l t s . M u l t i p l e r i s k f a c t o r i n t e r v e n t i o n t r i a l

r e s e a r c h g r o u p . J A M A 1 9 8 2 ; 2 4 8 : 1 4 5 6 - 1 4 7 7 .

H o l l i f i e l d J W , S l a t o n P E . T h i a z i d e d i u r e t i c s h y p o k a l e m i a and

c a r d i a c a r r h y t h m i a s . Acta Med S c a n d 1 9 8 1 ; s u p p l 6 4 7 : 6 7 - 7 3 .

A m e s R P , H i l l P . E l e v a t i o n of s e r u m l i p i d l e v e s d u r i n g d i u r e t i c

t h e r a p y of h y p e r t e n s i o n . A m J Med 1976;61:748-757.

L e r e n P , H e l g e l a n d A , H je rmann I , Holme I . T h e Oslo s t u d y : CHD

r i s k f a c t o r s , s o c i o e c o n o m i c i n f l u e n c e s , and i n t e r v e n t i o n . A m

Heart J 1 9 8 3 : 1 0 6 : 1 2 0 0 - 1 2 0 6 .

- 175 -