Download pdf - 2007 Geriatric Pharmacotherapy Updates

8/10/2019 2007 Geriatric Pharmacotherapy Updates

1/13

Updates The American Journal of Geriatric Pharmacotherapy

eriatric P harm acotherapy Updates

D a v i d R . R G u a y

P h a r m D

De pa r tm en t o f Expe r imen ta l and C l in i ca l Pha rmaco logy Co l l ege o f Pha rmacy Un ive rs it y o f M inneso ta M inneapo l i s

M inneso ta and D iv is i on o f Ge r ia t ri c s Pa r tne r ingCare S en io r Se rv ices Hea l thPa r tne rs I nc . M inneapo l is M inneso ta

W H I C H A S P I R I N D O S E S A R E

C A R D I O P R O T E C T I V E ?

T h e f i n d i n g s o f a r e c e n t s y s te m a t i c r e v i e w c o n f i r m p r e -

v i o u s a s se r t io n s t h a t t h e e v i d e n c e d o e s n o t s u p p o r t u s e

o f a s p i ri n d o s a g e s g r e a te r t h a n 7 5 t o 8 1 m g / d f o r t h e

p r e v e n t i o n o f c ar d i o v a s c u l a r ( C V ) d i se a se . A l t h o u g h

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

a s p i ri n d o s a g e s a s l o w a s 3 0 m g / d is a d e q u a t e t o f u l l y

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

h i g h a s 1 3 0 0 m g / d ( t a k e n a s 6 5 0 B I D ) a r e a p p r o v e d

f o r u s e. I n t h e U n i t e d S t a te s , t h e m o s t c o m m o n l y

p r e s c r i b e d d o s a g e i s 8 1 m g / d ( 6 0 % ) , f o l l o w e d b y

3 2 5 m g / d ( 35 % ). T h e a v a il a bl e e v i d e n c e , m o s t l y f r o m

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

d o s a g e s e x c e e d in g 7 5 to 8 1 m g / d d o n o t e n h a n c e e f fi -

c a c y b u t d o e n h a n c e t h e r i s k o f h e m o r r h a g i c a d v e r se

e v e n t s, p r im a r i l y i n re l a t io n t o N S A I D g a s t r o p a t h y .

R e f e r e n c e

Campbe l l CL, Smyth S , Monta lescot G , S te inhubl SR .

Aspirin do se for the prev ent ion o f cardiovascular disease:

A systematic review.

JAMA

2 0 0 7 ; 2 9 7 : 2 0 1 8 - 2 0 2 4 .

R I V A S T I G H I N E I N H I L D C O G N I T I V E

I H P A I R H E N T

I n a 4 - y e a r t r i a l , p a t i e n t s w i t h m i l d c o g n i t i v e i m p a i r -

m e n t w e r e r a n d o m i z e d t o r e c ei v e r i v a s ti g m i n e ( n =

5 0 8 ) o r p l a c e b o ( n = 5 1 0 ). P r o g r e s s i o n t o A l z h e i m e r ' s

d i se a s e o c c u r r e d i n 1 Z 3 % o f r i v a s t ig m i n e r e c i p ie n t s

a n d 2 1 .4 % o f p l a c e b o r e c i p ie n t s ( h a z a r d r a t i o [ H R ] =

0 . 8 5 ; 9 5% C I , 0 . 6 4 - 1 . 1 2 ; P = N S ) . T h e 2 s t u d y g r o u p s

d i d n o t d i f f e r si g n i f ic a n t l y i n t e r m s o f c h a n g e s f r o m

b a s e li n e t o e n d p o i n t i n s t a n d a r d i z e d Z s c o re s f o r th e

c o g n i t i v e t e s t b a t t e ry . A d v e r s e - e v e n t f r e q u e n c i e s w e r e

s i m i l a r in t h e 2 g r o u p s ( o v e r a l l a d v e r s e e v e n t s: 9 5 . 6 %

r i v a s t i g m i n e , 9 2 . 7 % p l a c e b o ; s e r i o u s a d v e r s e e v e n t s :

2 Z 9 % a n d 3 0 . 5 % , r e s p e c t iv e l y ) . A s e x p e c t e d , t h e p r e -

d o m i n a n t a d v e r s e e v e n ts w e r e c h o l i n e r g i c i n n a t u r e .

N a u s e a , v o m i t i n g , d i a r r h e a , a n d d i z z i n e s s o c c u r r e d

a t 2 - t o 4 - f o l d h i g h e r f r e q u e n c i e s i n t h e r i v a s t i g m i n e

g r o u p c o m p a r e d w i t h t h e p l ac e b o g r o u p .

R e f e r e n c e

Feldman HH, Fer r i s S , Winblad B , e t a l . Ef fec t of

r ivas t igmine on delay to diagnosis of Alzheim er 's dis -

ease f rom mi ld cogni t ive impa i rment : The InDDEx

study [publ ished cor rect io n appears in Lancet Neurol

2007;6 :849] . Lancet Neurol 2 0 0 7 ; 6 : 5 0 1 - 5 1 2 .

H O H E I N T R A V E N O U S A N T I H I C R O B I A L

T H E R A P Y I N O L D E R A D U L T S

U s e o f h o m e i n t r a v e n o u s a n t i m i c ro b i a l t h e r a p y c a n b e

a v i a bl e o p t i o n f o r th e l o n g - t e r m m a n a g e m e n t o f i n f e c-

t i o n s i n c o m m u n i t y - d w e l l i n g o l d e r i n d i v id u a l s . F r o m

2 0 0 0 t o 2 0 0 3 , 2 0 5 p a t ie n t s f r o m t h e V e t er a n s A f f ai rs

A n n A r b o r H e a l t h c a r e S y s te m r e c ei v ed 2 31 c o u r se s

o f i n t ra v e n o u s a n t i m i c r o b i a ls ; 1 0 7 c o u r s e s i n p a t ie n t s

a g e d > 6 0 y e a r s a n d 1 2 4 c o u r s e s i n p a t ie n t s a g e d

< 6 0 y e a r s . I n b o t h a g e g r o u p s , t h e m o s t c o m -

m o n i n d i c a t i o n w a s o s t e o a r t i c u l a r i n f e c t i o n a n d t h e

p r e d o m i n a n t p a t h o g e n s w e r e c o a g u l a s e - p o s i t i v e a n d

c o a g u l a t i v e - n e g a t i v e s ta p h y l o c o c c i . O l d e r p a t i e n t s w e r e

s i g n i fi c a n t ly m o r e l ik e l y t h a n y o u n g e r p a t ie n t s t o

r e q u i r e a f a m i l y m e m b e r ' s a s s i st a n c e w i t h t h e i n f u s i o n s

( 3 5 % v s 2 3 % , r e s p e c t i v e l y ; P = 0 . 0 3 ) a n d w e r e m o r e

l i k e ly t o b e s e e n i n u r g e n t c a r e ( 3 1 . 4 v s 1 4 . 3 v i si t s p e r

1 0 0 0 t h e r a p y - d a y s ; P < 0 . 0 0 1 ) o r t o c a ll t h e t e a m p h a r -

m a c i s t w i t h q u e s t i o n s ( 1 4 . 3 v s 8 . 5 7 p e r 1 0 0 0 t h e r a p y -

d a y s ; P = 0 . 0 4 ) . O v e r a l l , c l i n ic a l o u t c o m e s ( e f f i c a c y a n d

t o x i c i t y ) w e r e s i m i l a r i n b o t h a g e g r o u p s , w i t h a s in g l e

e x c e p t i o n . N e p h r o t o x i c i t y ( d e f i n e d a s a n i n c r e a s e in

s e r u m c r e a t i n in e o f >1 m g / d L o r a d o u b l i n g o f t h e

v a l u e f r o m d a y 1 o f o u t p a t i e n t t h e r a p y ) w a s s i g n i fi -

c a n t ly m o r e c o m m o n i n t h e o l d e r p a t ie n t s t h a n i n t h e

y o u n g e r p a t i e n t s ( 3 .0 3 v s 0 . 4 6 p e r 1 0 0 0 t h e r a p y - d a y s ;

P = 0 .02) .

Accepted for publ icat ion Oc tober 30 20 0Z

P r i n t e d in t h e U S A R e p r o d u c t i o n in w h o l e o r p a r t is n o t p e r m i t t e d

d o i: 10 1 0 1 6 /j a m j o p h a r m

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The American Journal of Geriatric Pharmacotherapy Updates

R e f e r e n c e

Cox AM, M alani PN, Wiseman SW, Kauffman CA. Ho m e

intraven ous antimicrobial infu sion therapy: A viable optio n

in o lder adults.

J Am Geriatr Soc

2 0 0 7 ; 5 5 : 6 4 5 - 6 5 0 .

N E W I N D I C A T I O N F O R Z O L E D R O N I C A C I D

B a se d o n th e r es u lt s o f t h e H O R I Z O N ( H e a l t h

O u t c o m e s a n d R e d u c e d I n c id e n c e w i t h Z o l c d r o n i c

A c i d O n c e Y e a r ly ) t r i a l, z o l c d r o n i c a c i d ( R c c l a s t

[ N o v a r ti s P h a r m a c e u t ic a l s C o r p o r a t i o n , E a s t H a n o v e r ,

N e w J e r se y ] ) h a s re c e i v ed U S F o o d a n d D r u g

A d m i n i s t r a t i o n ( F D A ) a p p r o v a l f o r a n e w i n d i c a t i o n ,

t h e t r e a t m e n t o f p o s t m e n o p a u s a l o s t e o p o r o s is . F o r t h is

i n d i c a t i o n , i t i s a d m i n i s t e r e d o n c e a n n u a l l y a s 5 m g

I V , i n f u s e d o v e r 1 5 m i n u t e s . Z o l c d r o n i c a c i d i s t h e

s e c o n d i n t r a v e n o u s b i s p h o s p h o n a t c t o r e c e iv e a p p r o v a l

f o r t h i s i n d i c a t i o n . I t i s n o t i n d i c a t e d f o r t h e p r e v e n -

t i o n o f p o s t m c n o p a u s a l o s t c o p o ro s i s . Z o l c d r o n i c a c id

i s a v a i l a b l e i n r e a d y - t o - u s e i n f u s i o n b o t t l e s . T h e m o s t

c o m m o n a d v e r s e e v e n t s a s s o c i a t e d w i t h i t s u s e a r e

f e v er , f l u l ik c s y m p t o m s , m y a l g i as , a r t h r a l g i as , a n d

h e a d a c h e ( i c , i n f u s i o n r e a c t i o n ) . M o s t a d v e r s e e v e n t s

o c c u r w i t h i n 3 d a y s o f a d m i n i s t r a t i o n a n d d i s a p p e a r

w i t h i n 3 d a y s o f o n s e t , a l t h o u g h t h e y m a y l a st u p t o

7 t o 1 4 d a y s i n s o m e p a t i e n t s . T h e i n c i d e n c e o f i n f u s i o n

r e a c t i o n s d e c r ea s e s m a r k e d l y w i t h s u b s e q u e n t d o s e s , s o

t h e r e is n o n c c d f o r p r e v e n ti v e m e d i c a t i o n s .

N B : Z o m c t a ( N o v a r t is P h a r m a c e u ti c a ls C o r p o r a -

t i o n ) , w h i c h i s u s e d p r i m a r i l y f o r t h e t r e a t m e n t o f p a i n

c a u s e d b y b o n e m e t a s t a s e s a n d t h e h y p e r c a l c e m i a o f

m a l i g n a n c y , h a s t h e s a m e a c t i v e in g r e d i e n t a s R c c l a s t.

Z o m c t a r e c i p ie n t s s h o u l d n o t r e c e iv e R c cl a st

A N T I D E P R E S S A N T S A N D B O N E

M I N E R A L D E N S I T Y

T h e p r o s p e c t i v e S t u d y o f O s t e o p o r o t i c F r ac t u r e s ( S O F )

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

m i n e r a l d e n s i ty ( B M D ) i n 2 7 2 2 o l d e r c o m m t m i t y - d w d l i n g

wo m en (me an age , 78 .5 yea rs). Pa r t ic ipan ts were c l a ss if ied

as se lect ive serotonin reuptake inhibi tor (SSRI) users (n =

198) , t r i cyc l i c an t idepressan t (TCA) use rs (n = 118) , and

a n t i d e p r e s sa n t n o n u se r s ( n = 2 4 0 6 ) . H i p B M D w a s m e a -

sured a t t he s ix th an d e igh th SO F s tudy v is it s, which to ok

place a me an of 4 .9 yea rs apa r t . Af t e r ad jus tmen t fo r po ten-

t ia l confound ers , me an to t a l h ip B M D dec reased by 0 .82%,

0 .47%, and 0 .47% per yea r i n SSRI use rs , TCA use rs , and

ant idepressan t nonuse rs , r e spec t ive ly (P < 0 .001 , SSRI use rs

vs an t idepressan t nonuse rs) . SSRI use rs a lso had h ighe r ra t es

of bon e loss a t t he 2 h ip subreg ions . T he re su l t s were no t

apprec i ab ly a l t e red wh en w om en w i th Ger i a t r i c Depress ion

Scale scores _>6 we re e xd ud ed fro m t he analysis.

R e f e r e n c e

Diem SJ, Blackwel l TL , Ston e KL , e t a l . Use o f ant i -

depressants and ra tes of hip bo ne loss in older wome n:

The s tudy of os t eoporo t i c f rac tures .

Arch Intern Med

2 0 0 7 ; 1 6 7 : 1 2 4 0 - 1 2 4 5 .

T h e p r o s p e c ti v e O s t c o p o r o t i c F r a c t u re s in M e n c o h o r t

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

p y o n B M D i n 5 9 9 5 m e n a g e d > 6 5 y e a rs . I n a d j u s t e d

c r o s s -s e c ti o n a l d a t a a na ly s es , t h e m e a n B M D a m o n g

S S R I u se r s ( n = 1 6 0 ) w a s 3 . 9 % l o w e r a t t h e t o t a l h i p

a n d 5 .9 % l o w e r at t h e l u m b a r s p i n e c o m p a r e d w i t h t h a t

i n a n t i d e p r e s s a n t n o n u s e r s ( n = 5 7 0 8 ) ( P = 0 . 0 0 2 f o r

t o t a l h i p ; P < 0 . 0 0 1 f o r l u m b a r s p in e ) . C h a n g e s i n B M D

a m o n g T C A u s er s (n = 9 9 ) a n d t r a z o d o n c u s e rs ( n =

5 2 ) d i d n o t d i f f e r si g n i f ic a n t l y f r o m t h o se i n a n t i d e p r e s -

s a n t n o n u s e r s . A d j u s t m e n t f o r p o t e n t i a l c o n f o u n d e r s

d i d n o t s i g n i f i c a n tl y a l t e r t h e r e su l t s . T h e o b s e r v e d d i f -

f e r e n c e in B M D i n S S R I u s e rs w a s s im i la r t o t h a t n o t e d

a m o n g r e c ip i e n ts o f s y s te m i c c o r t i c o s te r o i d s .

R e f e r e n c e

Han ey EM , C han BK, D iem SJ , e t al , fo r t he Osteop oro t i c

F rac tures in M en S tudy Group . Assoc ia t ion of l ow bone

mine ral densi ty wi th se lective seroton in reuptake inhibi -

to r use by o lde r men.

Arch Intern Med

2 0 0 7 ; 1 6 7 : 1 2 4 6 -

1251.

E d i t o r ' s n o t e : T h e a c c u m u l a t in g d a t a r e g a r d i n g

t h e a d v e r s e b o n e e f f e c ts o f S S R I s a r e c o m p e l l i n g , a n d

a n u m b e r o f t h e B r a d f o r d - H i l l c r i t er i a f o r e st a b li s h -

m e n t o f c a u sa l r e l at i o n s h i p s i n o b s e r v a t i o n a l s t u d i e s

h o l d t r u e . D e s p i t e s om e m e t h o d o l o g i c p r o b le m s , t h e

c o n s i s t e n c y o f e f f e ct s i n t h e s e 2 s t u d i e s ( b o t h w i t h e a c h

o t h e r a n d w i t h p r e v io u s s tu d ie s ) a n d t h e m a g n i t u d e o f

t h e a s so c i a t i o n s a t l e a s t p a r t i a l l y su p p o r t a c a u sa l r e l a -

t io n s h i p . T h e f i n d i n g t h a t t h e m a g n i t u d e o f t h e S S R I

e f f e c t w a s s i m i l a r t o t h a t o b s e r v e d w i t h s y s t e m i c c o r ti -

c o s t e r o i d s is o f c l in i c al c o n c e r n . A s w i t h c o r t i c o s t e r o i d

p r e s c r i b i n g , t h e r e i s li k e ly t o b e s o m e u n n e c e s s a r y u s e

o f S S R I s i n t h e g e n e r a l m e d i c a l c o m m u n i t y ; o n t h e

o t h e r h a n d , t h e r e a r e t h o s e w h o t r u l y n e e d S S R I s a n d

s h o u l d r e c e iv e t h e m d e s p i te p o t e n t i a l b o n e c o n c e r n s .

T h e i n d i c a t io n s f o r i n i t ia t i n g a n d c o n t i n u i n g S S R I

t h e r a p y r e q u i r e m o r e c a r e f u l s c r u t i n y i n li g h t o f t h e i r

a d v e r s e e f fe c t s o n b o n e .

T H E T R U T H R E G A R D I N G R O S I G L I T A Z O N E

A N D C A R D I O V A S C U L A R R I S K

A r e c e n t m e t a - a n a l y s is o f 4 2 r a n d o m i z e d s t u d ie s o f

r o s i g li t az o n e w i t h d u r a t io n s o f > 6 m o n t h s s u g g es t s

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Upd ates The Am erican Journa l of Geriatric Pharmacotherapy

t h a t t h c r is k o f m y o c a r d i a l i n f a r c ti o n ( M I ) a n d d c a t h

f r o m C V c a u s c s i s i n c r c a s c d a m o n g p a t i c n t s t a k i n g

r o s i g l it a z o n e . T h e m e a n a g e o f p a r t i c ip a n t s i n t h e

4 2 s t u d i c s w a s 5 6 y e a rs a n d t h c m c a n b a s c l i n c g ly c o s y -

l a t cd h c m o g l o b i n ( H b A k ) v a l u e w a s - 8 . 2 . T h c o d d s

r a t io ( O R ) f o r M I i n t h e r o s i g l i t a z o n c g r o u p c o m p a r e d

w i th t h e c o n t r o l g r o u p w a s 1 . 4 3 ( 95 C I , 1 . 0 3 - 1 . 9 8 ;

P = 0 . 0 3 ) , a n d t h e O R f o r d e a t h f r o m C V c a u s e s w a s

1 . 6 4 ( 95 C I , 0 . 9 8 - 2 . 7 4 ; P = 0 . 0 6 ) .

R e f e r e n c e

Psaty BM, Furberg CD. Rosigli tazone and cardiovascu-

lar risk. N E r ~ I J M e d . 2007;356:2522-2524.

R E C O R D ( R o s i gl i ta z o n c E v a lu a te d fo r C a rd i a c

O u t c o m c s a n d R e g u l a t i o n o f G l y c c m i a i n D i a b c tc s ) i s a

r a n d o m i z c d , o p c n - la b c l, n o n i n f c r i o r i t y t ri a l i n v o lv i n g

4 4 4 7 p a t i e n ts w i t h t y p e 2 d i a b et e s i n a d e q u a t e l y c o n -

t r o l l c d b y m c t f o r m i n o r a s u l f o n y lu r c a . A n u n p l a n n c d

i n t e r i m a n al y si s o f d a t a f r o m t h e R E C O R D t r ia l

c o n c c n t r a t c d o n t h c C V s a f e ty a s p c ct s o f a d d i n g r o si g -

l i t a z o n c to m c t f o r m i n o r a s u lf o n y l u r c a c o m p a r c d w i t h

t h e c o m b i n a t i o n o f m c t f o r m i n p l u s a s u lf o n y l u rc a .

B c c a u sc o f a m c a n f o l lo w - u p o f o n l y 3 . 7 5 y c a r s a t t h c

t im e o f t h e i n t e r im a n a ly s i s, t h e r e w a s l im i t e d s t a t i st i -

c a l p o w e r t o d c t c c t t r c a tm c n t d i f f e re n c e s . A n a d ju d i -

c a t c d p r i m a r y c n d p o i n t ( h o s p i t a li z a t io n o r d c a t h f r o m

C V c a u s c s ) o c c u r r c d i n 2 1 7 r o s ig l i t a z o n c s u b j c c t s a n d

2 0 2 c o n t r o l s u b j c c t s ( H R = 1 . 0 8 ; 9 5 C I , 0 . 8 9 - 1 . 3 1 ) .

A f t e r t h c i n c l u s i o n o f c n d p o i n t s p c n d i n g a d j u d i c a t io n ,

t h e H R w a s 1 .1 1 ( 95 C I , 0 . 9 3 - 1 . 3 2 ) . T h e r e w c r c

n o s i g n i f i c a n t i n t c r g r o u p d i f f e r e n c e s i n r a t c s o f M I ,

d c a t h f r o m C V c a u sc s , o r d c a t h f r o m a n y c au s c. H o w -

e v e r, h c a r t f a i l u r e w a s s i g n i f i c a n t l y mo r c f r e q u e n t i n

r o s ig l i t a z o n e r e c ip i e n t s c o mp a r e d w i th c o n t r o l s u b -

j c c ts ( H R = 2 . 1 5; 9 5 C I , 1 . 3 0 - 3 . 5 7 ) ( sc c W a r n i n g s

sec t ion . )

R e f e r e n c e

Home PD, Pocock SJ, Beck-Nielsen H, e t a l , for the

RECORD Study Group. Rosigli tazone evaluated for

cardiovascular ou tco m es--a n inter im analysis .

N E r ~ l J

M e d . 2 0 0 7 ; 3 5 7 : 2 8 3 8 .

E d i t o r ' s n o t e : A t t h i s t i m c , t h c t r u t h a b o u t t h c

a s s o c i a t i o n b c tw c c n r o s ig l i t a z o n c a n d C V r i s k i s n o t

k n o w n . C e r t a in ly , t h c r c a r c w c l l - k n o w n l i a b i li t ic s a ss o -

c i a t c d w i th r o s ig l i t a z o n c t h e r a p y , i n c lu d in g s i g n i f i c a n t

w e ig h t g a in , a d v e r s e e ff e c t s o n s e r u m lo w - d e n s i t y li p o -

p r o t e i n c h o l e s t e ro l ( L D L - C ) c o n c e n t r a t i o n s , i n cr e a s ed

r i s k o f h c a r t f a i l u r e ( s u p p o r t c d b y t h c p r c v io u s s t u d y ) ,

a n d i n c r ca s c d r is k o f f ra c t u r e s i n w o m c n . G i v e n t h c

a v a il a b le t h e r a p i e s f o r d i a b e t e s , t h e c l i n i c ia n s h o u ld n o t

b c c o m f o r t a b l e u s in g a n a g c n t t h a t m a y b c a s s oc i a tc d

w i t h a n e x ce s s r i s k f o r s ev e re C V d i s e a s e o r d e a th f r o m

C V c a u se s . T h e l a c k o f C V r i s k d a t a f o r p io g l i t a z o n c i s

n o t p a r t i c u l a r l y r e a s su r i n g , as w e d o n o t k n o w w h e t h e r

th e s e C V r i s k s a r c s p e c i f i c t o t h e i n d iv id u a l d r u g o r

a re appl icab le to the en t i r e drug c la ss ( ie , bo th ava i l -

a b l e g l i t a z o n c s ) . U n le s s f u r t h e r w e l l - d e s ig n e d s t u d -

i cs p ro v id c c o n v in c in g c v id c n c c o f t h c C V s a f e ty o f

r o s ig l i t a z o n e , t h e a n a ly s e s r e v i e w e d h e r e m u s t b e t a k e n

s e r io u s ly . U l t im a t e ly , t h c d c c i s i o n t o u s c o r n o t u s c t h i s

d r u g w i l l b c m a d c b y p a t i c n t s / s u r r o g a t c s a n d t h c i r

h e a l t h c a r e p r o v id e r s . I t i s i n c u mb e n t o n r e s e a r c h e r s

a n d d r u g m a n u f a c t u r e r s t o p r o v i d c t h c h i g h c s t - q u a l i t y

d a t a o n w h ic h t o b a s e t h i s d e c i s i o n .

M O R T A L I T Y W I T H A N T I P S Y C H O T I C D R U G

U S E I N O L D E R A D U L T S W I T H D E M E N T I A

A p o p u l a t i o n - b a s e d , r c t r o s p c c t i v e , m a t c h e d - c o h o r t

s t u d y ( 2 7 , 2 5 9 ma tc h c d p a i r s ) e v a lu a t e d t h c a s s o -

c i a ti o n b c t w c c n a l l- c au s c m o r t a l i t y a n d a n t i p s y c h o t i c

u s e i n b o t h c o m m u n i t y - d w e l l i n g a n d i n s t i t u ti o n a l -

i z c d o l d c r a d u l t s w i t h d c m c n t i a i n O n t a r i o , C a n a d a

( 1 9 9 7 - 2 0 0 3 ) . 1 N c w u s c o f a t y p ic a l a n t ip s y c h o t i c s w a s

a s s o c i a t c d w i th a s i g n i f i c a n t l y i n c r c a s c d r i s k o f mo r t a l i -

t y at 3 0 d a y s c o m p a r c d w i t h n o n u s c i n b o t h c o m -

m u n i t y d w e l le r s ( a d ju s t e d H R = 1 .3 1 ; 9 5 C I , 1 . 0 2 -

1 . 7 0 ; a b s o lu t c r i s k d i f f e r e n c e , 0 . 2 p c r c c n t a g c p o in t )

a n d i n s t i t u t i o n a l i z e d s u b j e ct s ( a d ju s t e d H R = 1 . 5 5 ;

9 5 C I , 1 . 1 5 - 2 . 0 7 ; a b s o lu t c r i s k d i f f e r e n c e , 1 . 2 p c r -

c e n t a g e p o in t s ) . T h e e x c e s s r i s k a p p e a r e d t o p e r s i s t

t o 1 5 0 d a y s , b u t u n e q u a l r a t c s o f d a t a c c n s o r in g o v e r

t i m c m a y ha v e c o n f o u n d e d t h c r c s u lt s . N c w u s c o f co n -

v c n t i o n a l a n t i p s y c h o t i c s w a s a s s o c i a t c d w i th a h ig h c r

mo r t a l i t y r i s k a t a l l t ime p o in t s r e l a t i v e t o n e w u s e o f

a ty p i c a l a n t i p s y c h o t i c s : at 3 0 d a y s , t h e a d ju s t e d H R

f o r c o n v c n t i o n a l a n t i p s y c h o t i c s i n c o m m u n i t y d w c l l -

c r s was 1 .55 (95 CI , 1 .19- 2 .02 ; abso lu te r i sk d i f fEr -

e n c e , 1 . 1 p e r c e n t a g e p o in t s ) a n d i n i n s t i t u t i o n a l i z e d

s u b j e c t s, w a s 1 . 2 6 ( 95 C I , 1 . 0 4 - 1 . 5 3 ; a b s o lu t e r i sk

d i f f e r e n c e , 1 .1 p e r c e n t a g e p o in t s ) . S e n s i t i v i t y a n a ly s e s

r c v c a l c d t h a t u n m c a s u r c d c o n f o u n d e r s t h a t i n c r c a s c

t h e r i s k o f d e a t h m i g h t d i m i n i s h o r e v e n e l i m i n a t e t h e

o b s e r v e d a s s o c i a t io n s .

E d i t o r ' s n o t e : A l t h o u g h t h is s t u d y h a d i m p o r t a n t

l imi t a t i o n s , i t s r c s u l t s a r c c o n g r u c n t w i th t h o s c o f

2 p r e v io u s mc ta - a n a ly s c s S ,3 T h i s s t u d y h i g h l i g h t s t h c

n c c d t o c a r e f u ll y b a l a n c c b c n c f i t a g a in s t r i sk w h e n

c o n s id c r in g a n t i p s y c h o t i c u s c i n o ld c r a d u l t s w i th

d e m e n t i a .

65


4/13

The Am erican Journa l of Geriatric Pharmacotherapy Upd ates

R e f e r e n c e s

1. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic

drug use and morta l i ty in older adults with dementia .

A n n I n t e r n M e d . 2007;146:775-786.

2. Kryzhanovskaya LA , Jeste DV, Young C A, et al. A review

of treatment-em ergent adverse events du r ing olanzapine

clinical trials in elderly patients with dementia. J Cl in

Psychiatry. 2006;67:933-945.

3. Schneider L S, Dagerm an KS, Insel P . Risk of death w ith

atypical antipsychotic drug treatments for dementia:

Meta-analysis of rand om ized placebo-controlled tr ials .

J A M A . 2005;294:1934-1943.

D I A B E T E S C A R E I N T H E N U R S I N G

H O M E S E T T I N G

A re t rospec t ive cha r t r ev iew of 108 re s idents wi th d iabe -

t e s l iv in g i n 1 1 n u r s in g h o m e s i n th e m id w e s t e r n U n i t e d

S ta t e s f o u n d t h a t c a r e f a i l e d t o me e t t h e A me r i c a n

Diabe tes Assoc ia t ion (ADA ) s tan dards of ca re for ou t -

p a t i e n t a d u l ts . A l t h o u g h b lo o d g lu c o s e ( B G ) c o n c e n t r a -

t i o n s w e r e m o n i to r e d in 9 8 o f s u b j ec t s , o n ly 3 8 m e t

BG goa ls . Hb Alc goa ls were achieved in 67 of subjec ts .

I n t h e 94 o f s u b j ec t s w h o s e b lo o d p r es s u r e ( B P ) w a s

mo n i to r e d , o n ly 5 5 m e t B P g o a ls . L ip id c o n c e n t r a t i o n s

were check ed ann ua l ly in 31 of subjec ts , annu a l elec -

t r o c a r d io g r a ms w e r e p e r f o r me d i n 3 7 o f s u b j e ct s , a n d

u r in e w a s c h e c k e d a n n u a l l y f o r mic r o a lb u m in u r i a i n 7

o f s u b j e ct s . F i f t y - tw o p e r c e n t o f s u b j e ct s w e r e t a k in g a n

a n g io t e n s in - c o n v e r t i n g e n z y m e in h ib i t o r o r a n g io t e n s in -

recepto r b locke r , and 42 were tak ing low-d ose a sp i r in .

M o n t h l y f o o t e x a m i n a ti o n s w e r e c o n d u c t e d in 87 o f

s u b j ec t s a n d a n n u a l d i l a te d e y e e x a min a t i o n s i n 4 2 o f

s u b j ec t s. I n f l u e n z a v a c c in a t i o n w a s p r o v id e d a n n u a l l y i n

8 9 o f s u b j e ct s , a n d a t le a s t 1 p n e u m o c o c c a l v a c c in a ti o n

was prov ided in 46 of subjec ts .

E d i t o r ' s n o t e : T h e f a il u re to m e e t A D A s t a n d a r d s

o f c ar e f o r o u tp a t i e n t a d u l t s i n t h i s c o h o r t o f t h e i n s t i -

t u t i o n a l i z e d e l d e r ly i s n o t u n e x p e c t e d . T h e p r e s en c e

o f n u m e r o u s c o m o r b i d i t i e s i n th i s p o p u l a t i o n a n d t h e

t i m e c o n s t r a i n t s o n h e a l t h p r o f e s si o n a ls m a k e d i a b e te s

m a n a g e m e n t a c o m p l e x a n d d i f f i c u l t t a sk . P e r h ap s i t

i s n o t a p p r o p r i a t e t o a p p l y t h e A D A o u t p a t i e n t a d u l t

g u id e l i n e s t o n u r s in g h o me r e s id e n t s . T h e t ime i s r i p e

f o r d e v e l o p m e n t o f g u i d e l i n e s t a i l o r e d t o t h i s p a t i e n t

p o p u l a t i o n , w h i l e t h e f i n a n c ia l i m p l ic a t io n s o f su c h

g u id e l i n e s w o u ld h a v e t o b e a d d r e s s e d p r o s p e c t i v e ly .

R e f e r e n c e

Hol t R M , Schwar tz FL , Shubrook JH. Diabe tes ca re in

extended-care facilities: Appropriate inten sity o f care?

Diabetes Care. 2007;30:1454-1458.

A N T I D E P R E S S A N T A U G M E N T A T I O N

S T R A T E G I E S I N O L D E R A D U L T S

I t i s w e l l k n o w n th a t s i g n i fi c a n t p r o p o r t i o n s o f p a t i e n ts

o f a ll ag e s d o n o t r e s p o n d o p t ima l ly to t h e i n i t ia l c h o ic e

o f a n t i d e p r e ss a n t t h e r a p y o r e v e n t o s ev er al s u b s e q u e n t

t r ia l s o f a l te rna t ive agents , a s a r e su l t o f e i the r inabi l i ty

to t o l e r a t e t h e s e l e ct e d ag e n t ( s ) o r b io lo g i c h e t e r o g e n e -

i t y o f a n a s -y e t u n k n o w n e t io lo g y . I n a s t u d y e v alu a t-

i n g r a t e s o f p r ima r y a n d s e c o n d a r y f a i l u r e o f i n i t i a l

p a r o x e t i n e m o n o t h e r a p y c o m b i n e d w i t h i n t e r p e r s o n a l

p s y c h o th e r a p y a n d t h e e f f e ct o f a u g m e n ta t i o n t h e r a p ie s

(1 , 2 , o r 3 were a l lowed , based on the c l in ica l r e sponse )

add ed to the in i tia l an t idepressan t , 105 o f 195 (54 )

o ld e r a d u l t s ( a g e > 7 0 y e a r s ) w i th ma jo r d e p r e s s io n

r e s p o n d e d i n a d e q u a t el y to t h e c o m b i n a t i o n o f o r al

p a r o x e t i n e p lu s i n t e r p e r s o n a l p s y c h o th e r a p y . I n a d e q u a t e

r e s p o n s e i n c lu d e d e i t h e r a n i n a d e q u a t e p r ima r y r e s p o n s e

( p r ima r y f a i l ur e ), w h ic h o c c u r r e d i n

7 7

subjects (73 ) ,

o r an in i t ia l r e sponse fo l lowed by ea r ly r e lapse ( second-

a ry f a i lu re ), wh ich occu r red in 28 subjec ts (27 ) . S ix ty-

n in e p a ti e n t s (6 6 ) r e c eiv e d a u g me n ta t i o n t h e r a p y a n d

3 6 ( 3 4 ) d id n o t ( p r ima r i l y b e c a u s e o f w i th d r a w a l o f

c o n s e n t o r c o mo r b id i t i e s ) . T h e 3 a u g me n ta t i o n a g e n t s

w e r e s u s ta in e d -r e le a s e b u p r o p io n ( s t a rt i n g a t 1 5 0 m g /d

f o r 1 w e e k , f o l l o w e d b y t i t r a t i o n t o a ma x imu m o f

4 0 0 m g / d b a s e d o n t h e re s p o n s e ) , n o r t r i p ty l i n e ( t i t r a te d

to p r o d u c e p l a s ma le ve ls o f 8 0 - 1 2 0 ~ a g / L , a n d l i t h i u m

( ti t_ ra te d t o p r o d u c e p l a s ma l e ve ls o f 0 . 5 - 0 . 7 m E q /L ) .

T h e p r o p o r t i o n s o f t h e 6 9 p a t i e n t s w h o r e c e iv e d a u g -

me n ta t i o n t h e r a p y w i th 1 , 2 , o r al l 3 a g e n t s w e r e 6 8 ,

17 , and 14 , r e spec t ive ly . Reco very ra te s were low er

a m o n g t h o s e r e q u i ri n g a u g m e n t a t i o n t h e r a p y c o m p a r e d

w i t h t h o s e w h o r e s p o n d e d t o t h e i n i t i a l r e g i m e n o f

p a r o x e t i n e p lu s p s y c h o th e r a p y : 5 0 i n t h o s e r e q u ir i n g

a u g m e n t a t i o n t h e r a p y b e c au s e o f a n i n a d e q u a t e p r i m a r y

r e s p o n s e a n d 6 7 i n t h o s e r e q u i r i n g a u g me n ta t i o n

th e r a p y b e c a u s e o f a n e a r ly re l ap s e , c o m p a r e d w i th 8 7

i n t h o s e w h o d i d n o t r e q u i re a u g m e n t a t i o n t h e r a p y ( P 5 5 y e a rs w i t h k n o w n C V

d i se a se o r d i a b e t e s a n d a t l e a s t 1 o t h e r r i sk f a c t o r f o r

v a s c u l a r d is e a se . T h i s 5 - y e a r s t u d y w as c o n d u c t e d a t

1 4 5 s it es i n 1 3 c o u n t r i e s . O u t c o m e s w e r e c o m p a r e d

i n r e c i p i e n t s o f v i t a m i n s ( d a i l y f o l i c a c i d 2 . 5 m g , v i t a -

m i n B 6 5 0 m g , a n d v i t a m i n B 12 1 m g ) a n d p l a c e b o .

A t t h e e n d o f th e t r i a l, t h e g e o m e t r i c m e a n p l a s m a

h o m o c y s t e i n e c o n c e n t r a t i o n f el l b y 2 .2 ~ l m o l / L i n t h e

v i t a m i n g r o u p a n d r o s e b y 0 . 8 0 ~ l m o l / L i n t h e p l ac e b o

g r o u p . V e n o u s th r o m b o e m b o l i s m ( V T E ) o c c u r r e d

i n 8 8 s u b j e ct s o v e r a m e a n f o l l o w - u p o f 5 y ea r s . T h e

i n c id e n c e r at e o f V T E w a s t h e s a m e i n b o t h g r o u p s

( 0 . 3 5 p e r 1 0 0 p e r s o n - y e a r s ; H R = 1 . 0 1; 9 5 C I , 0 . 6 6 -

1 . 5 3 ). V i t a m i n t h e r a p y d i d n o t r e d u c e t h e r i sk o f d e e p

v e i n t h r o m b o s i s ( H R = 1 . 0 4; 9 5 C I , 0 . 6 3 - 1 . 7 2 ) , pu l -

m o n a r y em b o l i s m ( H R = 1 .1 4 ; 9 5 C I , 0 . 5 7 - 2 . 2 8 ) , o r

u n p r o v o k e d V T E ( H R = 1 .2 1; 9 5 C I , 0 . 6 6 - 2 . 2 3 ) .

R e f e r e n c e

Ray JG , Kearon C, Y i Q , e t a l, fo r t he H ear t Outcom es

P r e v e n t i o n E v a l u a t io n 2 ( H O P E - 2 ) I n v e s ti g a to r s .

Hom ocyste ine - lower ing the rapy and r isk for venous

thromboembol i sm: A randomized t r i a l . A n n I n t e r n

M e d . 2 0 0 7 ; 1 4 6 : 7 6 1 7 6 Z

F O L I C A C I D F O R S T R O K E P R O P H Y L A X I S ?

A c c o r d i n g t o r e s u lt s o f a m e t a - an a l ys i s o f 8 r a n d o m i z e d

c o n t r o l l e d t r ia l s, f o l ic a c i d su p p l e m e n t a t i o n a p p e a r s t o

b e a n e f fe c t iv e st r a te g y f o r p r i m a r y p r e v e n t i o n ( b u t n o t

s e c o n d a r y p r e v e n t i o n ) o f s t ro k e . F o l i c ac id s u p p l e m e n -

t a t i o n r e d u c e d t h e r isk o f s t r o k e b y 18 ( r e l a ti v e r i sk

[ R R ] = 0 . 8 2 ; 9 5 C I , 0 . 6 8 - 1 . 0 0 ; P = 0 . 0 4 5 ) . I n s tr a ti -

f i e d a n a ly se s , g r e a t e r b e n e f i c i a l e f fe c t s w e r e s e e n w h e n

t h e d u r a t i o n o f t r e a t m e n t w a s > 3 y e a rs ( R R = 0 .7 1 ; 9 5

C I , 0 . 5 7 - 0 . 8 7 ; P = 0 . 0 0 1 ) , w h e n t h e p l a s m a h o m o -

c y s t ei n e c o n c e n t r a t i o n d e c r e a s e d b y > 20 ( R R = 0 . 7 7 ;

9 5 C I , 0 . 6 3 - 0 . 9 4 ; P = 0 . 0 1 2 ) , w h e n d i e ta r y g r a in

f o o d s t u f f s w e r e n o t f o r t i f i e d o r o n l y p a r t ia l l y f o r t i f i e d

w i t h f o l a te ( R R = 0 . 7 5 ; 9 5 C I , 0 . 6 2 - 0 . 9 1 ; P = 0 . 0 0 3 ) ,

a n d w h e n t h e r e w a s n o h i s t o r y o f p r e v i o u s s t ro k e ( R R =

0 . 7 5 ; 9 5 C I , 0 . 6 2 - 0 . 9 0 ; P = 0 . 0 0 2 ) . I n t h e c o r r e -

s p o n d i n g c o m p a r a t o r g r o u p s , t h e e s t i m a t e d R R s w e r e

a t t e n u a t e d a n d n o n s i g n i fi c a n t .

R e f e r e n c e

Wan g X, Q in X, De mirtas H , e t a l. Eff icacy of fol ic acid

supplementat ion in st roke prevent ion: A meta-analysis.

L a n c e t . 2 0 0 7 ; 3 6 9 : 1 8 7 6 1 8 8 2 .

G E N I S T E I N I N O S T E O P E N I C

P O S T M E N O P A U S A L W O M E N

A 2 - y e a r , d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d tr i a l c o n -

d u c t e d in 3 8 9 p o s t m e n o p a u s a l w o m e n w i t h o s t e o p e n i a

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

e s t r o g e n g e n i s t e i n . A t 2 y e a r s , B M D h a d i n c r e a s e d i n

g e n i s t e i n r e c i p i e n t s a n d d e c r e a se d i n p l a c e b o r e c i p i e n t s ,

b o t h a t t h e l u m b a r s p i n e ( m e a n c h a n g e : 0 . 0 4 9 g /

c m 2 [ 95 C I , 0 . 0 3 5 t o 0 . 0 5 9 ] v s - 0 . 0 5 3 g / c m 2 [ 95

C I , - 0 . 0 5 8 t o - 0 . 0 3 5 ] , r e s p e ct iv e ly ; m e a n d i ff e re n c e :

0 . 1 0 g / c m 2 [9 5 C I , 0 . 0 8 t o 0 . 1 2 ]; P < 0 . 0 0 1 ) a n d

t h e f e m o r a l n e c k ( m e a n c h a n g e : 0 . 0 3 5 g / c m 2 [9 5

C I , 0 .0 2 5 t o 0 . 0 4 2 ] vs - 0 . 0 3 7 g / c m 2 [9 5 C I , - 0 . 0 4 4

t o - 0 . 0 2 7 ] ; m e a n d i f f er e n ce : 0 . 0 6 2 g / c m 2 [9 5 C I ,

0 . 0 4 9 t o 0 . 0 7 3 ] ; P < 0 . 0 0 1 ) . G e n i s t e i n a l so w a s a s so c i -

a t e d w i t h s i g n i f i c a n t r e d u c t i o n s i n u r i n a r y e x c r e t i o n o f

t h e b o n e m a r k e r s p y r i d i n o l i n e a n d d e o x y p y r i d i n o l i n e

a n d i n c r e a se s in l e v e ls o f b o n e - s p e c i f i c a l k a l i n e p h o s -

p h a t a s e a n d i n s u l i n -l i k e g r o w t h f a c t o r I c o m p a r e d w i t h

p l a c e b o ( r a n g e , P < 0 . 0 0 1 t o P = 0 . 0 0 2 ) , a n d d i d n o t

s i g n i f ic a n t l y a f f e c t e n d o m e t r i a l t h i c k n e s s . H o w e v e r ,

g e n i s t e i n r e c i p i e n t s r e p o r t e d g a s t r o i n t e s t i n a l a d v e r s e

e f f e c ts m o r e f r e q u e n t l y t h a n d i d p l a c e b o r e c i p i en t s

( 1 9 v s 8 , r e sp e c t i v e l y ; P = 0 . 0 0 2 ) , a n d t h e se e f f e c t s

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T h e f i n d in g s o f W I S D O M ( W o m e n ' s I n te r n a ti o n a l

S t u d y o f L o n g D u r a t i o n O e s t r o g e n A f t e r M e n o p au s e ) ,

w h i c h w a s th e i n t e r n a t i o n a l e q u i v a l e n t o f t h e U S

W o m e n ' s H e a l t h I n i t i a t i v e ( W H I ) t r i a l , p o i n t t o t h e

d e l e te r io u s e f f e c ts o f h o r m o n e r e p l ac e m e n t t h e r a p y

( H R T ) w h e n i n it i at e d l o n g a f te r m e n o p a u s e . T h i s t r i al

c o m p a r e d e s t r o g e n o n l y ( c o n j u g a te d e q u i n e e s t ro g e n s

[ C E E ] 0 . 6 2 5 m g / d ) w i t h c o m b i n a t i o n h o r m o n e t h e ra -

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w a s t e r m i n a t e d d u r i n g r e c r u i t m e n t ( m e d i a n f o l l o w -u p ,

1 1 .9 m o n t h s ; 6 4 9 8 w o m a n - y e a r s ) a f te r p u b l i ca t i o n o f

e a r ly r e s u lt s f r o m t h e W H I t r ia l . T h e m e a n ( S D ) a g e

o f p a t ie n t s a t r a n d o m i z a t i o n t o H R T w a s 6 2 . 8 ( 4 . 8)

y e ar s . W h e n c o m b i n a t i o n h o r m o n e t h e r a p y (n = 2 1 9 6 )

w a s c o m p a r e d w i t h p l a c e b o ( n = 2 1 8 9 ) , t h e r e w a s a

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n u m b e r s o f w o m e n w i t h b r e a s t c a n c er o r o t h e r c a n c e rs ,

c e r e b r o v a sc u l a r e v e n t s , f r a c t u r e s , o r a l l - c a u se m o r t a l i -

t y . N o s i g n i f i ca n t d i f f e re n c e s w e r e f o u n d b e t w e e n

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D I S E A S E m M O N O T H E R A P Y D O U B L E

T H E R A P Y O R T R I P L E T H E R A P Y ?

T i o t r o p i u m , t i o t r o p i u m - s a l m e t e r o l , a n d t i o t r o p i u m -

sa l m e t e ro l - f lu t i c a so n e w e r e c o m p a r e d i n 4 4 9 p a t i e n t s

w i t h m o d e r a t e t o s e ve re c h r o n i c o b s tr u c ti v e p u l m o n a r y

d is ea se ( C O P D ) o v e r a 1 - y e a r p e r i o d . T h e p r o p o r t i o n s o f

p a t i e n t s h a v i n g a n e x a c e r b a ti o n o f C O P D d i d n o t d i f f e r

b e t w e e n t i o t r o p i t u n a l o n e a n d t i o t r o p i u m - s a l m e t e r o l

(62 .8 and 64 .8 , r e spec t ive ly ; d i f fe rence : -2 .0 pe rcen t -

a g e p o i n t s ; 9 5 C I , - 1 2 . 8 t o 8 . 8 ) o r b e t w e e n t i o t r o p i t u n

a lone and ti o t rop i tun -sa lme te ro l - f lu t i cason e (60 .0 ; d i f -

f e r e n c e: 2 . 8 p e r c e n t a g e p o i n t s ; 9 5 C I , - 8 . 2 t o 1 3 . 8 ) .

In sens i ti v i ty ana lyses , po in t e s t ima tes and 95 CIs

sh i f te d i n a d i r e c t io n f a v o r i n g t i o t r o p i u m - sa l m e t e r o l a n d

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p i t u n a l o n e , t i o t r o p i t u n - sa l m e t e r o l -f l u t i ca so n e w a s a s so d -

a t e d w i t h s i g n i fi c a nt i m p r o v e m e n t s i n l u n g f u n c t i o n ( P =

0 . 0 4 9 ) a n d d i s e ase - sp e d fi c q u a li t y o f li fe ( P = 0 . 0 1 ) a n d

r e d u c e d f r e q u e n d e s o f h o s p it a li z at io n s f o r C O P D e x ac e r-

b a t i o n s ( i n d d e n c e r a te r a t io [ I R R ] = 0 . 5 3 ; 9 5 C I , 0 . 3 3

to 0 .86) and a l l -cause hosp i t a l i za t ions ( IRR = 0 .67 ; 95

C I , 0 . 4 5 t o 0 . 9 9 ) . T i o t r o p i u m - sa l m e t e r o l d id n o t s ig n if i-

c a n t ly a f fe c t h m g f u n c t i o n o r h o sp i t a l i z at i o n r a te s c o m -

p a r e d w i t h t i o t r o p i u m a l o n e . T h u s , t h e a d d i t i o n o f a

l o n g - a c t i n g b r o n c h o d i l a t o r a n d a c o r t i c o s t e r o i d to a n t i -

c h o l i n e r g ic m o n o t h e r a p y w a s a s so c i at e d w i t h b e n e f i t s in

t e r m s o f l u n g f u n c t i o n , q u a l i ty o f l if e, a n d h o sp i t a li z a t io n

r a te s f o r C O P D e x a c e r b a ti o n s .

R e f e r e n c e

Aaron SD, Vandemheen KL, Gergusson D , e t a l , fo r

the Canadian Thorac ic Soc ie ty /Canadian Resp i ra tory

Cl in ica l Resea rch Conso r t ium. T io t rop iu m in combina -

t ion wi th placebo, sa lmeterol , or f lut icasone-salmeterol

for t r ea tment o f chronic o bs t ruc t ive pu lmon ary d i sease:

A randomized t r i a l .

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T H E R A P Y I N O L D E R P A T I E N T S

T h e T N T ( T r e a ti n g to N e w T a r g e t s ) s t u d y c o m p a r e d

l o w - a n d h i g h - d o s e s t a t in t h e r a p y i n 1 0 , 0 0 1 p a t i e n t s

b e t w e e n t h e a g e s o f 3 5 a n d 7 5 y e a rs w h o h a d c o r o -

n a r y h e a r t d is ea se ( C H D ) a n d L D L C c o n c e n t r a t i o n s

< 1 3 0 m g / d L . A p r e s p e c if i e d s e c o n d a r y a n al ys is o f

t h e T N T s t u d y i n c l u d e d d at a f r o m 3 8 0 9 p a ti e n ts w h o

w e r e a g e d > 6 5 y e a r s a t s t u d y e n t ry . I n t h e c o m p a r i s o n

o f a t o rv a s t at in 1 0 a n d 8 0 m g / d , h i g h - d o s e t h e r a p y

w a s a s so c i a t e d w i t h a 2 . 3 r e d u c t i o n in a b so l u t e r i sk

a n d a 1 9 r e d u c t i o n in R R fo r t h e c o m p o s i t e p r i m a r y

e n d p o i n t o f m a j o r C V ev e n ts ( H R = 0 . 8 1 ; 9 5 C I ,

0 . 6 7 - 0 . 9 8 ; P = 0 . 0 3 2 ) . N u m e r i c b u t n o n s i g n if i c an t

r e d u c t i o n s w e r e o b s e r v e d i n h i g h - v e r s u s l o w - d o s e

s t a ti n r e c i p ie n t s f o r t h e f o l l o w i n g c o m p o n e n t s o f th e

c o m p o s i t e e n d p o i n t : m o r t a l it y r a te s f ro m C H D , n o n -

f a ta l n o n - p r o c e d u r e - r e l a t e d M I , a n d f a ta l o r n o n f a t a l

s t r o k e ( i s c h e m i c , e m b o l i c , h e m o r r h a g i c , o r u n k n o w n ) .

T h e e f fe c ts o f t h e r a p y o n b o t h p r i m a r y a n d s e c o n d -

a r y e f f i c a c y e n d p o i n t s , a s w e l l as a d v e r se - e v e n t o u t -

c o m c s , d i d n o t d i f f e r s i g n if i ca n t ly b e t w e e n t h o s c a g c d

> 6 5 y c a rs a n d t h o s c a g c d < 6 5 y c a r s. T h c b c n c f i ts o f

h i g h - d o s c s t a t in t h c r a p y in t h c o l d c r p a ti c n t s w c r c n o t

o b t a i n e d a t t h e c o s t o f p e r s i s te n t e l e v a t io n s i n c r e a t i n e

p h o s p h o k i n a s e c o n c e n t r at i o n s .

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A N T I O X I D A N T S T O P R E V E N T

C A R D I O V A S C U L A R E V E N T S I N W O M E N

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S t u d y ) , 8 1 7 1 w o m e n h e a l t h p r o f e s s i o n a l s a g e d

> 4 0 y e a r s w i t h a h i s t o r y o f C V d i s e ase o r a t l e a s t 3 ri sk

f a c t o r s f o r C V d i s e a s e w e r e r a n d o m i z e d t o r e c e i v e

a s c or b ic a c id 5 0 0 m g / d , v i t a m i n E 6 0 0 I U Q O D ,

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d u r a t i o n o f f o l l o w - u p w a s 9 . 4 y e a r s. T h e p r i m a r y e n d

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Updates The American Journal of Geriatric Pharmacotherapy

e x p e r i e n c e d _ > 1 C V d i s e a s e o u t c o m e . I n t h e s t u d y

p o p u l a t i o n a s a w h o l e , a s c o r b i c a ci d h a d n o s i g n if i ca n t

e f f e c t o n t h e p r i m a r y e n d p o i n t ( R R = 1 .0 2 ; 9 5 C I ,

0 . 9 2 - 1 . 1 3 ) , n o r d i d v i ta m i n E ( R R = 0 . 9 4 ; 9 5 C I ,

0 . 8 5 - 1 . 0 4 ) o r b e t a - c a r o te n e ( R R = 1 . 0 2 ; 9 5 C I ,

0 . 9 2 - 1 . 1 3 ) . N o n e o f t h e 3 a g e n t s h a d a si g n if i ca n t

e f f e c t o n a n y o f t h e s e c o n d a r y o u t c o m e s ( i e , t h e i n d i-

v i du a l c o m p o n e n t s o f t h e p r i m a r y e n d p o i n t ) i n t h e

s t u d y p o p u l a t i o n a s a w h o l e . V i t a m i n E w a s a s s o c ia t e d

w i t h a s i g n if i ca n t r e d u c t i o n i n t h e p r i m a r y e n d p o i n t i n

t h e p r e s pe c i fi e d su b g r o u p o f w o m e n w i t h p r e v io u s C V

d i se a se ( R R = 0 . 8 9 ; 9 5 C I , 0 . 7 9 - 1 . 0 0 ; P = 0 . 0 4 ; P f o r

t h e i n t e r a c t i o n = N S ) . T h e r e w e r e n o s i g n if i c an t 2 - o r

3 - w a y in t e r a c t i o n s b e t w e e n a g e n t s f o r t h e p r i m a r y e n d

p o i n t ; h o w e v e r , w o m e n r a n d o m i z e d t o r e ce iv e a sc o r bi c

a c i d a n d v i t a m i n E h a d f e w e r st r o k e s ( R R = 0 . 6 9 ; 9 5

C I , 0 . 4 9 - 0 . 9 8 ; P = 0 . 0 4 ; P v al u e f o r t h e i n t e r a c t i o n =

0 . 0 3 ) . T h e o n l y s i g n if i ca n t re l a ti o n s h i p w i t h a n a d v e r s e

e v e n t w a s s e e n a m o n g b e t a - c a r o t e n e r e c ip i e n t s , w h o

h a d a sm a ll in c r e a se in sy m p t o m s su g g e s t i v e o f g a s tr i c

u p s e t ( R R = 1 . 0 6 ; 9 5 C I , 1 . 0 0 - 1 . 1 1 ; P = 0 . 0 5 ) .

E d i t o r ' s n o t e : T h i s t r i a l a d d s t o t h e n e g a t i v e f i n d -

i n g s f o r a n t i o x i d a n t s i n t h e p r o p h y l a x i s o f C V d i s ea s e .

T h i s t r i a l e v a l u a t e d w h e t h e r t h e s e a g e n t s w o u l d p r o -

d u c e a p o s it i v e e f fe c t i n w o m e n , a n d t h e a n s w e r w a s

a n u n e q u i v o c a l no

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Coo k NR, A lbe r t CM, G az iano JM, e t a l. A randomized

factoria l t r ia l of vi tamins C and E an d be ta carotene in the

secondary preve nt ion of cardiovascular events in w omen :

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A L L C A U S E M O R T A L I T Y W I T H

O R A L H Y P O G L Y C E M I C S A N D

A N T I H Y P E R G L Y C E M I C S

A r e t r o s p e c t i v e a n al y si s o f d a t a f r o m t h e V e t e r a n s

H e a l t h A d m i n i s t ra t i o n ( V H A ) D i a b e t es E p i d e m i o l o g y

C o h o r t e x a m i n e d t h e e f f ec t o f v ar io u s o r a l a g en t s

f o r t y p e 2 d i a b e t e s o n r a t e s o f al l- c a us e m o r t a l i t y

( N = 3 9 , 7 2 1 ) . T h e a d j u s t e d O R s ( A O R s ) f o r a l l- c a u se

m o r t a l i t y w e r e 0 . 8 7 f o r m e t f o r m i n m o n o t h e r a p y u s er s

( 95 C I , 0 . 6 8 - 1 . 1 0 ) , 0 . 9 2 fo r m e t f o r m i n + s u lf o n yl -

u r e a u s er s ( 9 5 C I , 0 . 8 2 - 1 . 0 5 ) , a n d 1 . 0 4 f o r g l i ta z o n e

m o n o t h e r a p y u s e rs ( 9 5 C I , 0 . 7 5 - 1 . 4 6 ) , a ll r e l at i v e t o

s u l fo n y l u r e a m o n o t h e r a p y u s e rs , fo r w h o m t h e A O R

w a s f ix e d a t 1 . 0 . T h e A O R f o r n o d r u g u s e r s w a s 0 . 9 0

( 9 5 C I , 0 . 7 4 - 1 . 0 9 ) . T h u s , n o s i g n if i c an t d r u g e f f e c t

o n a l l- c a u se m o r t a l i t y w a s f o u n d r e l at i v e t o s u l fo n y l -

u r e a m o n o t h e r a p y i n th i s V H A p a t i e n t d a t ab a s e.

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Kahle r KH, Ra jan M, Rhoads GG, e t a l . Impac t o f

oral ant ihyperg lycem ic therap y on a l l-cause m orta l i ty

among pa t i en t s w i th d i abe tes in the Ve te rans Hea l th

Admini s t ra t ion .

Diabetes Care

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A N T I T H R O M B O T I C T H E R A P Y F O R

N O N V A L V U L A R A T R I A L F I B R I L L A T I O N

A 2 9 - s t u d y m e t a - a n a ly s i s i n v o l v in g 2 8 , 0 4 4 m o s t l y o l d e r

p a t i e n t s f o u n d t h a t w a r f a r i n w a s 4 0 m o r e e f f e ct iv e t h a n

a n t i p l a t e l e t t h e r a p i e s f o r s t r o k e p r e v e n t i o n i n p a t i e n t s

w i t h n o n v a l v u l a r a t r i a l f i b r i l l a t i o n . A d j u s t e d - d o se w a r -

f a r i n ( 6 t r i a l s , 2 9 0 0 p a t i e n t s ) a n d a n t i p l a t e l e t a g e n t s

( 8 t r ia ls , 4 8 7 6 p a t i e n t s ) r e d u c e d t h e r is k o f s tr o k e b y

6 4 ( 9 5 C I , 4 9 - 7 4 ) a n d 2 2 ( 9 5 C I , 6 - 3 5 ) , r e s p e c -

t iv e ly , c o m p a r e d w i t h c o n t r o l s . A d j u s t e d - d o s e w a r f a r i n

( 1 2 t r ia l s , 1 2 , 9 6 3 p a t i e n t s ) w a s s i g n i f i c a n t l y m o r e e f fE c -

t iv e th a n a n t i p l a te l e t a g e n t s ( R R r e d u c t i o n = 3 9 ;

9 5 C I , 2 2 - 5 2 ) . O t h e r c o m p a r i s o n s w e r e i n c o n c lu s i v e .

A b so l u t e i n c r e a se s i n t h e r i sk f o r m a j o r e x t r a c r a n i a l

b l e e d i n g w e r e sm a l l ( 0 . 3 p e r y e a r ) .

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C H O I C E I N T H E O L D E S T P A T I E N T S W I T H

A T R I A L F I B R I L L A T I O N ?

T h e B A F T A ( B i r m i n g h a m A t r i a l F i b r i l l a t i o n T r e a t m e n t

o f th e A g e d ) s t u d y s e t o u t t o d e t e r m i n e t h e b e s t a n t i-

t h r o m b o t i c f o r p a t i e n t s a g e d _ >7 5 y e a rs . W a r f ar i n , d o se d

t o p r o v i d e a n i n t e r n a t io n a l n o r m a l i z e d r a ti o ( I N R ) o f 2 t o

3 , w as f o u n d t o p r o v i d e g r e a t e r p r o t e c t i o n a g a i n st s t r o k e

t h a n a sp ir in 7 5 m g / d w i t h o u t s i g ni f ic a n tl y i n c re a s in g t h e

b leed ing r i sk . Warfa r in rec ip i en t s had 24 pr imary event s

(21 s t rokes , 2 o the r i n t rac ran ia l hemorrhages , 1 sys t emic

e m b o l u s ) , a n d a sp i r i n r e c i p i e n t s h a d 4 8 p r i m a r y e v e n t s

( 4 4 s t r o k e s , 1 o t h e r i n t r a c r a n i a l h e m o r r h a g e , 3 sy s t e m i c

emb ol i ) . Th e re spec t ive yea r ly even t r isks wer e 1 .8 and

3 .8 ( R R = 0 . 5 8 [ 95 C I , 0 . 2 8 t o 0 . 8 0 ] , P = 0 . 0 0 3 ;

a b so l u t e y e a r ly R R = 2 [ 9 5 C I , 0 . 7 t o 3 . 2 ] ). T h e y e a r ly

e x t r a c ra n i a l h e m o r r h a g e ri sk s w e r e 1 .4 a n d 1 .6

( R R = 0 . 8 7 [ 9 5 C I , 0 . 4 3 t o 1 . 7 3 ] ; a b so l u t e y e a r ly

R R = 0 .2 [ 9 5 C I , - 0 . 7 t o 1 . 2 ] ) .

R e f e r e n c e

Mant J , Hobbs FD, F le t che r K , e t a l , fo r t he BAFTA

Inves t iga tors , Mid land Resea rch P rac t i ces Ne twork

369


8/13


(MidReC). Warfar in versus aspir in for st roke preven-

t ion in an e lde r ly communi ty popula t ion wi th a t r i a l

f ib r i l l a t i on ( the Bi rmingham At r i a l F ibr i l l a t ion

T r e a t m e n t o f t h e A g e d S t u d y , B A F T A ) : A r a n -

domised cont ro l l ed t r i a l .

Lancet

2 0 0 7 ; 3 7 0 : 4 9 3 -

503.

IS T H E R E A C L I N I C A L L Y S I G N I F I C A N T

D R U G D R U G I N T E R A C T I O N B E T W E E N

C L O P I D O G R E L A N D S T A T I N S ?

T h e o r e t i c a l c o n c e r n s a n d e x v i v o re s u l ts h a v e s u g -

g e s t e d a p o t e n t i a l d e t r i m e n t a l i n t e r a c t i o n b e t w e e n

c l o p i d o g r e l a n d s ta ti n s m e t a b o l i z e d b y t h e c y t o c h r o m e

P 4 5 0 ( C Y P ) 3 A 4 is o zy m e . D a t a fr o m t h e C H A R I S M A

( C l o p i d o g r e l f o r H i g h A t h e r o t h r o m b o t i c R i s k a n d

I s c h e m i c S t a b i l i z a t i o n , M a n a g e m e n t , a n d A v o i d a n c e )

t r i a l w e r e a n a l y z e d t o d e t e r m i n e w h e t h e r s i m i l a r

c o n c e r n s a r o s e i n v i v o i n h u m a n s . W h e n d a t a f o r

s t a t i n s t h a t a r e m e t a b o l i z e d p r i m a r i l y b y C Y P 3 A 4

( a t o r v a s t a t i n , l o v a s t a t i n , a n d s i m v a s t a t i n [ A L S ] ) w e r e

c o m p a r e d w i t h d a t a f o r o t h e r s t a t i n s ( p r a v a s t a t i n a n d

f l u v a s t a t i n [ P F ] ) , s i m i l a r o u t c o m e s w e r e o b s e r v e d i n

p a t i e n t s r e c e iv i n g A l S o r P F w h o w e r e a l so r e c e i v in g

l o n g - t e r m c l o p i d o g r e l 7 5 m g / d . O f 1 5 , 6 0 3 e n r o l l ee s ,

1 0 , 0 7 8 r e c e i v e d a s ta t in a t b a s e li n e ( 8 2 4 5 A L S ,

1 7 4 8 P F ) a n d 5 4 9 6 d i d n o t ( p a t i e n t n u m b e r s a s

r e p o r t e d ) . A t a m e d i a n f o l lo w - u p o f 2 8 m o n t h s , t h e

p r i m a r y e n d p o i n t ( a c o m p o s i t e o f M I , s t ro k e , o r C V

d e a t h ) o c c u r r e d i n 6 .8 o f c l o p i d o g r e l r e c i p i e n ts a n d

7 .3 o f p l a c e b o r e c i p i e n t s i n t h e o v e r a ll p o p u l a t i o n

( H R = 0 . 9 3 ; P = 0 .2 2 ) . T h e f r e q u e n c y o f t h e p r i m a r y

e n d p o i n t w a s a l so s i m i la r w h e t h e r a t o r v a s t a t i n o r

p r a v a s t a t i n w a s a d m i n i s t e r e d w i t h c l o p i d o g r e l . T h e

i n t e r a c t i o n b e t w e e n a t o r v a s t a t i n o r p r a v a s t a t i n a n d

r a n d o m i z e d t r e a t m e n t w a s n o n s i g n if i c an t . T h u s , t h e r e

a p p e a r s t o b e n o c l in i c a ll y s i g n i f i c a n t d e t r i m e n t a l i n t e r -

a c t i o n b e t w e e n c l o p i d o g r e l a n d s t at in s m e t a b o l i z e d b y

C Y P 3 A 4 .

E d i t o r ' s n o t e : M o s t l a b o r a t o r y - b a s e d s t u d i e s h a v e

f o u n d n o i n t e r a c t i o n b e t w e e n c l o p i d o g r e l a n d s t a t i n s

m e t a b o l i z e d b y C Y P 3 A 4 , n o r w a s a n y i n t e r a c ti o n

n o t e d i n t h i s i n v i v o s t u d y i n h u m a n s . T h e r e i s n o

n e e d t o s e l e c t s t a t i n s f o r c l o p i d o g r e l r e c i p i e n t s o n t h e

b as is o f C Y P 3 A 4 m e t a b o l i s m .

R e f e r e n c e

Saw J , Brennan DM, S te inhubl SR, e t a l , fo r t he

C H A R I S M A I n v e st ig a t o rs . L a c k o f e v id e n c e o f a

c lop idogre l - s t a t in in t e rac t ion in the CHARISMA t r i a l .

J A m Coil Cardiol 2 0 0 7 ; 5 0 : 2 9 1 - 2 9 5 .

A R E T H E R E R A C I A L D I F F E R E N C E S I N

B L E E D I N G R I S K W I T H W A R F A R I N I N

P A T I E N T S W I T H A T R I A L F I B R I L L A T I O N ?

I n a n a n a ly s is o f r a c i a l / e t h n i c d i f f e r e n c e s i n c r u d e e v e n t

r a t e s f o r w a r f a r i n - r e l a t e d i n t r a c r a n i a l h e m o r r h a g e ( I C H )

t h a t u s e d c o m b i n e d p h a r m a c y a n d l a b o r a to r y d a ta f r o m

t h e K a is e r P e r m a n e n t e S o u t h e r n C a l if o r n ia h e a l th m a i n -

t e n a n c e o r g a n i z a t i o n , t h is a d v e r s e e v e n t o c c u r r e d m o r e

f r e q u e n t l y i n n o n w h i t e s ( i n c l u d i n g b l a ck s , H i sp a n i c s ,

a n d A s ia n s) t h a n i n w h it e s. B e t w e e n 1 9 9 5 a n d 2 0 0 0 ,

1 8 , 8 6 7 q u a l i f y i n g a t r i a l f i b r i l l a t i o n h o sp i t a l i z a t i o n s

we re iden t i f i ed (78 .5 wh i t e , 8 .0 b l ack , 9 .5 H i sp anic ,

3 .9 A s i a n ) ; 1 7 3 q u a l if y i n g I C H e v e n t s o c c u r r e d o v e r

a m e a n o f 3 . 3 y e a r s o f f o l lo w - u p . T h e a n t i c o a g u l a t i o n

i n t e n s i t y a c h i e v e d w a s s i g n i fi c a n tl y l o w e r a m o n g b l a ck s

c o m p a r e d w i t h a ll o t h e r g r o u p s ( P < 0 . 0 0 1 ) a n d d i d

n o t d i f fe r b e t w e e n t h e o t h e r g r o u p s . W a r f a ri n u s e w as

a s so c i a t e d w i t h a n i n c r e a se d I C H r i sk i n a l l r a c e s , b u t

t h e m a g n i t u d e o f ri sk w as g r e a t e s t a m o n g n o n w h i t e s .

T h e r e w e r e n o s e x - r e l a t e d d i f f e r e n c e s . U s i n g w h i t e s

a s t h e r e f e r e n c e , t h e H R f o r I C H w a s 4 . 0 6 f o r A si an s

( 9 5 C I , 2 . 4 7 - 6 . 6 5 ) , 2 . 0 6 f o r H i s p a n ic s ( 9 5 C I ,

1 . 3 1 - 3 . 2 4 ) , a n d 2 . 0 4 f o r b la c ks ( 9 5 C I , 1 . 2 5 - 3 . 3 5 ) .

K n o w n r is k fa c to r s f o r I C H ( a d v a n c e d a g e , h y p e r t e n -

s i o n , a n d a n t i c o a g u l a t i o n i n t e n s i t y ) w e r e s i m i l a r i n t h e

r a c i a l g r o u p s a n d d i d n o t e x p l a i n t h e e x c e s s i v e r i sk o f

I C H o b s e r v e d in n o n w h i t e s . H o w e v e r , b e c a u s e t h e

s t u d y e x a m i n e d h y p e r t e n s i o n a s a d i c h o t o m o u s v a r i ab l e

( p r e s e n t / a b s e n t ) , t h e r e w a s n o a d j u s t m e n t f o r s t a g e o f

h y p e r t e n s i o n o r a d e q u a c y o f B P c o n t r o l . O t h e r f a c to r s

k n o w n t o a f f e c t I C H r i sk ( e g , a l c o h o l o r i ll ic it d r u g u se )

a n d d r u g i n t e r a c t i o n s b e t w e e n o v e r - t h e - c o u n t e r / h e r b a l

m e d i c a t i o n s a n d w a r f a r i n c o u l d n o t b e a s se s se d . A l so ,

d a y - t o - d a y f l u c t u a t i o n s i n a n t i c o a g u l a t i o n i n t en s i ty , a

p o s s i b l e e x p l a n a t i o n f o r t h e o b se r v e d r a c i a l d i f f e r e n c e s ,

were no t a ssessed .

R e f e r e n c e

Shen AY, Yao IF, Brar SS, et al . Rac ial/eth nic differences

in the r isk ofint racranial hem orrhag e amo ng pat ients wi th

atrial fibrillation.

J A m Coil Cardiol

2 0 0 7 ; 5 0 : 3 0 9 - 3 1 5 .

T H R O M B O E M B O L I S M P R O P H Y L A X I S I N

P E R I P H E R A L A R T E R I A L D I S E A S E

I n W A V E ( W a r f a r i n A n t i p l a t e l e t V a s c u l a r E v a l u a t i o n ) ,

c o m b i n a t i o n a n t i c o a g u l a n t / a n t i p l a te l e t t h e r a p y w a s

n o m o r e e f f e c ti v e t h a n a n t i p l a t e le t t h e r a p y a l o n e

i n p r e v e n t i n g m a j o r C V c o m p l i c a t i o n s . H o w e v e r ,

i t w a s a s so c i a t e d w i t h a n i n c r e a se d r i sk f o r l i f e -

t h r e a t e n i n g b l e e d in g . T w o t h o u s a n d o n e h u n d r e d s ix ty -

o n e p a t i e n t s w e r e r a n d o m i z e d t o r e c e iv e a n a n t i c o a g u -

370


9/13

Updates The AmericanJournal of Geriatric Pharmacotherapy

l a n t (w a r f a ri n o r a c c n o c o u m a r o l ; ta r g e t I N R , 2 . 0 - 3 . 0 )

p lu s a n t i p l a t c l c t t h e r a p y ( a s p ir i n 8 1 - 3 2 5 m g /d , t i c l o p i-

d in e , o r c l o p id o g r e l ) o r a n t i p l a t e l e t t h e r a p y a lo n e . T h e

m e a n d u r a t i o n o f fo l l o w -u p w a s 35 m o n t h s . M I , s t r o k e ,

o r d e a t h f r o m C V c a u s e s o c c u r r e d i n 1 3 2 o f 1 0 8 0

( 12 .2 ) r e ci p ie n t s o f c o m b i n a t i o n t h e r a p y a n d 1 4 4 o f

1 0 8 1 ( 1 3.3 ) r e c ip ie n t s o f a n t i p l a t e l e t m o n o th e r a p y

( R R = 0 . 9 2 ; 9 5 C I , 0 . 7 3 - 1 . 1 6 ; P = N S ) . M I , s t r o k e ,

s e v e r e i s c h e mia , o r d e a th f r o m C V c a u s e s o c c u r r e d i n

172 (15 .9 ) and 188 (1Z4 ) o f the r e spec t ive grou ps

( R R = 0 . 9 1 ; 9 5 C I , 0 . 7 4 - 1 . 1 2 ; P = N S ) . L if e -

t h r e a t e n in g b l e e d in g , w h ic h w a s d e f in e d a s f a t a l o r

i n t r a c r a n i a l b l e e d in g o r b l e e d in g r e q u i r i n g s u r g i c a l

i n t e r v e n t i o n o r t r a n s f u s io n o f a t le a s t 4 u n i t s o f b lo o d

a n d / o r b l o o d p r o d u c t s , i n c l u d in g f r es h - f ro z e n pl a sm a ,

o c c u r r e d i n 4 3 ( 4.0 ) a n d 1 3 ( 1 .2 ) o f c o m b in a t i o n -

th e r a p y a n d a n t i p l a t e l e t - m o n o th e r a p y re c ip i e n ts , re -

s p e c ti v e ly ( R R = 3 . 4 1 ; 9 5 C I , 1 . 8 4 - 6 . 3 5 ; P < 0 . 0 0 1 ) .

R e f e r e n c e

An and S, Yusuf S, Xie C, e t a l , for the W arfar in Anti-

platelet Vascular Evalu ation Trial Investigators. Oral

anticoagulant and antiplatelet therapy and peripheral

arterial disease.

N EnglJ Med. 2007;357:217 22Z

IS E S T R O G E N T H E R A P Y B E N E F I C I A L

I N P R E V E N T I N G C O R O N A R Y

A R T E R Y C A L C I F I C A T I O N I N Y O U N G

P O S T H E N O P A U S A L W O H E N ?

I n a s u b an a l y si s o f th e W H I s t u d y , t h e e f fe c ts o f C E E

0 . 6 2 5 m g / d a n d p l a c e b o o n c o r o n a r y a r te r y c al ci fi ca -

t i o n w e r e c o m p a r e d i n 1 0 6 4 w o m e n w h o h a d u n d e r -

g o n e h y s t e r e c t o m y a n d w o r e a g e d b e t w e e n 5 0 a n d

5 9 y e a r s a t r a n d o m i z a t i o n . T h e m e a n c o r o n a r y a r t e r y

c a l c iu m s c o r e a f t e r c o mp le t i o n o f t h e t r i a l w a s s i g n if i -

c a n t l y lo w e r i n e s t r o g e n r e c ip ie n t s c o m p a r e d w i th p l a -

cebo rec ip ien ts (83 .1 vs 123 .1 , r e spec t ive ly ; P = 0 .02) .

A f t e r a d j u s t m e n t f o r c o r o n a r y r is k fa c t or s , t h e O R s f o r

c o r o n a r y a r t e r y c a l c iu m s c o r es o f > 0 , >1 0 , a n d > 1 0 0 i n

e s t r o g e n v e r s u s p l a c e b o re c ip i e n ts w o r e 0 . 7 8 ( 9 5 C I ,

0 . 5 8 - 1 . 0 4 ) , 0 . 74 ( 0 . 5 5 - 0 . 9 9 ) , a n d 0 . 6 9 ( 0 . 4 8 - 0 . 9 8 ) ,

r e s p e c t i v e l y . T h e c o r r e s p o n d i n g O R s f o r w o m e n w h o

w e r e a t l e a s t 8 0 a d h e r e n t t o t h e a s s ig n e d t h e r a p y w e r e

0 . 6 4 ( P = 0 . 0 1 ) , 0 . 5 5 ( P < 0 . 0 0 1 ) , a n d 0 . 4 6 ( P = 0 . 0 0 1 ) .

F o r c o r o n a r y a r t e r y c a l c iu m s c o r e s > 3 0 0 r e la t iv e t o

s c or es < 1 0 , t h e O R w a s 0 . 5 8 b y i n t e n t i o n - t o - t r e a t

a n a ly s i s ( P = 0 . 0 3 ) a n d 0 . 3 9 i n w o me n w i th a t l e a s t

8 0 a d h e r e n c e ( P = 0 . 0 0 4 ) .

E d i t o r ' s n o t e : T h e s e r e su l t s l e n d s u p p o r t to t h e t i m -

i n g h y p o t h e s i s , w h i c h s u g g e s t s t h a t H R T h a s p o t e n -

t i a l l y b e n e f i c i a l C V e f f e c t s i n y o u n g p o s t m e n o p a u s a l

w o m e n ( a ge < 6 0 y e a rs ) a n d d e t r i m e n t a l C V e f fe c t s i n

o l d e r p o s t m e n o p a u s a l w o m e n ( a g e > 6 0 y e a r s ) . T w o

o n g o i n g s t u d i e s - - K E E P S ( K r o n o s E a rl y E s t r o g e n

P r e v e n t i o n S tu d y ) a n d E L I T E ( E a r ly V e r su s L a t e

I n t e r v e n t i o n T r i a l w i t h E s t r a d i o l ) - - w i l l p r o v i d e a d d i -

t i o n a l d a t a r e g a r d i n g t h i s h y p o t h e s i s . I t i s i m p o r t a n t

t o c o n t i n u e e m p h a s iz i n g th a t H R T s h o u l d n o t b e c o n -

s id e r e d a p r e v e n t i v e t h e r a p y f o r C V d i s e a s e i n w o me n ,

e v e n i n t h o s e w h o a r e p o s t m e n o p a u s a l a n d a g e d

< 6 0 y e a r s , u n t i l m o r e d a t a a r e a v a i l ab l e f o r re v i ew .

R e f e r e n c e

Manson JE , Al l i son MA, Rossouw JE, e t a l , fo r the

W H I and WH I-CA GS Invest iga tors . Es t rogen the ra-

py and coronary-artery calcification.

N Engl J Med.

2007;356:2591-2602.

C L O P I D O G R E L I N C A R D I O V A S C U L A R

D I S E A S E

B a s e d o n a c a r e f u l a n d t h o r o u g h s y s t e m a ti c r e v ie w

c o n d u c t e d b y i n v e st i g at o r s in t h e f i el d o f C V m e d i -

c i n e, t h e f o l l o w i n g k e y p o i n t s c a n b e m a d e r e g a r d i n g

c lo p id o g r e l u s e .

1 . C l o p i d o g r e l m o n o t h e r a p y i s n o m i n a l l y s u p e r i o r

t o a s p i r i n f o r r e d u c in g i s c h e mic v a s c u l a r e v e n t s i n

h ig h - r i s k p a t i e n t s . I t h a s imp r o v e d g a s t r o in t e s t i n a l

t o l e r a b i l i t y b u t i s a s s o c i a t e d w i th e x ce s s ra s h , d i a r r h e a ,

a n d a d v e r s e h e m a t o l o g i c o u t c o m e s ( e g , t h r o m b o t i c

t h r o m b o c y t o p e n i c p u r p u r a , n e u t ro p e n i a) .

2 . C o m p a r e d w i t h a s p i r i n a l o n e , t h e c o m b i n a t i o n

o f c lo p id o g r e l + a s p i r i n i s b e n e f i c i a l i n h ig h - r i s k p a -

t i e n t s ( i e , t h o s e w i t h u n s t a b l e a n g i n a a n d / o r n o n -

S T -e le v at io n M I [ U A / N S T E M I ] , S T - el ev a ti o n M I

[ S T E M I ] , a n d s t e n t i n g ) . L o n g - t e r m b e n e f i t i s d r i v e n

b y r e d u c t i o n s i n n o n f a t a l M I , b u t t h e r e i s l i tt l e im p a c t

o n s t r o k e o r d e a th . Ma jo r b l e e d in g c o mp l i c a t i o n s a r e

inc reased .

3 . C o m p a r e d w i t h c l o p i d o g r el a l o n e , t h e c o m b i n a -

t i o n o f c l o p id o g r e l + a s p i ri n h a s n o b e n e f i t i n t e r ms

o f r e d u c in g i s c h e mic s t r o k e . M a jo r b l e e d in g c o m p l i c a-

t i o n s a r e i n c r e a s e d .

4 . R a n d o m i z e d c o n t r o l l e d t ri a ls c o m p a r i n g c l o p id o -

g r c l a n d t i c l o p id in c h a v e f o u n d n o ma jo r d i f f e r e n c e s

i n e f f ic a c y / to l e r a b il i ty . N o n r a n d o m i z e d s t u d ie s f o u n d

a n i n c r e a s e i n h e ma to lo g i c a d v e r s e e v e n t s w i th t i c l o -

p id in e . T i c lo p id in e i s l e s s e x p e n s iv e t h a n c lo p id o g r e l ,

b u t c l o p i d o g re l is b e t t e r t o l e r a te d a n d m o r e c o n v e n i e n t

( o n c e - d a i l y d o s in g ) .

5 . In c lin ical p ract ice , long - te rm use of dop ido gre l

appea r s to have no bene f i t and i s a ssoc ia ted wi th

an excess r isk of m ode ra te b leeding in pa t ien ts wi th

37


10/13


stable CV disease; thus, such use is not recommended.

Clopidogrel may be used for 1 to 9 months in high-

risk patients with UA/NSTEMI who are at low risk for

bleeding. It may be used for _>1 month with lytic therapy

in patients with STEMI. (There have been no direct

studies in patients with primary percutaneous coronary

intervention [PCI]). Clopidogrel may be used for up to

1 month with bare metal stents and for a longer period

(_>6 months) with drug-eluting stents in patients with PCI.

6. Use of clopidogrel is not recommended as first-

line therapy for patients with cerebrovascular accident,

unless there is a clear indication for clopidogrel (eg,

acute coronary syndrome or stent placement).

Z Preintervention (PCI, coronary artery bypass

grafting [CABG]) treatment with clopidogrel appears

to have no definite benefit. In addition, there is an

increased bleeding risk associated with CABG.

8. Clopidogrel therapy should be stopped at least

5 days and preferably 7 days before elective CABG and

other surgical procedures.

9. Adjunctive use of clopidogrel with glycoprotein

II b/ II Ia inhibitors is effective and safe at a 600-mg dose

in high-risk patients with acute coronary syndromes.

10. The definit ion, prevalence, diagnosis , mecha-

nism, and clinical relevance of clopidogrel resistance

are unclear.

R e f e r e n c e

Eshaghian S, Kaul S, Amin S, et al. Role of clopidogrel

in managing atherothrombotic cardiovascular disease.

Ann Intern Med

2007;146:434-441.

H E P A R I N I N D U C E D T H R O M B O C Y T O P E N I A

A T A T E A C H I N G H O S P I T A L

A retrospective review of recipients ofhepar in and direct

thrombin inhibitor (DTI) therapy was conducted using

hospital records for a 1-year period at a large tertiary-

care hospital. Among 58,814 patient admissions, an

estimated 24,068 patients were exposed to unfraction-

ated heparin, and 133 patients received DTI therapy.

Among the latter, 49 new cases of heparin-induced

thrombocytopen ia (HIT) and 15 cases of suspected

(but unconfirmed) HIT were identified. The overall

incidence of newly recognized HIT was 0.2 . New

cases of HI T occurred in 0.76 of patients receiving

therapeutic doses of intravenous heparin and


11/13

Updates The AmericanJournal of Geriatric Pharmacotherapy

H R = 0 . 7 0 [9 5 C I , 0 . 5 4 - 0 . 9 1 ] v s s u l f o n y l u r e as ) . A

s i m i la r p a t t e r n w a s s e e n i n a t h i r d s t u d y o f m e t f o r m i n .

M e t f o r m i n w a s n o t a s s o c i a t e d w i t h i n c r e a s e d h o s p i t a l

a d m i s s i o n s f o r h e a r t f a i l u r e o r f o r a n y o t h e r c a u s e . I n

4 s t u d i e s , t h e u s e o f g l i t a z o n e s w a s a s s o c i a t e d w i t h

a 1 7 r e d u c t i o n i n a l l- c a u se m o r t a l i t y ( p o o l e d O R =

0 . 8 3 ; 9 5 C I , 0 . 7 1 - 0 . 9 7 ; P = 0 . 0 2 ) . H o w e v e r , g l i ta -

z o n e u s e w a s a s so c i a t e d w i t h a 1 3 i n c r e a s e i n r i sk o f

h o s p i t a l a d m i s s i o n f o r h e a r t f a i lu r e ( p o o l e d O R = 1 .1 3 ;

9 5 C I , 1 . 0 4 - 1 . 2 2 ; P = 0 . 0 0 4 ) . T h e 2 s t u d i e s i n v o l v i n g

s u l fo n y l u r e a s h a d c o n f l i c t i n g r e s u l ts , p r o b a b l y b e c a u s e

o f d if f e re n c e s in t h e c o m p a r a t o r t r e a t m e n t s . I t s h o u l d

b e n o t e d t h a t a l l 8 s t u di e s h a d i m p o r t a n t l i m i t a t i o n s.

R e f e r e n c e

Eur ich DT , M cAl i s te r F A, B lackburn D F , e t a l. Benef i ts

and ha rm s of an t id iabe t i c agen t s in pa t i en t s wi th d ia -

betes an d h eart fa ilure: Sys tematic review. BMJ. 2 0 0 7 ;

3 3 5 : 4 9 Z

C A L C I U M A N D V I T A M I N D D O S E S F O R

O S T E O P O R O T I C F R A C T U R E S

A m c t a - a n a l y s i s o f 2 9 r a n d o m i z e d t ri a ls in c l u d i n g a

t o t a l o f 6 3 , 8 9 7 s u b j e c ts e v a l u a t e d t h e u s e o f c a l c i u m o r

c a l c i u m + v i t a m i n D s u p p l e m e n t a t i o n t o p r e v e n t fr a c -

t u r e s a n d b o n e l o s s i n p e o p l e a g e d > 5 0 y e a r s . I n t h e

1 7 t r ia l s t h a t r e p o r t e d f r a c t u r e a s a n o u t c o m e ( n =

5 2 , 6 2 5 ) , t r e a t m e n t w i t h c a l c iu m a n d v i t a m i n D w a s

a s s o c i a t ed w i t h a 1 2 r e d u c t i o n i n f r a c t u r e s o f a ll t y p e s

( r is k r a t io = 0 . 8 8 ; 9 5 C I , 0 . 8 3 - 0 . 9 5 ; P < 0 . 0 0 1 ) . I n

t h e 2 3 t r ia ls t h a t r e p o r t e d B M D a s a n o u t c o m e ( n =

4 1 , 4 1 9 ) , t r e a t m e n t w i t h c a l c iu m a n d v i t a m i n D w a s

a s s o c i a t ed w i t h a n 0 . 5 4 r e d u c t i o n i n t h e r at e o f b o n e

l o ss a t t h e h ip (9 5 C I , 0 . 3 5 - 0 . 7 3 ; P < 0 . 0 0 1 ) a n d a

1 . 1 9 r e d u c t i o n i n t h e r a t e o f b o n e l o ss i n t h e s p i n e

( 9 5 C I , 0 . 7 6 - 1 . 6 1 ; P < 0 . 0 0 1 ) . T h e f r a c t u r e r i sk

r e d u c t i o n w a s 2 4 g r e a t e r i n t ri a ls i n w h i c h c o m p l i -

a n c e w a s _ >8 0 ( P < 0 . 0 0 1 ) . T h e t r e a t m e n t e f f e c t w a s

g r e a t e r w i th a n e l e m e n t a l c a l c iu m d o s a g e _ > 12 00 m g / d

c o m p a r e d w i t h < 1 2 0 0 m g / d ( ri sk r a ti o = 0 . 8 0 v s

0 . 9 4 , r e s p e c t iv e l y ; P = 0 . 0 0 6 ) a n d a v i t a m i n D d o s a g e

_ >8 00 I U / d c o m p a r e d w i th < 8 0 0 I U / d ( ri sk r a ti o =

0 . 8 4 v s 0 . 8 7 , r e s p e c t i v e l y ; P = 0 . 0 3 ) . T h u s , i n p a t i e n t s

a g e d _ >5 0 y e a r s w h o a r e a t r i s k f o r o s t e o p o r o t i c f r a c -

t u r e s , t h e e l e m e n t a l c a l c i u m d o s e s h o u l d b e a t l e a s t

1 2 0 0 r a g / d ; i f v i t a m i n D i s n e e d e d , t h e d o s e s h o u l d b e

a t l e as t 8 0 0 I U / d .

R e f e r e n c e

Tang BM, Es l ick GD , No wso n C , e t a l . Use o f ca lc ium or

ca lc ium in com bina t ion wi th v i t am in D supplem enta t ion

to pre vent fractures and b one loss in peop le aged 50 years

and older: A meta-analysis. Lancet. 2007;370:657 666.

I S V I T A M I N D A L IF E S A V E R ?

A r e c e n t m c t a - a n a ly s i s e v a l u a t e d 1 8 r a n d o m i z e d c o n -

t r o l l e d tr ia ls o f v i t a m i n D s u p p l e m e n t a t i o n t h a t e n r o l l e d

a to t a l o f 5 7 , 3 1 1 p a r t i c ip a n t s a n d i n v o l v e d 4 7 7 7 a ll -

c a u s e d e a t h s o v e r a m e a n s t u d y f o l l o w - u p p e r i o d o f

5 . 7 y e a r s . I n t h e 9 t r i a l s t h a t m e a s u r e d s e r u m c o n c e n -

t r a t io n s o f th e a c t i v e v i t a m i n D m e t a b o l i t e , t h e r e w a s

a 1 . 4- t o 5 . 2 - f o l d d i f f e re n c e in s e r u m c o n c e n t r a t i o n s

o f 2 5 - h y d r o x y v i t a m i n D 3 b e t w e e n t h e i n t e r v e n ti o n

( v i t a m i n D s u p p l e m e n t a t i o n ) a n d c o n t r o l g r o u p s . T h e

s u m m a r y R R f o r d e a th f r o m a n y c a u se w a s 0 .9 3 ( 95

C I , 0 . 8 7 - 0 . 9 9 ) , r e p r e s e n t i n g a si g n if i ca n t ( a l t h o u g h

m o d e s t ) 7 r e d u c t i o n i n m o r t a l i t y i n r e c i p ie n t s o f

v i t a m i n D . T h e r e w a s n o i n d i c a t i o n o f s t a ti s ti c a l h e t -

e r o g e n e i t y o r p u b l i c a t i o n b i a s . C a l c i u m s u p p l e m e n -

t a t i o n d i d n o t a l t e r t h e s u m m a r y R R f o r v i t a m i n D

s u p p l e m e n t a t i o n .

E d i t o r ' s n o t e : T h e s e d a t a ra is e a n u m b e r o f q u e s -

t i o n s . C o u l d t h e 7 m o r t a l i t y r e d u c t i o n b e i n c r e a s e d

b y h ig h e r v i t a m i n D i n t a k e , h i g h e r s e r u m 2 5 - h y d r o x y -

v i t a m i n D c o n c e n t r a t i o n s , a l o n g e r p e r i o d o f su p p l e -

m e n t a t i o n , o r i m p r o v e d a d h e r e n ce ? W h i c h c a u s es o f

d e a t h a c c o u n t e d f o r t h e r e d u c e d m o r t al i ty ? W h a t w e r e

t h e m e c h a n i s m s o f t h is b e n e f it ? W a s t h e m o r t a l i t y r e d u c -

t i o n s e a s o n al ( i c, p r i m a r i l y i n w i n t e r , w h e n v i t a m i n D

l e v e ls t y p i c a l ly fa ll )? C e r t a i n l y , f u r t h e r r e s e a r c h i s n e e d e d

t o e l u c i d a te t h e s p e ci f ic b e n e f it s a n d t h e o p t i m a l i n t a k e

a n d s e r u m m e t a b o l i t e c o n c e n t r a t i o n s . N o n e t h e l e s s , a

m o r e p r o a c t i v e a p p r o a c h t o t h e i d e n t i f i c a t i o n , p r e v e n -

t i o n , a n d t r e a t m e n t o f v i t a m i n D d e f i c ie n c y s h o u l d

b e c o m e a c o m p o n e n t o f r o u t i n e m e d i c a l ca r e.

R e f e r e n c e

Aut ie r P , Gandin i S . Vi tam in D supplem enta t ion and

t o t a l m o r t a l i t y : A m e t a - a n a ly s i s o f r a n d o m i z e d c o n -

trol led t r ia ls . Arch Intern Med. 2007;167:1730 173Z

F I R S T A P P R O V E D P R E S C R I P T I O N

A D H E R E N C E D E V I C E

O n J u n e 2 1 , 2 0 0 7 , t h e F D A a p p r o v e d E M M A

( E l e c tr o n i c M e d i c a t i o n M a n a g e m e n t A s s is t an t ,

I N R a n g e S y s t em s , In c . , A l t o o n a , P e n n s y l v a n ia ) , a p r o -

g r a m m a b l e s t o r a g e a n d d i s p e n s i n g d e v i ce f o r u s e i n th e

h o m e s e t ti n g . T h i s c o m p u t e r i z e d m e d i c a t io n b o x w a s

d e s i g n e d f o r u s e u n d e r t h e s u p e r v i s i o n o f a l i c e n s e d

h e a l t h c a r e p r o v i d e r . T h e F D A f e l t t h a t t h i s d e v i c e

c o u l d b e p a r t i c u l a r l y u s e f u l f o r o l d e r p a t i e n t s a n d

t h o s e t a k i n g c o m p l e x r e g i m e n s ( e g , t h o s e i n f e c t e d w i t h

7


12/13

The Am erican Jou rnal od Geriatric Pharma cotherapy Up date s

HIV). The device is categorized as a remote medica-

tion managcmcnt systcm in Class II (spccial controls).

R e f e r e n c e

US Food and Drug Administration, HHS. Medical

devices; general hospital and personal use devices; classi-

fication of remote medication management system. Final

rule.

Fed Regist.

2007;72:59175-59177.

P H A R M A C O G E N O M I C S R E A C H E S

T H E C L I N I C

Personalized medicine, in which prescribers take the

pharmacokinetic/pharmacodynamic effects of an indi-

vidual's genetics into account, has finally entered the

clinic. For the first time, pharmacogenomic information

is cited in the prescribing information for a widely used

drug. The labeling for warfarin now contains infor-

mation regarding the effects of variation in 2 genes,

onc affecting warfarin mctabolism ( C Y P 2 C 9 ) and thc

othcr affecting its pharmacodynamics (VKORC1). Thc

revised product labeling provides guidance on how to

apply this information. Ongoing thcrapy should always

be guided by continued monitoring of the INR.

R e f e r e n c e

New labeling information for warfarin (marketed as

Coumadin). h t t p : / / w w w . f d a . g o v / c d e r / d r u g / i n f o p a g e /

warfarin/default.htm. Accessed November 1, 2007.

The FDA has approved the Verigene Warfarin

Metabolism Nucleic Acid Test (Nanosphere, Inc.,

Northbrook, Illinois) for use in identifying patients

with variants of

C T P 2 C 9

and

V K O R C 1 .

This test is not

intended to be a stand-alone tool for determining the

optimal dosage of warfarin, but is to be used together

with clinical evaluation and other tools (including INR)

to determine the best treatment for patients.

R e f e r e n c e

FDA clears genetic lab test for warfarin sensitivity,http://

w w w . f d a . g o v / b b s / t o p i c s / N E W S / 2 O O T / N E W O 1 7 0 1 .

html. Accessed November 1, 2007.

W A R F A R I N A N D D I E T A R Y S U P P L E M E N T S

In a prospective, longitudinal study of 171 adults com