L.A. Kalish et al.

/ Controlled Clinical Trials 25 (2004) 76C1030

!i". 3. Locations o# a$ric$lar ac$%$nct$re %oints. &ne ear 'as needled d$rin" each treat(ent) alternatin" ears at
consec$ti*e *isits. Control %oints are indicated +, #illed trian"les) ) and are la+eled in italics (t'o needles). -tandardi.ed
%oints are indicated +, +$ll/0s e,es) (t'o needles). 1atients in the indi*id$ali.ed treat(ent "ro$% 'ere needled in t'o
locations selected #ro( a(on" the indi*id$ali.ed (#illed circles) ) and/or standardi.ed (+$ll/0s e,es) ) %oints. -ee &leson
2553 ) 4$an" 2563 and Ta+le 5 #or %recise descri%tions o# anato(ic locations.
5a,#air 5edical) 4on" Kon"). 6e are not a'are o# relia+ilit, or *alidit, st$dies o# this instr$(ent.
4o'e*er) i t i s i n 'ides%read $se a(on" %ractitioners o# a$ric$lar ac$%$nct$re. The t'o (ost
acti*e %oints constit$ted the /7/7%rescri%tion/0/0 #or indi*id$ali.ed a$ric$lar ac$%$nct$re.
6.6. Ac$%$nct$re needlin"
1atients 'ere "i*en an o%%ort$nit, to as8 the ac$%$nct$rists 9$estions related to the
%lace(ent o# needles onl,. :isc$ssion a+o$t the %atient/0s +lood %ress$re) treat(ent "ro$%) or
the location o# %oints 'as %rohi+ited. All st$d, ac$%$nct$re occ$rred in %ri*ate treat(ent roo(s.
The %atients re(o*ed their o$ter clothin" incl$din" shoes and stoc8in"s. A clean sheet 'as
%ro*ided to co*er the %atient and s$%%orti*e rolls or %illo's 'ere $sed #or %atient co(#ort. The
s8in 'as cleaned 'ith an alcohol 'i%e o*er the needlin" locations +e#ore the ac$%$nct$re needle
'as inserted. :$rin" the #irst ac$%$nct$re *isit) the ac$%$nct$rist de(onstrated the %oint locator
on his/her o'n hand +e#ore $sin" it on the %atient/0s ear.
T' o t,%es o# needles 'ere $sed) needles 'ith and 'itho$t "$ide t$+es (-eirin Kasei) -hi(i.$)
;a%an< Car+o) -$.ho$) China). The choice 'as le#t $% to the treatin" ac$%$nct$rist. All needles
'ere sterile) dis%osa+le (one ti(e $se onl,)) and (ade o# s$r"ical="rade stainless steel. -i.es
$tili.ed are sho'n in Ta+le 4 (#ootnote a).
1atients in all three treat(ent "ro$%s recei*ed a$ric$lar ac$%$nct$re in t'o locations at e*er,
treat(ent session. A$ric$lar ac$%$nct$re 'as $nilateral at each *isit) 'ith the side alternatin"
+et'ee
n
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004) 76C103 1
le#t and ri"ht ears at consec$ti*e treat(ent *isits. The startin" ear 'as
chosen rando(l,. > # i t 'as not %ossi+le to alternate ears (#or e?a(%le in the
case o# local in#la((ation or other irritation)) the sa(e ear 'as $sed as
d$rin" the %re*io$s treat(ent *isit.
6.6.1. >ndi*id$ali.ed ac$%$nct$re The indi*id$ali.ed ac$%$nct$re "ro$%
recei*ed cor%oreal ac$%$nct$re treat(ent accordin" to the
%rescri%tion (locations and (ethods o# sti($lation) (ade +, the dia"nosin"
ac$%$nct$rist. ># the %rescri%tion incl$ded onl, anterior cor%oreal %oints) the
%atient 'as needled in the s$%ine %osition. @eedles 'ere retained #or 30 (in
and sti($lated accordin" to the %rescri%tion at the ti(e o# initial insertion)
and a"ain at 10 and 20 (in. ># +oth anterior and %osterior %oints 'ere
%rescri+ed) anterior %oints 'ere needled #irst (s$%ine %osition) and retained
#or 20 (in 'ith the %rescri+ed needle sti($lation at the ti(e o# initial
insertion and at 10 (in. The needles 'ere then re(o*ed and the %atient
%laced in the %rone %osition. The %osterior %oints 'ere then needled and
retained #or 10 (in) 'ith the %rescri+ed needle sti($lation at the ti(e o#
insertion. -ee Ta+le 4 and !i". 2 #or s%eci#ic in#or(ation re"ardin" needle
de%th) an"le o# needle insertion and %oint locations. A$ric$lar ac$%$nct$re
locations 'ere deter(ined +, the treatin" ac$%$nct$rist as descri+ed a+o*e.
A$ric$lar ac$%$nct$re needles 'ere inserted %rior to cor%oreal needles. All
a$ric$lar %oints 'ere needled $nilaterall, $sin" 15 (( lon") 0.20 ((
dia(eter needles that 'ere inserted 'itho$t sti($lation) %er%endic$lar to the
s8in to a de%th o# 1 C 2 (( or dee% eno$"h to +e en"a"ed sec$rel, in
s$+c$taneo$s tiss$e and retained 'itho$t sti($lation d$rin" the 30=(in
treat(ent %eriod (see !i". 3).
6.6.2. -tandardi.ed ac$%$nct$re -tandardi.ed cor%oreal ac$%$nct$re
consisted o# 5 +ilateral cor%oreal %oints (total o# 10 %oints))
needled in the s$%ine %osition $sin" a ne$tral (ethod o# sti($lation
(o+tainin" /7/7de 9i/0/0 'itho$t an, #$rther sti($lation). At 10) 20 and 30
(in) the ac$%$nct$rist to$ched each cor%oreal needle +$t did not sti($late
the needles. The ac$%$nct$re %oints 'ere L> 11 ) - T 36) AB 20) LC 03 and
-1 06. -ee Ta+le 4 and !i". 2 #or s%eci#ic in#or(ation re"ardin" an"le o#
needle insertion) de%th and location o# %oints.
T' o a$ric$lar needles) 4eart and ;ian" Da Ao$) 'ere inserted %rior to
cor%oreal needlin") 'itho$t sti($lation and retained #or 30 (in (see !i". 3 ).
6.6.3. Control ac$%$nct$re 1atients rando(i.ed to the control ac$%$nct$re
"ro$% had 5 cor%oreal locations needled +ilaterall,
(total o# 10 %oints) and 2 a$ric$lar locations needled $nilaterall, at each
*isit. -ee Ta+le 5) !i"s. 2 and 3 #or anato(ic descri%tions o# the locations.
&$r (ain o+Eecti*es in desi"nin" the control treat(ent 'ere to choose
non=ac$%$nct$re %oints 'e tho$"ht to +e the least reacti*e 'hile
(aintainin" (as8in" as +est as %ossi+le. The #ollo'in" criteria "$ided o$r
choices o# control %oints
F




not +e considered acti*e accordin" to TC5 theor,)
in the sa(e *icinit, o# the standardi.ed and (ost co((onl, $sed
indi*id$ali.ed %oints)
distant #ro( %oints tho$"ht to ha*e an e##ect o n the cardio*asc$lar and
s,(%athetic ner*o$s s,ste()
%oints on the e?tre(ities sho$ld incl$de locations a+o*e the el+o' and
8nee (considered to +e less reacti*e than %oints +elo' el+o's and 8nees
accordin" to TC5 9i circ$lation theor,))
sho$ld +e needled *er, shallo'l, 'ith no sti($lation 'hatsoe*er) and
the n$(+ers o# %oints sho$ld (atch the standardi.ed "ro$%
.
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004) 76C1032
Ta+le 5 Control treat(ent "ro$% %oint s%eci#ications
aLe" s$%ine head o# the #i+$la a%%ro?i(atel, 4 in. do'n the le" #ro(
the head o# the #i+$la) then hal# the distance #ro( the BL to AB
channel on the %osterolateral le" to'ard the +ell, o# the (.
"astrocne(i$s
!oot s$%ine
3rd and 4th
(etatarsals
a%%ro?i(atel
, 1.0 C 1.5
in. a+o*e the
3rd and 4th
'e+ s%ace
+et'een the
3rd and 4th
(etatarsals+
et'een BL
and AB
(eridians
near AB
41
+et'een
AB and -T
(eridian
s+6ith
ar(s
#le?ed)
%al(s
do'n.
c@ot a%%lica+le (a$ric$lar needles sho$ld +e in %lace d$rin" +oth
s$%ine and %rone %ositions).
>n all cor%oreal locations) needles 'ere inserted %er%endic$lar to the s8in
'itho$t sti($lation. -$%ine cor%oreal %oints 'ere to$ched +, the
ac$%$nct$rist at 10 (in and 'ithdra'n at 20 (in. The %atient 'as then
t$rned o*er to lie %rone and the re(ainder o# the cor%oreal needles inserted.
A#ter an additional 10 (i n ( 3 0 (i n tot a l ti (e ) ) th e n e e d l e s ' e re to
$c hed an d r e ( o * e d ' i t h o$ t s t i ( $ la ti on. A$ ri c $la r
ac$%$nct$re needles 'ere inserted %rior to cor%oreal needlin") 'itho$t
sti($lation and 'ere retained 'itho$t sti($lation d$rin" the 30=(in
treat(ent %eriod.
7. Blood %ress$re (eas$re(ent
>n order to red$ce /7/7'hite coat h,%ertension)/0/0 st$d, n$rses certi#ied
+, the @GC> too8 nearl, all o# the st$d, +lood %ress$re (eas$re(ents
2573. -t$d, %h,sicians 'ere allo'ed to ta8e +lood %ress$res #o
rThi"h
%rone+%o%lite
al #ossa a%%ro?i(atel, 4 in. a+o*e the %o%liteal #ossa)
then hal# the distance #ro( the BL to the AB channel
on the %osterolateral thi"h+et'een BL and AB
(eridians
Ar( %rone+
!orear(
%rone+olecranon
and (edial
e%icond,le o# the
h$(er$s
(edial e%icond,le o# the
h$(er$sa%%ro?i(atel, 4 in.
a+o*e the olecranon %rocess
and hal# 'a, to'ard the (edial
e%icond,le
e?tensor
s$r#ace o#
the #orear(
(id'a,
+et'een T4
and ->
H+et'een ->
and T4
(eridians
+et'een
-> and T4
(eridian
s1oint 1atient %ositionAnato(ic land(ar8 1oint location Celationshi% to (eridians
Gar @/Ac
Gar
@/Ac:ar
'in/0s
t$+ercle
s$%erior
and
(edial
to
:ar'in/
0s
t$+ercle)
at the
(ost
s$%erior
%ortion
o# the
sca%hoi
d #ossa)
+et'een
the heli?
and the
antiheli?
%osterior ear lo+e on the %osterior earlo+e) in the (ost
s$%erior and (edial %ortion o# the lo+e< +o$nded
s$%eriorl, +, the (ost in#erior %ortion o# the %osterior
"roo*ein the a$ric$lar area #or #in"er %oints
no na(ed
%oints in this
are
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004) 76C103 3
clinical %$r%oses) s$ch as 'hen (onitorin" a %atient ta%erin" or res$(in"
antih,%ertensi*e (edication) +$t 'ere disco$ra"ed #ro( ta8in" other st$d,
(eas$re(ents.
1atients 'ere as8ed to +are their ri"ht ar(s #or the +lood %ress$re
(eas$re(ent. ># the slee*e 'as ti"ht) the %atient 'as as8ed to re(o*e his or
her shirt or %$ll the ar( o$t o# the slee*e. A "o'n 'as (ade a*aila+le i# the
%atient #elt (ore co(#orta+le $sin" one. 1$lse and +lood %ress$re
(eas$re(ents 'ere (ade a#ter the %atient had +een seated 9$ietl,) 'ith
+ac8 s$%%orted and #eet #lat on the #loor) i n an erect +$t co(#orta+le %ost$re
#or at least 5 (in. The %atient re(ained seated in this #ashion $ntil all
re%licate +lood %ress$re (eas$re(ents 'ere co(%leted) 'aitin" at least 2
(in +et'een re%licate (eas$re(ents.
-t$d, (eas$re(ents 'ere (ade $sin" n$(+ered Ba$(ano(eter 'all=
(o$nted (erc$r, s%h,"(o(ano(eters (6.A. Ba$( and Co.) Co%ia"$e)
@D) that 'ere certi#ied ann$all,. &nce a %atient co(%leted screenin") st$d,
n$rses did not disc$ss (eas$re(ents 'ith the %atient or the ac$%$nct$re
sta##. At each st$d, *isit) the o##icial +lood %ress$re (eas$re(ents 'ere
co(%leted +e#ore other (eas$res) i.e.) %h,sical e?a( and co(%letion o#
sel#=ad(inistered 9$estionnaires. 1atients 'ho ate) s(o8ed) in"ested
ca##eine or e?ercised d$rin" the ho$r %rior to a +lood %ress$re (eas$re(ent
'ere as8ed to ret$rn a#ter an ho$r had %assed.
-tandardi.ed %roced$res 'ere $sed to deter(ine the (id%oint o# the
$%%er ar() (eas$re ar( circ$(#erence at this (id%oint) deter(ine +lood
%ress$re c$## si.e) a%%l, the c$##) deter(ine %ea8 in#lation le*el and (eas$re
+lood %ress$re 223. &rdinaril,) three re%licate +lood %ress$re (eas$re(ents
'ere ta8en at each *isit) the #irst re%licate readin" dro%%ed) and the +lood
%ress$re #or that *isit calc$lated as the a*era"e o# the second and third
readin"s. ># the second and third s,stolic or second and third diastolic
%ress$res di##ered +, 6 ( ( 4 " o r (ore) t'o additional (eas$res 'ere
ta8en) #or a total o# #i*e) and the second thro$"h #i#th (eas$re(ents
a*era"ed.
Blood %ress$re (eas$re(ent %roced$res 'ere o+ser*ed %eriodicall, +,
@GC> sta##) and anal,ses o# #inal di"it %re#erences #or each st$d, n$rse 'ere
%er#or(ed %eriodicall, thro$"ho$t the trial in order to (onitor co(%liance
'ith the (eas$re(ent %rotocol.
H. Antih,%ertensi*e (edications
1atients 'ith +lood %ress$res .140 (( 4" s,stolic or . 0 (( 4"
diastolic at the 'ee8 10 st$d, *isit or later 'ere started on
antih,%ertensi*e (edication) ordinaril, an ACG inhi+itor or an"iotensin
rece%tor +loc8er. 4o'e*er) the thera%, co$ld +e indi*id$ali.ed +, the
st$d, %h,sician +ased on the s$+ Ee ct /0s % r i o r ( e dic at i o n his to r,)
+lo o d %re s s$r e r e s %on s e and co nco (i ta n t (e d i c a l %ro +le (s
. Antih,%ertensi*e (edications 'ere initiated i((ediatel, i# the +lood
%ress$re o# an, rando(i.ed st$d, s$+Eect (eas$red . 1H0 (( 4" s,stolic
or . 11 0 ( ( 4 " diastolic. >n addition) antih,%ertensi*es 'ere initiated in
the #irst 10 'ee8s #ollo'in" rando(i.ation i# an ad*erse e*ent de*elo%ed
that 'o$ld +e a(eliorated +, +lood %ress$re red$ction) or i# t'o
consec$ti*e +lood %ress$re (eas$re(ents (at least 7 da,s a%art) o# -B1.
170 or :B1 .105 'ere detected) startin" at the 'ee8 4 *isit or later.
1atients 'ere seen at inter*als o# no "reater than 2 'ee8s $ntil their +lood
%ress$re #ell to +elo' 140 (( 4" s,stolic and 0 (( 4" diastolic. 6ith
these sa#e"$ards in %lace) 'e #elt that it 'as ethical to 'ithhold
(edications #or $% to 3 (onths (incl$din" screenin") 'ith a +lood %ress$re
a+o*e 140/0 (( 4"
.
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004)
76C1034
. Ad*erse e*ents
The incidence o# ad*erse e##ects o# ac$%$nct$re in ($lti%le st$dies is lo'
25H)53. 6e (onitored %atients #or ad*erse e*ents o# an, 8ind) incl$din"
%ossi+le e##ects o# ac$%$nct$re) o# re(ainin" o## o# antih,%ertensi*e
(edications and o# ta8in" antih,%ertensi*es (#or those 'ho 'ent +ac8 on
(edication). An, other $ne?%ected (edical e*ent 'as also recorded.
1atients 'ere as8ed 'hether the, had de*elo%ed an ad*erse e*ent or side
e##ect o# treat(ent each ti(e their +lood %ress$re 'as (eas$red. The
relationshi% o# the ad*erse e*ent to ac$%$nct$re thera%, and/or
antih,%ertensi*e thera%, 'as assessed +, the st$d, %h,sician and n$rses.
-erio$s ad*erse e*ents 'ere de#ined and re%orted accordin" to %olicies o#
the 4$(an Cesearch Co((ittees o# the @GC>) the 5A4 and the @CCA5.
10. Ac$%$nct$re +elie#s
1atients/0 +elie#s or e?%ectations re"ardin" the e##icac, o# a (edical
inter*ention can in#l$ence their treat(ent res%onse 260 C 633. 6e e(%lo,ed
a sel#=ad(inistered instr$(ent +ased on the /7/7treat(ent credi+ilit,
scale/0/0 o # Bor8o*ec and @a$ 2643 to assess +elie#s and e?%ectations
re"ardin" the e##icac, o# ac$%$nct$re #or treatin" h,%ertension. Iario$s
*ersions o# this instr$(ent ha*e +een e(%lo,ed in ac$%$nct$re st$dies 2653 .
Iincent 2663 #o$nd one *ersion to ha*e "ood internal consistenc, and test C
retest relia+ilit,. The three 9$estions e(%lo,ed in -4AC1 'ereF (1) 4o'
con#ident are ,o$ that ac$%$nct$re can control ,o$r +lood %ress$reJ< (2)
4o' con#ident 'o$ld ,o$ +e in reco((endin" ac$%$nct$re treat(ents to a
#riend 'ith hi"h +lood %ress$reJ< and (3) :oes treatin" hi"h +lood %ress$re
'ith ac$%$nct$re (a8e sense to ,o$J Ces%onses 'ere assessed $sin" a
#i*e=%oint Li8ert scale. The instr$(ent 'as ad(inistered d$rin" screenin") at
the 'ee8 2 *isit and at the 'ee8 10 *isit.
11 . Assess(ent o# (as8in"
The s$ccess o# %atient (as8in" 'as assessed 'ith a sel#=ad(inistered
instr$(ent. 1atients 'ere as8ed to indicate 'hich treat(ent "ro$% the,
tho$"ht the, 'ere rando(i.ed to) +, circlin" one o# #o$r choicesF the three
treat(ent "ro$%s and /7/7don/0t 8no'./0/0 > # the, indicated one o# the
three treat(ent "ro$%s) a second 9$estion as8ed ho' con#ident the, 'ere o#
their ans'er (on a 5=%oint Li8ert scale) and a list o# 10 ,es/no 9$estions
addressed 'hich #actors their assess(ent 'as +ased on. Ce%resentati*e
#actors incl$ded chan"e (or lac8 o#) in +lood %ress$re and in o*erall 'ell
+ein") sensations d$rin" ac$%$nct$re) chan"es in $se o# (edication)
location o# ac$%$nct$re %oints and /7/7E$st "$essin"./0/0 The instr$(ent
'as ad(inistered at the (onths 4 and 12 *isits) i.e.) a#ter the %ri(ar,
end%oint 'as assessed.
12. !$nctional health stat$s
!$nctional health stat$s 'as (eas$red in -4AC1 %artici%ants $sin" the
-!=36) a *alidated sel#=re%ort 9$estionnaire that has +een in 'ide $se #or
(ore than a decade 2673 . The -!=36 #oc$ses on ei"ht di(ensions o#
health. 1re*io$s st$dies ha*e sho'n that h,%ertensi*e %atients score
lo'er on the -!=3
6
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004) 76C103
5
than do nor(otensi*e %atients 26H C 703. > n addition to "eneral health)
do(ains (ost consistentl, a##ected are those related to %h,sical
s,(%to(s. A linear relationshi% has +een o+ser*ed +et'een the $se o#
antih,%ertensi*e (edications and #$nctional health stat$s 26H3. -4AC1
%artici%ants 'ere as8ed to co(%lete the -!=36 d$rin" screenin" and at
the 'ee8 10 and (onth 12 *isits.
13. -ched$le o# (eas$re(ent
Ta+le 6 sho's the sched$le o# ac$%$nct$re treat(ents and st$d,
assess(ents d$rin" the rando(i.ed trial. -ched$lin" o# ac$%$nct$re is
descri+ed a+o*e. Blood %ress$re 'as (eas$red e*er, 2 'ee8s $ntil the
'ee8 10 *isit) then at (onths 4) 6) and 12. 5ore #re9$ent +lood
%ress$re (eas$re(ents 'ere (ade as clinicall, indicated.
Co(%rehensi*e %atient e*al$ations 'ere %er#or(ed at the 'ee8 10 and
(onth 12 *isits.
The tar"et dates #or all *isits 'ere (eas$red #ro( the #irst da, o#
ac$%$nct$re. Iisit 'indo's 'ere esta+lished aro$nd the tar"et dates #or
each *isit. !or *isits thro$"h 'ee8 10) each 'indo' e?tended #ro( 6
da,s %rior to 7 da,s a#ter the tar"et date. !or later *isits) each 'indo'
e?tended #ro( 1 (onth %rior to 1 (onth a#ter the tar"et date.
14. -tatistical considerations
A (ini($( sa(%le si.e o# 1H0 rando(i.ed %atients 'as esta+lished
on an ad hoc +asis #or this %ilot st$d,. Altho$"h not desi"ned to e*al$ate
e##icac, de#initi*el,) i t i s $se#$l to %roEect the (a"nit$de o# treat(ent
e##ects that this and lar"er sa(%le si.es 'o$ld +e a+le to detect 'ith hi"h
%ro+a+ilit,.
Ta+le 6
-ched$le o#
treat(ent and
st$d,
assess(ents
a- c r e e n i n "
6 e e 8 5 o n t h
1 2 3 4 5 6 H
1 0 4 6 1 2
Ac$%$nct$re treat(ent+ccK K K K K K
B l o o d % r e s s $ r e
K K K K
a># the %atient dro%%ed o$t o# the st$d, %rior to (onth 12) the (onth 12 assess(ents 'ere to
+e co(%leted at the ti(e o# dro%o$t.
+>deall,) t'ice %er 'ee8 #or 6 'ee8s. 4o'e*er) i # this co$ld not +e adhered to) treat(ent
co$ld e?tend to H 'ee8s in order to co(%lete as (an, as %ossi+le o# 12 ac$%$nct$re
treat(ents.
cAt 'ee8s 2 and 6F +oth a standard (%re=ac$%$nct$re) and %ost=ac$%$nct$re
+lood %ress$re 'ere (eas$red.
dLa+orator, assess(ent incl$ded co(%lete +lood co$nt) $rinal,sis) creatinine) +lood $rea
nitro"en) electrol,tes) #astin" +lood s$"ar and li%id %ro#iles
.
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004)
76C1036
6ith three treat(ent "ro$%s) there are t'o de"rees o# #reedo( #or
treat(ent co(%arisons. :enotin" CtlLcontrol) -tdLstandardi.ed and
>ndLindi*id$ali.ed) the #ollo'in" t'o ortho"onal contrasts 'ere
%res%eci#ied as +ein" o# %ri(ar, i(%ortance
F
Ctl *ers$s (-tdM>nd)F control *ers$s acti*e (standardi.ed and
indi*id$ali.ed co(+ined))
-td *ers$s >ndF standardi.ed *ers$s indi*id$ali.ed
.The %o'er calc$lations are +ased on the chan"e in +lood %ress$re #ro(
+aseline to 'ee8 10. An esti(ate o# the standard de*iation o# the chan"e in
+lood %ress$re is re9$ired to %er#or( the calc$lations. 6e $sed +aseline
and 3=(onth +lood %ress$re (eas$re(ents #ro( o*er 4000 %atients in the
5edical Cesearch Co$ncil (5CC) h,%ertension trial #or older %atients 2713 to
%ro*ide these esti(ates (-. 1ococ8) %ersonal co(($nication). A#ter
re(o*in" the treat(ent e##ects and adE$stin" #or +aseline *al$es +, anal,sis
o# co*ariance) the %atient=to=%atient standard de*iations o# chan"e in -B1
and :B1 'ere 16.6 and .H (( 4") res%ecti*el,. Ta+le 7 sho's the
e?%ected di##erences in +lood %ress$re chan"e that 'o$ld +e detected 'ith
H5N %o'er) $sin" an anal,sis adE$sted #or +aseline *al$e and a t'o=sided
aL0.05 test.
Ta+le 7 ill$strates that the %ilot trial 'ill onl, ha*e hi"h statistical %o'er i#
there are #airl, lar"e treat(ent e##ects) #or e?a(%le i# the e?%ected -B1
red$ction 'ith acti*e ac$%$nct$re is H.53 (( 4" "reater than 'ith control
ac$%$nct$re. A total sa(%le si.e o# 00 'o$ld %ro*ide "ood %o'er i# this
treat(ent di##erence is 3.H2 (( 4".
The %ri(ar, e##icac, anal,sis 'ill co(%are treat(ent "ro$%s 'ith res%ect
to +lood %ress$re chan"e #ro( +aseline to 10 'ee8s. All rando(i.ed
%atients 'ith a*aila+le o$tco(e data 'ill +e incl$ded in this anal,sis and
%atients 'ill +e classi#ied accordin" to their ori"inal treat(ent assi"n(ent)
accordin" to the intention=to=treat %rinci%le 2723. The si(%lest co(%arison is
'ith a t'o=sa(%le t test. 6e e?%ect the distri+$tion o# chan"e scores to +e
a%%ro?i(atel, nor(all, distri+$ted. 4o'e*er) non%ara(etric anal,sis 'ill +e
$sed to chec8 ro+$stness o# the concl$sions. !$rther anal,ses) adE$stin" #or
+aseline co*ariates (incl$din" +aseline +lood %ress$re) 'ill $se anal,sis o#
co*ariance.
Ta+le 7 Treat(ent "ro$% di##erence ( ,) (
( 4") detecta+le 'ith H5N %o'er
Total sa(%le si.e 1H0 360 540 720 00
-,stolic +lood %ress$re Ctl *ers$s (-tdM>nd) H.53 6.03 4.3 4.27 3.H1 -td *ers$s >nd .H
6.7 5.6 4.3 4.41
:iastolic +lood %ress$re Ctl *ers$s (-tdM>nd) 5.04 3.56 2.1 2.52 2.25 -td *ers$s >nd 5.H7
4.11 3.36 2.1 2.60
CtlLcontrol) -tdLstandardi.ed) >ndLindi*id$ali.ed. 6e ass$(ed standard de*iations #or
s,stolic +lood %ress$re and diastolic +lood %ress$re) adE$sted #or +aseline *al$e) o# 16.6
and .H (( 4") res%ecti*el,) and loss o# 15N o# end%oint data d$e to %atient dro%o$t and
loss to #ollo'=$%. !or e?a(%le) 'ith 1H0 %atients) and ass$(in" 15N (issin" data (153
e*al$a+le %atients)) i# %atients recei*in" TC5=+ased ac$%$nct$re (-tdM>nd) ha*e an
e?%ected H.53 (( 4" "reater decline in s,stolic +lood %ress$re than %atients recei*in"
control ac$%$nct$re) there 'ill +e an H5N chance o# declarin" this treat(ent contrast
si"ni#icant $sin" a t'o=sided aL0.05 test
.
L.A. Kalish et al. / Controlled Clinical Trials 25 (2004) 76C103 7
>n addition to e?%lorator, and "ra%hical (ethods) (i?ed e##ects (odels
2733 'ill +e $sed to (odel the traEector, o# +lood %ress$re o*er ti(e. These
(odels can incl$de nonlinear traEectories) interaction ter(s +et'een ti(e
and treat(ent to allo' di##erent traEectories #or the di##erent treat(ent "ro$%s)
+aseline co*ariates to adE$st #or %atient characteristics and ti(e=*ar,in"
co*ariates) #or e?a(%le to (odel the e##ects o# introd$cin" con*entional
(edications. The "oal is to descri+e the +lood %ress$re traEector, o*er ti(e
'hile adE$stin" a%%ro%riatel, #or #i?ed and ti(e=*ar,in" co*ariates and #or
intras$+Eect correlation.
A %otential %ro+le( that (a, +e ind$ced +, the introd$ction o#
con*entional (edical treat(ent is the %ossi+ilit, that the e##ects o# treat(ent
on +lood %ress$re co$ld (as8 an e##ect o # ac$%$nct$re. !or e?a(%le) i# the
standardi.ed and indi*id$ali.ed ac$%$nct$re treat(ents tr$l, do control
+lood %ress$re +etter than the control ac$%$nct$re treat(ent) +$t (ore
%atients in the control "ro$% "o on con*entional thera%,) 'hich itsel# lo'ers
+lood %ress$re) 'e co$ld o+ser*e no di##erence +et'een the "ro$%s. &ne
a%%roach is to carr, the last (eas$re(ent ta8en +e#ore con*entional
thera%, #or'ard to s$+se9$ent *isits. Another a%%roach to +e e?%lored is
o$tlined +, 6hite et al. 2743 . Brie#l,) a n ass$(%tion is (ade that) i# %atients
on con*entional treat(ents 'ere not treated) their +lood %ress$res 'o$ld +e
a+o*e the "ro$% (edian. The (edian is then $sed as a (eas$re o# location
(rather than the (ore con*entional (eas$re) the (ean) and anal,.ed 'ith
statistical (ethods) 'hich are in*ariant to the sha%e o# the distri+$tion a+o*e
the (edian) #or e?a(%le 9$antile re"ression 2753.
The n$(+er o# %atients 'ho start antih,%ertensi*e (edications o*er ti(e
'ill +e ta+$lated. 1artic$lar attention 'ill #oc$s on the %ercenta"e o# %atients
'ho (eet %rotocol criteria #or res$(in" antih,%ertensi*e (edications +e#ore
or at the 'ee8 10 *isit. >n addition) ti(e=to=e*ent (ethods 'ill +e $sed to
descri+e the %ercenta"e 'ho start (edications o*er ti(e.
G?%lorator, s$+"ro$% anal,ses 'ill incl$de treat(ent co(%arisons 'ithin
s$+"ro$%s #or(ed #ro( +aseline characteristics s$ch as TC5 dia"nostic
"ro$%) antih,%ertensi*e (edication histor, and "ender.
15. -creenin" e?%erience
-creenin" +e"an in 5arch 2001 and ended in ;$l, 2002. >nitial contact
'as doc$(ented #or 1442 %ros%ecti*e %artici%ants o# 'hich 5 (6N)
$nder'ent the #or(al screenin" inter*ie') 424 (2N) "a*e in#or(ed consent
and 12 (13N) 'ere $lti(atel, rando(i.ed.
1ros%ecti*e %artici%ants 'ere as8ed ho' the, heard a+o$t the st$d,. A
recr$it(ent so$rce 'as o+tained #or H7N. A(on" these) the re%orted
so$rces 'ere %rint (edia (35N< (ostl, ad*ertise(ents and an article in the
local %ress)) (ailin"s (2HN< (ostl, #ro( a %ostcard (ass=(ailin"
ca(%ai"n)) tele*ision ne's re%orts a+o$t the st$d, (14N)) (edical
%ractitioner (11N< HN #ro( the -4AC1 4,%ertension Center %h,sician/0s
%ractice and 3N #ro( other %ractices)) %osted ad*ertise(ents and #l,ers
(6N)) 'ord o# (o$th (6N) and other so$rces (4N). These %ercenta"es add
to and O100N +eca$se 4N re%orted (ore than one so$rce.
&# the 1442 %otential %artici%ants contacted) 101H (71N) 'ere e?cl$ded
d$rin" initial screenin" (2N sel#=re%orted a trial e?cl$sion criterion) 37N
$ninterested) 5N closed o$t 'itho$t additional screenin" 'hen recr$it(ent
"oals 'ere co(%leted) and 424 (2N) %ro*ided 'ritten in#or(ed consent
(14N s$ +s e9$ en tl , e ? c l $ de d + ase d o n t r i a l e l i " i+ il it , c r i t
e r i a ) 2N ' i t h d r e ' # o r l ac8 o# int er e s t ) 1 3 N rando(i.ed).
A(on" all those $ninterested in the trial) 33N either "a*e no s%eci#ic
reason) did not ret$rn %hone calls) or did not sho' $% #or in=%erson
screenin" *isits. The (ost co((on other e?cl$sion