Controlled Clinical Trials 25 (2004) 76 C 103

Design paper
Stop Hypertension it! t!e "c#p#nct#re $esearc!
%rogra& (SH"$%)' clinical trial design and screening
res#lts
(eslie ") *alis!a+, + -e.erly -#c/yns0i1+ %atricia Connellaa+
"llison 2e&&el+ C!ristine 2oert/c+1+ 3ric ") 4ac0lina+2d+
4ay %ian5S&it!+ Step!anie Ste.ensa+e+ 6a&es
T!o&psond7+ %eter 8alas0atgis+ %eter 4) 9ayne7+ $andall
4) :#s&an1
;e 3ngland $esearc! <nstit#tes+ = 2alen Street+ 9aterton+ 4" 02472+
>S"
1Di.ision o7 Hypertension and 8asc#lar 4edicine+ Cardiac >nit+ 4edical Ser.ices+ 4assac!#setts 2eneral
Hospital+ Depart&ent o7 4edicine+ Har.ard 4edical Sc!ool+ -oston+ 4"+ >S"
c;ational Center 7or Co&ple&entary and "lternati.e 4edicine+ ;ational <nstit#tes o7 Healt!+ -et!esda+ 4D+
>S"
dDepart&ent o7 "nest!esia and Critical Care+ 4assac!#setts 2eneral Hospital+ Har.ard 4edical Sc!ool+ -oston+ 4"+
>S"
e4ar1le!ead Holistic Healt! Cons#ltants+ 4ar1le!ead+ 4"+ >S"
7;e 3ngland Sc!ool o7 "c#p#nct#re+ 9aterton+ 4"+ >S"
$ecei.ed 14 6an#ary 2003? accepted @ "#g#st 2003
"1stract
Hypertens ion is a &aAor p#1lic !ealt ! pro1le& it! serio#s &edical and 7inan cial conseB# ences)
-arrier s t o s#cc ess7# l con .en tion al p !ar& a colo gical tr eat& en t incl # d e sid e e77ects+ o#t5 o75po
c0e t eCp ense s+ pa tien t nonco& pliance and ins#77icient dosages ) "c#p#nct# re !as 1een st#died as an
alte rnati.e t!erap y 7or contr olling 1lood press #re (-%) 1#t pre.io# s st#di es !a.e seri o#s &et!odol
ogical li&it ations) T!is paper descri1es t!e design o7 t!e Stop Hype rtension it! t!e "c#p #nct#re
$esearc! %rogra& (SH" $%) tri al+ a pilot rando& i/ed clinical trial desig ned to gat!er preli&in ary data
regard ing t!e e77icacy o7 traditiona l C!inese &edi cine (TC4)1ased ac#p#nct #re 7or contr ol o7 essential
!ypert ension) T!e desig n o 7 t!e SH"$ % tri al 1a lanced rigoro#s clinical trial &et !odology it! princ
iples o7 TC4 ) 3ligi 1le participa nts !ad syst olic -% (S- %) 140 C 17= && Hg and diast olic -% (D-%) =0
C 10= && Hg in t!e a1sence o7 anti!ypert ensi. e t!era py) Dolloi ng screen ing+ participa nts ere
rando& i/ed to one o7 t!ree gro#ps ' indi.id#a li/ed+ standardi/ ed or c ontrol ac#p#nct #re) Treat&ent s
er e desig ned acco rding to princ iples o7 TC4 ? nonspec i7ic e77ects associated it! t!e inte r.entions
ere standardi/ ed across t!e rando& i/ed gro#ps ) Dor indi .id#ali/ed ac#p#nct #re+ points ere tailored
to eac!
, Corresponding a#t!or) C#rrent a77iliation' Clinical $esearc! %rogra&+ C!ildrenEFs Hospital+ -oston+ 300 (ongood
".e)+ -oston+ 4" 02115+ >S") Tel)' G15617535552663? 7aC' G15617535552312)
35&ail addresses' leslie)0alis!Hc!ildrens)!ar.ard)ed# (()") *alis!)+ e&ac0linHneri)org (3)") 4ac0lin)
)1
2C#rrent a77iliation' Sa&#eli <nstit#te+ "leCandria+ 8" + >S")
$eprint reB#ests to 3ric ") 4ac0lin) Tel)' G156175=2357747C251? 7aC' G156175=265@246
)01=752456IJ 5 see 7ront &atter D 2004 3lse.ier <nc) "ll rig!ts reser.ed) doi'10)1016IA)cct)2003)0@)006
()") *alis! et al) I Controlled Clinical Trials 25 (2004) 76C103 77
participa nt) Standar di/ed ac#p#nct #re #sed a p respeci7i ed set o7 point s) T!e
in.as i.e s!a& con trol ac#p #nct#re regi&en as desig ned to 1e non5acti.e) 3ac !
parti cipant recei .ed a EKEKprescript ionEFEF 7or indi .id#ali/ed ac #p#nct#re 7ro&
an ac#p#nct #rist !o as &as0 ed to treat&en t assi gn&ent+ an d as s#1seB#e
ntly treat ed 1y an independ ent ac#p#nct #rist) %a tients and t!ose a ssessing -%
er e &as0 ed to treat&en t gro#p) "c#p#nct# re as deli .ered tice a ee0 7or 6
ee0 s) Do llo5# p .isi ts er e e . ery 2 ee0 s t o ee0 10 and t!en at &ont!s 4+
6+ = and 12) T!e pri&ary endpoi nt ill 1e c! ange in S-% 7ro& 1asel ine to 10 ee0
s) D-%+ - % traA ectories o.er t!e 125& ont! 7oll o5#p and anti!y pertensi.e &edi
cation reB#ire&e nts ill also 1e eCa&i ned) <nit ial contact as doc#&en ted 7or
1442 prospe cti.e parti cipants 7ro& 4arc! 2 001 to "pr il 2002? 424 pro.i ded in7or
&ed c onsent and 1=2 ere #lti&a tely rando& i/ed) D 2004 3l se.ier <nc) "ll rig!ts
reser .ed)
*eyords' "c#p#nct#re? -lood press#re? Hypertension? $ando&i/ed clinical trial?
Traditional C!inese &edicine
1) <ntrod#ction
Hypertension is a condition it! tre&endo#s 7inancial and p#1lic !ealt!
i&pact) "lt!o#g! 1lood pre ss# re (-%) can 1e c ont rol le d i n &ost ind i.i
d#a ls + i n pra c tice + t!e &aA ori ty o 7 !yp er ten si .e indi.id#als are
#nrecogni/ed andIor inadeB#ately treated it! con.entional p!ar&acologic
t!erapies L1M) "c#p#nct#re pro.ides an alternati.e treat&ent approac! it!
great potential ad.antages+ 1#t it! little rigoro#s scienti7ic e.idence to
s#pport it) T!e Stop Hypertension it! t!e "c#p#nct#re $esearc! %rogra&
(SH"$%) trial is a pilot rando&i/ed clinical trial designed to gat!er
preli&inary data regarding t!e e77icacy o7 ac#p#nct#re 7or treating
!ypertension it!o#t t!e #se o7 p!ar&acologic t!erapy) T!is paper descri1es
t!e design o7 SH"$% and o#r eCperience it! recr#it&ent and screening 7or
t!e trial)
1)1) Hypertension
Hypertension+ de7ined as systolic 1lood press#re (S-%) o7 /140 && Hg
andIor diastolic 1lood press#re (D-%) o7 / =0 && Hg L2M+ a77ects an
esti&ated 640 &illion persons orldide L3M+ incl#ding approCi&ately 50
&illion "&ericans L1+4M) T!e costs o7 inadeB#ately controlled 1lood press#re
can 1e &eas#red 7inancially and &edically) <ts 7inancial i&pact in t!e >nited
States is enor&o#sEN>SJ47)2 1illion in direct and indirect costs in 2002 L4M)
4edically+ t!e long5ter& conseB#ences o7 #ntreated !ypertension are a&ong
t!e &ost co&&on and serio#s ca#ses o7 &or1idity and &ortality in t!e
>nited States+ incl#ding &yocardial in7arction+ stro0e+ congesti.e !eart
7ail#re and renal 7ail#re)
Despite large5scale national e77orts to identi7y+ ed#cate and treat
indi.id#als it! !ypertension+ only 6=O o7 !ypertensi.e indi.id#als are
aare t!at t!ey are !ypertensi.e) "pproCi&ately !al7 o7 all !ypertensi.es
ta0e prescri1ed &edications+ 1#t 1lood press#re is adeB#ately controlled
in only a B#arter o7 t!e total L1+5M) "lt!o#g! t!e e77icacy o7 li7estyle
&odi7ications and anti!ypertensi.e dr#gs 7or essential !ypertension !as
1een ell esta1lis!ed in clinical st#dies L6 C @ M+ treat&ent it!
con.entional &edical treat&ents &ay 1e li&ited 1y side e77ects+ o#t5o75
poc0et costs+ patient nonco&pliance it! prescri1ed regi&ens+ ins#77icient
dosages o7 prescri1ed &edications to ac!ie.e an adeB#ate le.el o7
control+ !ealt!care pro.ider neglect o7 !ypertension+ and t!e indi.id#alEFs
ina1ility to &a0e lasting and &eaning7#l !ealt!y li7estyle c!anges L2+= C
14M
)
()") *alis! et al) I Controlled Clinical Trials 25 (2004)
76C1037@
1)2) "c#p#nct#re
"c#p#nct#re !as 1een a co&ponent o7 t!e C!inese !ealt!5care syste&
7or at least 2500 years and is idely practiced in t!e >nited States L15M )
"c#p#nct#re is 1ased on t!e traditional C!inese &edicine (TC4) concept
t!at t!ere are c!annels (or EKEK&eridiansEFEF) o7 energy 7lo (EKEKBiEFEF)
it!in t!e 1ody t!at !elp &aintain t!e !ealt! o7 t!e indi.id#al and t!at
disease and pain res#lt 7ro& i&1alances o7 Bi) Dor any partic#lar 9estern
&edically de7ined illness+ t!ere &ay 1e se.eral di77erent #nderlying patterns
o7 dis!ar&ony 7ro& t!e TC4 perspecti.e) T!ese patterns are diagnosed 1y
sy&pto&s and signs and 1y o1ser.ing t!e patientEFs o.erall a77ect
(co&pleCion and de&eanor)+ tong#e (color+ s!ape+ coating and teCt#re) and
radial p#lse (speed+ dept!+ r!yt!&+ s!ape+ B#ality and strengt!))
"c#p#nct#re is seen as a ay to access t!e energy c!annels and to
restore 1alance 1y adding energy !er e i t i s de 7i cie nt and r ele as i ng
e ne rgy !ere i t i s o 1s tr #c ted) T!e p rac tic e o 7 a c#p#nc t#re
enco&passes se.eral types o7 related tec!niB#es) "ll ac#p#nct#re in.ol.es
sti&#lation o7 speci7ic anato&ic locations on t!e 1ody (corporeal points) or
on t!e ear (a#ric#lar points)+ &ost co&&only 1y penetration o7 t!e s0in it!
t!in+ solid &etallic needles) Selection o7 corporeal points is 1ased on
0noledge o7 t!e EKEKaction and e77ectsEFEF o 7 t!e points+ as de.eloped
7ro& ancient teCts and o.er 2000 years o7 clinical eCperience) 4odern TC4
t!eory !olds t!at t!ere are also a#ric#lar points corresponding to partic#lar
organs+ areas o7 t!e 1ody or 1odily syste&s) "ccordingly+ &odern day
ac#p#nct#re treat&ents o7ten incl#de 1ot! corporeal and a#ric#lar points)
"c#p#nct#re needles are so t!in t!at t!ere is #s#ally &ini&al disco&7ort
!en t!ey penetrate t!e s0in) T!e needles are ad.anced to .arying tiss#e
dept!s+ depending on t!e location in t!e 1ody+ and a c!aracteristic EKEKde
BiEFEF 7eeling is elicited) T!e patient o7ten descri1es de Bi as a ar&t!+
7#llness+ tingling or ac!ing in t!e tiss#e+ !ile t!e ac#p#nct#rist &ay sense
t!e needle 1eing grasped or t#gged (EKEKli0e a 7is! 1iting t!e !oo0EFEF))
De Bi sensations !a.e 1een correlated it! t!e sti&#lation o7 "5delta
7i1ers+ 7olloed 1y C57i1ers and t!en 1y gro#p 2 7i1ers L16 C 1@M) $ecent
st#dies !a.e B#anti7ied t!e &ec!anical gr as pin g o 7 n e e d l e s a n d r e
l a t ed it to de 7or &a ti on o 7 s# 1 c # t a n eo # s c o n n e c t i .e ti ss# e
L1= M )S#c! &ec!anically ind#ced c!anges in connecti.e tiss#e str#ct#re
(ca#sed 1y needle insertion and rotation) !a.e 1een !ypot!esi/ed as
&ec!anis&s 1y !ic! ac#p#nct#re can a77ect a ide range o7 local and
re&ote p!ysiological processes L20M) < t !as 1een arg#ed t!at in clinical
trials in !ic! t!ere as B#estiona1le e77icacy o7 ac#p#nct#re+ t!e de Bi
sensation as not properly elicited and t!#s t!e 7ail#res &ay !a.e 1een
d#e to poor tec!niB#e)
%ossi1le &ec!anis&s 1y !ic! ac#p#nct#re red#ces 1lood press#re in
!ypertensi.e patients incl#de decreases in plas&a renin+ aldosterone and
angiotensin << acti.ity L21 C 24M + increased eCcretion o7 sodi#& L25M and
c!anges in plas&a norepinep!rine+ serotonin and endorp!in le.els L26 C
2@M) 3n0ep!alins and ! 5endorp!ins &ediate ac#p#nct#reEFs e77ects to
atten#ate 1rady0inin5ind#ced eCperi&ental !ypertension in la1oratory cats
L2= C 31M) So&e o7 t!ese &ec!anis&s are t!e sa&e ones targeted 1y
s#ccess7#l classes o7 p!ar&acological anti!ypertensi.e agents) "s an
eCa&ple+ angiotensin con.erting en/y&e ("C3) in!i1itors ac!ie.e t!eir
e77ect 1y in!i1iting t!e acti.ation o7 angiotensin < t o its &ore acti.e 7or&)
C!i# et al) L22M 7o#nd loer angiotensin < le.els in !ypertensi.e patients
!o recei.ed ac#p#nct#re+ co&pared it! a control gro#p o7 !ypertensi.e
patients !o did not recei.e ac#p#nct#re)
" re.ie o7 t!e literat#re re.eals &#ltiple p#1lis!ed reports o7 t!e
e77ecti.eness o7 ac#p#nct#re on 1lood press#re and ot!er !e&odyna&ic
para&eters in !#&ans L21 C 24+2@+32 C 45M ) T!ere is a strong pri&a
7acie case 7or #nderta0ing a &ore de7initi.e st#dy) T!e res#lts o7 all st#dies
to date+ !oe.er+ &#st 1e treated it! ca#tion 1eca#se o7 serio#s
&et!odological li&itations' s&all sa&ple si/es+ lac0 o
7
()") *alis! et al) I Controlled Clinical Trials 25 (2004) 76C103 7=
rando&i/ation+ inadeB#ate or #nspeci7ied 7ollo5#p+ poorly descri1ed t
reat&ent content+ poorly c!aracteri/ed st#dy s#1Aects and r#di&entary
statistical analyses) T!e need eCists 7or a rigoro#sly designed and
cond#cted rando&i/ed clinical trial in order to de7initi.ely e.al#ate t!e
e77ecti.eness o7 ac#p#nct#re 7or t!e &anage&ent o7 !ypertension)
Pne o7 t!e c!allenges in reac!ing de7initi.e concl#sions a1o#t t!e
e77icacy o7 ac#p#nct#re res#lts 7ro& .aria1ility in ac#p#nct#re &et!odology+
incl#ding t!e ac#p#nct#re points selected+ d#ration o7 eac! treat&ent
session+ lengt! o7 treat&e nt co#rse+ inter.als 1eteen treat&e nts and
7or& o7 needle sti&#lation (&an#al+ t!er&al or electrical)) T!#s it is critically
i&portant t!at clinical trials in.ol.e reprod#ci1le standardi/ed treat&ent
protocols)
1)3) %otential acceptance 1y patients
<n 1==7+ 41O o7 ad#lts in t!e >nited States #sed alternati.e &edical
t!erapies (incl#ding ac#p#nct#re) L46M + s#ggesting t!at t!ese t!erapies are
gaining acceptance it! t!e general p#1lic) S#r.eys !a.e de&onstrated t!at
t!e alternati.e treat&ents are o7ten o77ered 1eca#se o7 patient reB#est and in
t!e !opes o7 &ini&i/ing or a.oiding #nanted side e77ects o7 con.entional
&edicines L47M )
2) St#dy organi/ation
T!e SH"$% trial as 7#nded as a cooperati.e agree&ent 1y t!e ;ational
Center 7or Co&ple&entary an d " lt er n a t i . e 4e dic ine ( ; C C " 4 ) +
;a ti on al <n st it # t e s o 7 He al t!) T ! e ;e 3n gla nd $ ese ar c!
<nstit#tes (;3$<) as t!e organi/ational center 7or t!e st#dy) "ll clinical or0
as per7or&ed at t!e 4assac!#setts 2eneral H os pi tal (42H)) Trial
acti.ities at t!e 42H ere di .i de d 1eteen a Hype rt ensio n C enter and
an "c#p #nc t#r e Cent er) Cons #lta nts 7r o& t!e ; e 3ngl and Sc! ool o7
"c#p#nct#re and 9a0e Dorest >ni.ersity colla1orated on t!e design+
&onitoring and analysis o7 t!e trial) " data and sa7ety &onitoring 1oard+
appointed 1y ;CC"4+ pro.ided independent &onitoring o7 t!e st#dy) See
"ppendiC " 7or a co&plete list o7 in.estigators)
3) Tr eat&ent gro#ps+ treat&ent co&parisons and endpoints
%atients in SH"$% ere rando&i/ed to one o7 t!ree ac#p#nct#re
treat&ent gro#ps' indi.id#ali/ed (<nd)+ standardi/ed (Std) or control (Ctl)
(see Dig) 1 )) T!e protocols 7or all t!ree gro#ps are 1ased on principles o7
TC4 ac#p#nct#re+ incl#ding t!e control regi&en+ !ic! as designed to 1e
inacti.e)
T!e control treat&ent in.ol.ed needling o7 non5ac#p#nct#re points it!
&ini&al sti&#lation+ an EKEKin.asi.e s!a&EFEF ac#p#nct#re proced#re L4@M )
To &aintain 1linding+ patients ere told in t!e consent 7or& only t!at t!e
control treat&ent #sed points EKEKnot #sed to treat !ypertension)EFEF T!e
7act t!at t!e control points ere not traditional ac#p#nct#re points as not
&entioned and t!e ter&s EKEKs!a&EFEF and EKEKplace1oEFEF ere not
#sed) T!is lang#age as appro.ed 1y instit#tional re.ie 1oards 7ro& t!e
;3$< and t!e 42H (%artners Healt! Care Syste&))
T!e to pri&ary treat&ent co&parisons ill test t!e o.erall e77ect o7
ac#p#nct#re L(StdG<nd) .ers#s CtlM and speci7ically !et!er TC451ased
ac#p#nct#re t!at !as 1een indi.id#ally tailored to t!e patient !as an
ad.antage o.er a standardi/ed regi&en t!at is also 1ased on principles o7
TC4 L<nd .ers#s StdM
)
()") *alis! et al) I Controlled Clinical Trials 25 (2004)
76C103@0
Dig) 1) Clinical trial sc!e&a)
Pt!er treat&ent co&parisons LStd .ers#s Ctl+ <nd .ers#s CtlM ill 1e
per7or&ed as secondary analyses) Treat&ent co&parisons ill 1e &ade
7or eac! o7 se.eral endpoints
'




C!ange in S-% 7ro& 1aseline to 10 ee0s (pri&ary endpoint)?
C!ange in D-% 7ro& 1aseline to 10 ee0s?
C!aracteri/ation o7 t!e traAectories o7 S-% and D-% o.er t!e entire 15year
period+ incl#ding treat&ent gro#p co&parisons at ti&e5points ot!er t!an 10
ee0s+ an e.al#ation o7 !o B#ic0ly any 1ene7icial e77ect &ay 1egin+ and
!o long t!e e77ect &ay last?
%ercentage o7 patients !o initiate or res#&e con.entional
anti!ypertensi.es and t!e d#ration 7ro& rando&i/ation to
initiationIres#&ption o 7 con.entional anti!ypertensi.es?
<&&ediate e77ects (pre5 .ers#s post5ac#p#nct#re treat&ent) on S-% and
D-%? and
"c#p#nct#re 1elie7s+ &as0ing assess&ent+ ad.erse e.ents and B#ality
o7 li7e
)T!e c!oice o7 S-% rat!er t!an D-% 7or t!e pri&ary endpoint is 1ased on
1ot! &edical and statistical arg#&ents) 4edically+ S-% is &ore closely
related to long5ter& cardio.asc#lar o#tco&es t!an is D-% L4= C 51M) Dro&
t!e .iepoint o7 statistical e77iciency+ t!e &eas#re&ent t!at !as loer
intraperson .aria1ility (!ig!er it!in5person correlation) o#ld 1e pre7era1le)
9e esti&ated intraperson correlation o7 S-% and D-% &eas#re&ents 7ro&
t!e ;ational Center 7or Healt! Statistics (;CHS) L52M ) " s part o7 t!e ;CHS
s#r.ey+ 1lood press#re &eas#re&ents ere ta0en t!ree ti&es at a single
&edical eCa&) "geand gender5strati7ied pop#lation standard de.iations are
reported 1y t!e ;CHS 7or eac! &eas#re&ent and 7or t!e a.erage o7 t!e
t!ree &eas#re&ents) "ss#&ing t!e pairise it!in5person correlations are
eB#al it!in eac! strat#&+ t!ese standard de.iations can 1e #sed to
esti&ate t!e correlations) "cross age gro#ps 7ro& 45 to 74 years+ it!in5
person correlations ere !ig!er 7or S-% (range 0)@2 C 0)@4) t!an 7or D-%
(range 0)76 C 0)@0)+ s#ggesting t!at S-% o#ld res#lt in a &ore e77icient
treat&ent co&parison)
9e also #sed data 7ro& t!e %at#c0et Heart Healt! %roAect L53M ) < n a
repeated &eas#res analysis o7 1lood press#re &eas#re&ents o1tained
o.er t!e co#rse o7 se.eral &ont!s+ t!e esti&ated resid#al intraperson
correlations 7or S-% and D-% ere 0)74 and 0)67+ respecti.ely (H)
Deld&an+ pe rsonal co&&#nication)) T!ese .al#es are loer t!an t!e
.al#es 7ro& t!e ;CHS+ since t!ey represent correlations 1eteen
repeated &eas#re&ents ta0en o.er a period o7 &ont!s rat!er t!an at a
single sitting) Hoe.er+ a s i n t!e ;CHS data+ S-% !as t!e !ig!er
correlation+ s#ggesting t!at it o#ld yield a &ore sensiti.e &eas#re o7
treat&ent e77ect
)
()") *alis! et al) I Controlled Clinical Trials 25 (2004) 76C103 @1
4) Screening and eligi1ility
%rospecti.e st#dy participants ere identi7ied t!ro#g! a co&1ination o7
e77orts incl#ding direct recr#it&ent o7 patients recei.ing care at t!e
Hypertension Center+ 1roc!#res at t!e Hypertension Center and at ot!er
!ealt! clinics it!in and o#tside o7 t!e 42H+ postings t!ro#g!o#t t!e 42H+
&ass &ailings+ ad.ertise&ents in nespapers and &aga/ines+ posters in
t!e -oston s#1ays and internet listings) <n an e77ort to recr#it participants
t!ro#g! &edical practitioners+ an e5&ail posting as sent to all p!ysicians at
t!e 42H and at se.eral ot!er &aAor -oston5area !ospitals+ and
presentations ere &ade to !ealt! practitioners at se.eral local &edical
7acilities) $ecr#it&ent as also greatly en!anced 1y reports 7eat#ring t!e
trial on local and national tele.ision nes+ in t!e -oston 2lo1e and in ot!er
local nespapers)
T!e screening process in.ol.ed at least t!ree .isits to t!e Hypertension
Center o.er a period o7 ee0s) Dor sa7ety reasons+ s#1Aects ere sc!ed#led
7or 1lood press#re &eas#re&ents d#ring screening at inter.als no greater
t!an 14 days) S#1Aects co#ld 1e 7o#nd ineligi1le+ or co#ld drop o#t 1eca#se
t!ey 1eca&e #ninterested in t!e st#dy+ a t any ti&e d#ring screening) <n
partic#lar+ a stage 3 1lood press#re reading at any ti&e d#ring screening
(S-% / 1@0 andIor D-%/ 110) eCcl#ded potential participants 7ro& entering
t!e trial)
"7ter a .er1al introd#ction to t!e trial+ prospecti.e participants ere as0ed
se.eral screening B#estions in inter.ie 7or&at+ incl#ding so&e eligi1ility
criteria and &ini&al de&ograp!ic in7or&ation) T!is le.el o7 screening as
typically done o.er t!e p!one) "ll s#1seB#ent screening proced#res too0
place in t!e Hypertension Center a7ter pro.iding ritten consent) %roced#res
di77ered depending on !et!er or not patients ere on anti!ypertensi.e
&edications at t!e start o7 screening)
Dolloing an initial 1lood press#re c!ec0+ patients on anti!ypertensi.e
&edications ere e.al#ated 7or t!e potential le.el o7 ris0 associated it!
stopping t!eir &edications in order to participate in t!e trial) T!is e.al#ation
incl#ded a p!ysical eCa&+ clinical !istory+ &edication !istory+
electrocardiogra& (3C2) and assess&ent o7 li.er 7#nction+ electrolytes+
7asting 1lood s#gar+ renal 7#nction+ 7asting lipid pro7ile+ #rinalysis and a
co&plete 1lood co#nt)
Dolloing t!ese e.al#ations+ patients ere tapered o77 o 7
anti!ypertensi.es it! t!e goal o7 a.oiding t!e ris0s associated it! re1o#nd
!ypertension) 4edications ere discontin#ed one at a ti&e at ee0ly int er
.al s i n t!i s o rde r' di# re ti cs+ "C 3 in! i1i tor s+ ang iot ens in re cep to r
1lo c0e rs + cal ci #& c!a nne l 1loc0ers+ a adrenergic receptor antagonists+
direct acting .asodilators+ centrally acting agents and ! adrenergic receptor
1loc0ers) Co&1ination &edications ere discontin#ed one co&ponent at a
ti&e) -lood press#re as &eas#red 1e7ore discontin#ing eac! s#ccessi.e
&edication (at least ee0ly)) "ll &edications eCcept 7or ! adrenergic
receptor 1loc0ers and centrally acting agents ere discontin#ed a1r#ptly) !
adrenergic receptor 1loc0ers and centrally acting agents ere discontin#ed
&ore grad#ally' 1I2 7#ll dose 7or 3 consec#ti.e days+ 1I4 7#ll dose 7or 3
consec#ti.e days and 1I4 7#ll dose e.ery ot!er day 7or to dosages) T o
ee0s a7ter co&pletion o7 tapering+ t!e patient co#ld 1egin t!e 7inal
EKEKB#ali7yingEFEF seB#ence o7 1lood press#re &eas#re&ents (see 1elo)
and as reB#ired to repeat t!e 3C2 and la1oratory tests 7or electrolytes+
renal 7#nction+ 1lood s#gar+ lipids and #rinalysis) T!e li.er 7#nction tests and
co&plete 1lood co#nt did not !a.e to 1e repeated #nless clinically indicated)
%atients it! la1oratory .al#es t!at ere initially o#t o7 eligi1ility range 1#t
it!in range #pon repeat testing ere considered eligi1le)
%atients not on anti!ypertensi.e &edications ent t!ro#g! a si&ilar
screening process eCcept t!ey did not !a.e to repeat t!e la1oratory
&eas#re&ents or 3C2) T!e p!ysical eCa&+ &edical and &edication