- Email: [email protected]
The Australian National blood pressure study
TIPS - November 1981 I
II II
2'+3 I
The Australian National Blood Pressure Study
order drug (alpl,at-mcth,.I d-pa. propranolol or pind,,l,,I), or i~qh. t,,cn: added %ub,,cqucntl}. third ohc'l drug, (hxdr.da l i n e o r ¢ l o n i d l n e ) ~ c r c A l t o n i| nec¢.~%tlx i n l l l a l h , t h e t~hlec: t~.~ t,, r e d u c e i ) B P tt~ ell mm Itg or It.,,. but :t[lt:r 2 ~.C;IP, the gtmi
~a,, Io~ercd to 8it mm I in.
A. E. Doyle"
P L l e c l ~ t t a b l e h , ~ c r t " i d e n t i c a l Ill ;tp~.',:lr-
Utliver+ily of .+lelhourne. Ih,parlmenl of ,th,dirm,., .,tl~ton II¢,Vtlltd. Ih'uh'lherg. ~0+~4|'l~ l,,ll,i, t u s / , . h a
+race to the a~'tit¢ tablet,, In ;In a l k ' n l p l h, athlete"
Inlrodtmllon
more were asked to return for a ,,¢etmd pilif
There is very strong evidence that even a minor degree of hYl~rtension leads to an increased risk of premature death from either stroke or e o r o n a ~ heart di,~a.~L Since the development of antihypertensive drugs 30 years ago. several reixlrts have confirmed that effective treatment of
of mcasurcmc.nts I - 2 ~cek,. l a k ' r ±%t thi,, Mags:. thc average of the h m r readings ~a.~ estimated and individuals x,~ith a~,erilge
readings bet~,een ~5 and I ~1~mm lie and in ~hom nt)exclusion factors Acre pn:,,cnt (Table I) became eligible to join the ,,ruth.
severe hypertension reduces both mortal- "lAlfl+l I l wlu~,,,n f.,ch,r~ i'y and the incidence of cardiovascular Vi',ll Ru.v, tm l,*r ~.-*.¢l:~,l+,n complications=: the Veterans administra()n trcatnlcnt t,,~ h,.pt'ryon study of patients with diastolic blood l:ir,,t ,,.cr¢cnlng ~.i',II lcnMon in pa~l ~ m+,nth,, pressures between 90 and 114 mm Hga Angina pt'c.',,ri,, h~ R,,',*: suggested that patients with less severe .~'o m d ~-n:cnlng t NI qUCM I~ ~n;ldirc ~a hypertension might aim benefit. This study tilth,n, ot m, ~alrdiai was comparatively small: the subjects were infarction in past three m, ml h~ all men, and the blood pressures had been Hl~lor.~ : )( ',l "okc taken in hospital. There was a high prevalPrcgnan,3 ence of pre-existing cardiovascular disea,~ Taking t.~-~.lr,gcn and in subjects entering the stud)'. The major p r o g t . ' , i l c n , n c in question left unanswered by these studies o~mhinalt +n A,,thma. di~ ~:tc~, gout was whether antihypertensive drug treatPrima~ cau. c of ment would reduce mortality and the pre- Clinic ~isit h.t tx:rtcn,, on valence of cardiovascular complications in k ~.idcncc of a population with mild hypertension free of ¢crcbro~,a~ " u l a r t.h~c ;.I,~..'. pre-existing hypertensive cardiovascular lran,~ient ~c r~hral i ~ h ; , c m i ~ . ".dl.|ck,.. ,tCUlC complications. A second and related quescoronal3 i v.utficicnc~. tion was to what extent failure to treat such plasma ct, atlnlnc "2 individuals would lead t o the premature mg dl ' development of deaths and complications Other ,~CrlOt ". of cardiovascular origin. ¢omplicathm~ of The Australian National Blood Pressure h.~tx'rtenqon F.('(i ¢~.ldcncc of Study ~ was designed to give answers t o m.x o c a r d l a l l~.'hacmia both these questions. The study was a An.~ potcnllall?, tatal placebo controlled therapeutic trial of di~;w2 antihypertensive therapy in 3427 men and Taking tric~dtc a n t i - d e prc~,%.lnt ,, women with defined mild hypertension, recruited from the general population by screening. Those with pre-existing Those volunteering its do so attended a cardiovascular disease were excluded. special clinie, at which a historx and ph~,,ical examination, eh.'ctrocardiogralph and Methods biochenlical examination of urine and Subjects were recruited from the general plasma w e r e |~2rfi~rlllett. population by screening by trained nonThose entering the trial ~ser¢ randoml.~ medical persomtel under standardized allocated either tO the active or thc placch) conditionss, using random zero sphyg- group. Randomization ~ as stratified !~ sex momanometers. Diastolic pressures pha,~ a n d t o t h r e e a g e g r o u p s . V (dim=ppearance of the Korotkoff sounds) Subjects in the active group were gixen (DBP) was used throughout the study. chlorothiazide 500 mg dail.~ as the first Individuals with a mean of two immedi- order drug. Thereafter. if control of blood ately consecutive DBP of 95 mm Hg or pressure was not achieved, the do.~ was incrca.~d to 500 mg twice daily or a second * On behalf of the Management Committee.
comparabh:
takin*, in b o t h
p,lth:m,,
groui~.
,d
tablct-
,m e,,tlanatc
+~,P,
nhld¢ o| the nunllx.r,, of ,ublcct,. ill the actitc" g r o u p llkeh !o n.-quirc ,inc. t++,~,,r n~llr~." d r u g , , t o l ) b h l l n lht.. th:,,IroJ h.'du+dlIt Ill
l~ bl,,~l pn.'+,,ur¢, in ,wc,,rdancc x+lth thi,,
t:,,timat¢, t~,,, in three el the plalceb,, Cr,,up ',~.erc r a n d o m l / c d t,~ the lir,,t order placcl~, tablet or.h. tx~t+ in nlA¢ |o I1;ltC ;.I ,,:c,,nd ,+rdcr tablet added and the lelnainlilg t,nLm nine In ha~c ,t tlurd ,,rdur tablet added later. SubJect,, attended the cllnic~ ;it 2-~cckh
mte~al,, during ,,tablll.,atu,n and then at 4-monthh intcr~al,,, or rnorc frequently, at the di,,cn:tion of the 'qlld~, c e n t r e dth.'tor~,. At each 4-monthh ~i,it. bh,M pre~,,ure t~as measured, tablet do%', t~cre adiu-ted if neccs,,ar,, and e~ick.nce h,r t~:eurrence of trial end point,, (TEP) (Table II) and treatment side effect,, x~cre ,,ought. Full clinical, biochemical and electrocardiograph examination,, t~en: made annualh. If at anx ~i',it DBP ~a,, 1 ll| mm Hg or more. or systolic bh~,d pressure (SBP) 20*~ mm lfg ,it more. ";irther xi',iIS were arranged at short int.'r+als. It at three ,,uch
,.ucces~ive visits ~ ithin a ~-~eek p~:riod the blood pressure remained a l ~ e the~: thresholds, dcfiniti;e anti-h.~pcrtem, isc treatment ~ a , given, lhe,,c .,ublcets ~crc classified as "pressure limits exceeded'. This - a s not a TEP and they," sub lech, remained in the stud~. I -~BII Ii l u.d ~.nd p,,mt,
Fatal l)c.tth Item an~ CatU-c(,.tu,~ ,,! ,l~;tth ,+x.mcd) { a ) {. ',l rdlo% a,~.ular" tb)t )lher
i ['lrolllbOlh.' e l h.|~'llh,t r~1,.igl,. ~.~:l,'bh+~,.l'.,~:ul,tl d|',.~.'.l,,c | I.IIIMCI)I ¢crcblal I'..C'101~'lllh." .ttt.t~k', t~ Ith o1"~'~2l', t.'tj lie Llft.'lO~h.'al ",l~ll ~,
M~,~:ardial Inf,th:lh,{1 D'. '~, tit ) ~,stcg,,r~ I ,,r II t ) t h c r i ' . , c h a c n l i c h v a f l d1~4.',1',.4.• l'~. r , , ' ~
qLiC'~tlOllfl,llfk'
ot d~.'fmcd ! C(.i ~ntcrt., {. "ongc'~ID, C cardhlc l.~dtl[,,.' |}l~,%'Clil)l~ .IOcUI"%MT) ~'| |hk' .Iofl.t Rt.'tin;il h;.icfllorthag¢,,. ~:~.tkl;.th.", Or r~,tl'qlh~.'dcnl,i
1t~ pcrlcnsiw cnccphal,,path.~ (h~,,ct of renal fiulurc ~ ith pla,.ma crcJlimn¢ clc~atcd abosc 2 mg dl * Cardio~ a~.'ulaf dealhs arc Imutcd to the,< cau~'d b~ the condition', li,~tcd under nt ,n-tital Tk P. ~:' Ll.~.,,ietN,~rth.floltand Ha,mcdz, al P:¢,'. I ' ~ l !il~. ~, r.l.l"
TIPS November 1981
294
-
TABLE IlL Comparabilityof activeand placebogroupscharacteristicsat entry Active Number Mean(SD) I oral subjects Age (years)by 10 yeargroups
Sex ScreeningDBP (ram Hg)
ScreeningSBP (mm Hg) SerumCholesterol level(rag dl- *) Smoking
30-39 40-49 5O--59 60-fi9 Meanage Male Female 95-99 100-104 10.T--109 Meanscreening DBP mm Hg <220 >220 Meanm8HI" Non-smoker Smokers
Placebo Number Mean($D)
1721
1706
229 546 653 293
223 514 680 289 50.4 (9,0)
50.5 (8.9) 1085 621 814 589 303
1085 636 799 589 332 100.5 (4.0) 157.7 (15.0)
100.4 (3.8) 157.1 (14.4)
691 1030
742 964 229.8 (44.0)
231.9 (44.5) 1303 4i8
12¢~7 439 5,5 (!.4)
Serum UricAcid(mg dl-') Myocardialinfarction prior to 3 months
5.5 (I ,4)
6
Any TEP which occurred subsequently was counted against the trial regimen to which they had been randomized originally, in effect therefore, the study was a comparison between 2 regimens relevant to medical practice. In one, subje~s were treated by pharmacological agents from the time of diagnosis of mild hypertension, while in the other, subjects were kept under observation (on placebo tablets) from the time of diagnosis and treated by pharmacological agents only if their blood pressure subsequently rose above the defined mild range. All subjects were given advi:-~ on weight, smoking and diet, regardless of the regimen to which they had been randomized. To maintain continued attendance, subjects missing appointments were contacted by telephone, letters and through their own
8
doctors The need to take tablets as prescribed was stressed and compliance encouraged by question and by residual tablet count at each visit. Detaiils of the methods of management, and the statistical analysis have previously been published'. Results Of 104,171 subjects screened, 3931 were randomized. In 504, pressures fell before tablets were due to be dispensed and never again reached the threshold to qualify them to start tablets (i.e. 95 mm Hg DBP or 200 mm Hg SBP). The number eligible to start ,:tblets previously defined as the 'trial population' was therefore 3427 which was 3.3% of those screened. The :tctive and placebo groups in the trial popula~tion were well matched at entry
TABLE IV Statusof the trial populationat end of study Active n
Continuingon regimen Trial end points No trialend points "ibta}
Placebo %
n
Total %
n
%
91 1047 1138
5.3 fi0.8 66.1
127 953 1080
7.4 55.9 63.3
218 2000 2218
6.4 58.4 64.7
Prematurely~toppedrel~imen Trial end points after ztopping No trial end points Lost to follow-up Total
47 494 42 583
2.7 28.7 2.4 33.9
41 539 46 626
2.4 31.6 2.7 3b.7
88 1033 88 1209
2.6 30.1 2.6 35.3
Grand total
172!
100
1706
100
3427
100
(Table !11), for length of time in the stud)' and person-years exposure. The status of the trial popt,lation at the end of the study is shown in Table IV. About one-third prematurely stopped the regimen to which they were randomized. Those who stopped did not differ in entry characteristics from those who continued on their regimens, except that they included a higher proportion of smokers (29% and 23% respectively) and a higher proportion of women (42% and 34% respectively). There were no significant differences in entry characteristics between the subjects of the active and the placebo groups who stopped prematurely. Thus, in subjects who prematurely stopped their regimen, the match between the active and placebo group in respect to entry characteristics, time of stopping, TEP rates, types of end points and reasons for stopping, makes it unlikely that factors associated with premature stopping biased the results of the trial in favour of the active group. There were 2218 subjects, 64.7% of the thai population, who continued on their trial regimen either until a TEP occurred or until the end of the study. The 'on treatment' analysis takes into account the experience of these subjects together with the experience, prior to stopping, of the ! 209 who prematurely stopped their regimens. The 'intention to treat' analysis takes into account the person-years exposure to risk of all 3427 subjects and the TEPs that occurred before or after stopping in the 3339 subjects whose status was known at the end of the trial. Trial end points In both the above modes of analysis, the rates of TEPs were lower in the active than in the placebo group (Table V). There were significant differences in both analyses for total TEPs and cardiovascular deaths. The differences for total deaths and non-fatal TEPs were significant only in the 'on treatment' analysis. The differences in rates wer~ such that by the 'on treatment' analysis there were seven fewer total TEPs including two fewer deaths per 1000 person-years in the active group. The numbers of TEPs in different diagnostic categories are shown in Table VI. Over two-thirds of all TEPs were due to ischaemic heart disease, predominantly non-fatal events, which occurred in similar numbers in the active and placebo groups. By both modes of analysis fewer cases of fatal ischaemic heart disease occurred in the active than in the placebo group; the numbers were small and the differences
295
TIPS - N o v e m b e r 1981
just short of significance in t h e ' o n treatment" analysis (P = 0.05 I). There were about half the number of total cerebrovascular events ih "he active compared with the placebo gro,~p and this was so for fatal strokes, for non-fatal strokes and for transient ischaemic attacks with observed neurological signs. The difference was significant for all events (P < 0.025) and for all non-fatal events (P < 0.05). Non-cardiovascular deaths were similarly distributed between the two groups. The cumulative occurrence of total TEPs and of all deaths for subjects continuing on their regimen is shown in Fig. 1. Differences between the groups emerged early in the trial and when analysed by Cox's technique were significant for all TEPs (P < 0.01) and for all deaths (P < 0.05). Blood pressure responses
The average of all DBPs recorded after commencing either active or placebo tablets has been estimated. The relationship of these average DBPs to the initial screening pressure is shown in Tables VII and VIII. It is clear that there was a general tendency in the placebo group for the average DBPs to he lower than the screening pressures, While the average fail in pressure was greater in those with higher screening pressures (Table VII), the numbers whose average DBP fell below 90 were smaller in those with the higher screening pressures, Table VIH. The relationship between the occurrence of TEP rates and average DBPs is shown in Table IX. It is clear that for each DBP class there is little difference between the occurrence of TEPs between the actively treated and the 130
120
...... ACTIVE PLACEBO
j
/
~
T A B L E V. Incidence of trial end
points(TEP)"
Intention io t.'eat Active Placebo n ~ 1721 a = 17116 No, Rate No, Rate Fatal T E P Cardiovascular Non-cardiov&scular Total fatal
g 17 25
I. ! 2.4 3.6
1lg 17 35
Non-fataITEP
113
16.2
133
All T E P
138
19.7
1614 24.5*
i
2.¢~g 2.5 5. I
4 5 9
19.4
I! 14 og
!~
1.7
i~
2% 12 3 7*
142
15.5
lU,~
2(! 8f
91
17.2
127
24.5§
" R a t e s per 1000 person-years exposure to risk; t p <0.()5; t P <0.025; §P <(p.OI. T A B L E VI. Numbers of trial cad points by diagmwtic categories
Ischaemic heart disease Fatal Non-fatal (a) Myocardial infarction (b) Others Total Cerebrovascular events Fatal Non-fatal (a) Haemorrhage or thron~bosis (b) Transie:tt cerebral ischacmic attacks Total Other fatal Aortic a n e u ~ s m
Non-cardiovascular (a) Neoplasm (b) Other Other non-fatal Retinopathy Congestive cardiac failure Renal failure Total
A
B
Intention to treat Active Placebo
O n treatment Active Placel,a~
in premature ithdrawals afler qoppmg ( A-B} Active placclx,J
5
II
2
8
.t
28 b5 98
22 76 109
t8 50 7(~
!~ 6,3 88
lO IS 2S
I 21
3
6
2
4
I
,"
i0
Ib
7
13
3
3
4 i7
'~ 3!
3 12
.~ 2.~
1 5
!
0
!
o
I
o
.
9 8
8 9
I 4
2 4
S 4
¢~ 5
2
5
!
4
I
i
3 i 138
3 2 108
2 i t)l
I 2 127
I 0 47
2 ~ 41
placebo group, and there is no clear support for the idea that factors other than DBP might be influencing the occurrence of TEPs between the active and the placebo group. Furthermore, in both the placebo ~0 80 "" and actively-treated groups TEPs occurred m 70 more frequently as the average DBP rose. An exception to this statement is the low occurrence of TEPs in the actively-treated ¢~Ou"40 6050 ~ / /ALLTEP group whose DBPs remained above 100 but the numbers of individuals in this group are so small as to cast doubt on the validity Z 30 ,i" of this figure. / 20 . . . . it appears from these data that the differences in occurrence of TEPs between ......... the active and placebo groups arc due 40O 8O0 1200 lt~0 2O0O mainly to the fact that in the activelytreated group 85% of the population DAYSINTRIAL attained DBPs of below 95 mm Hg, Fig. i. Cumulative incidence-oflrial' end poims.
110 10¢
On Ircatmunl At'tire placeh~ n -- 1721 n = 17(~ No. Rate No. Rate
whereas in the placebo group only 45% attained such levels, it appears that the incidence of TEPs rises gith average DBPs above g5 mm Hg. It needs to be emphasized that the figures in the placebo group have been partl.,, distorted by the fact that I t}8 of t h e ~ ,,ubjects began active treatment during the study because their DBPs n~se persistenth above 110 m m Hg. If the D B P o f t h e ~ subjects had been ~llowed to remain untreated there would undoubtedly have been a shift in the placebo group to the higher average DBPs. It is of interest that in both the active and placebo froups thc,se with higher screening blood pressures, irrespective of average DBP. had more TEPs (Table X). This change was less obvious in the active
TIPS November 1981
296
-
]-ABLE VII. Bloot~ pressure levels throughout the trial
Screening diastolic pre,~sure (mm Hg)
Number o(* subjects Active Placebo
95-99 ItH;-104 105-10t~ r~,tal
756 558 321~ 1(~33
Mean of average DBP m m Hg while on trial n:gimen Active Placebo
Mean of screening DBP mm fig Active Placch~
763 563 291 1¢~17
96.q 1019 1116,7 100.5
97.0 I01,9 Iik'~.7 1181.4
87.2 88.8 t111.2 88.3
92. I 94.5 97.5 93.t~
glean of fallt in DBP mm Hg Aclive Placebo
9.7 13.1 16.5 12.2
5.0 7.4 q.2 ¢~.¢~
* This table does not include the 176 subiects s~ho ttid not have "my blood pressure readir~gs after entry. ~'Difference between screening DBP and average DBP. "fABLE VIII. The number o r patients with DBP within specified :ar~:~,esafter active or placebo t,catment ~'recning DBP
I IHk- I t~,~
tpS-t~t~
Average DBP <90 91694 ~5-99 • liNt Total
Active 543(71.8) 144 (19.1)) 46 (6.1) 23 (3.0) 75h ( IIX))
Placclx~ 255(33.4) 244 (31,9) 183(24) 81(10.6) 7h311 Ill))
Active 335 (60.0) 142 (25.4) 48 (8.b) 33 (g.t)) 558 ( I(H))
105- IOt~
Placch~ 421 (21.5) i74 (30.')) 146(25.~) 122~21.7) 563 ( I!*01
Actiw: 166 (51.t)) 84126.31 49(15.3) 21 (~.6) 320 (lq~0)
Placeh~ 31 (lit.hi ~4122.01 83(28.5) 113(38.8) 2~ I ( I(H))
I:igures in parenthesis are percentages. ] A B L E IX. "lhc relationship between trial end point rates and average DBP values Aw.wage DBP n -~ '~)-q4 ,~5-nt~ --I~P ~otals
Population %
1044 370 143 77 1634
Active TEPs %
(63.8) (22.0) (8.8) 14.7)
53 23 12 3 ~1
5.07 6.22 8.39 3.89 5.57
'fABLE X. Sho~ing lhat subJeCtS with higher ~rcening blood pressure produced a higher percentage of fEI~,,
Scrccning BP L~5-9~J 10(~-i04 IO5-1ll9
n 756 558 32O
Active "HiPs % 37 32 22
4.t~ 5.7 6.~
n 763 563 2~1
Placebo TEPs % 53 45 2t~
6.t~ 8.0 t~.t~
than the placebo group. It may reflect in patti the presence of a greater incidence of pre-existing hypertensive vascular disea~ in tho~- with higher screening pressures, or ma.~ rcdect the fact (Table VIIi) that those with ldgher screening pressures had a greater tendency to retain higher average D:BPs. Dia:ussion This study has provided valuable information about the natura' histo~ of mild, m~complicated hypertension. The data confirm those obtained from Life Assurance svatistics, that even minor elevations of blood pressure induce an increased risk o[ cardiova~ular disea~, and that effec-
,
Population %
4O7 482 412 31tL 1~17
(25.1) (2tLS) (25.5) (1~.5)
Placeh~ TEPs % 23 26 32 46 127
5.65 5.39 7.76 14.5~ 7.85
tive control of blood pressure to below 94 m m Hg can be expected to leducc this risk. The data also indicate that in about half of the population identified as having mild hypertension, the blood pressure fell to below 95 mm Hg over a 4-year period, and that when this occurred spontaneously, the occurrence of vascular co~nplications was nluch the same as in t h o ~ whose pressures were reduced to this leveli by pharmacological hearts. Of the remaining subjects the blood pressure r o ~ above I:he mild range in about 12% of the total populu, ion, and remained between 95 an¢~ 109 n m Hg in about J,0% of the whok. popuiation. It appear~.~ from t h e ~ data that about half of the total population whosq: blood pressures did not fall could have b~een expected to have derived benefit from :.mtihypertensive drug tr=zatment. From the practical therapeutic point of view, ~hesc data allow two alternative approaches,. One would be to treat all those who are found to have DBPs above 95 mm Hg on several occasions. This i~ a simple ap0roach, which has the merit ef ensuring th~:t al!! patients likely to be at risk receive treatment. The second: approach, perhaps
more logical, and certainly cheaper, is to continue to review these patients but not to offer active treatment until it is clear that the blood pressure is rising or remaining high. The major practical difficulties in such an approach are to define the point at which a decision is to be taken and to avoid bias in blood pressure measurement. The study does offer some broad guidelines, since it appears that the higher the screening pressures the less probable is it that the pressure will fall, but in individual patients, the decision as to when to initiate treatment will remain a difficult one, usually only to be resolved by close observation over some time. The results of the study show a significant reduction in cardiova~ular deaths, and in the occurrence of stroke. Although the risk of these events appeared to be small in this population of mild uncomplicated hypertension, the benefit of treatment is clearcut. It is reassuring that serious side effects of treatment were extremely infrequent and that satisfactory control of blood pressure could be achieved easily in almost all patients. These factors, taken with the reduction in risk suggest that when there is doubt about the need for treatment, the risks of withholding drugs are probably g~eater than those of giving them.
Readinglist I Paul. O. ( I '-~71 ) Br, Heart J. (Sappl) I 16, I 16,- 12 I 2 Veterans Administration Co-operative Stud,,, on Antihypcrlensivc Agents (1967) J. Am. Med. A~soc. 202. 102t~-1034 3 Veterans Administration Co-operative Study on Antihypcrtcnsivc Agents (1~70) .I. Am. Med. Assoc. 213, 1143-1152 4 Managemt nt Committee ( I ~Stl) l.an('et i. 126 I 5 Abcrnath). J. D. (1~74) Med. J. ,4ust. I. 821-824
Profes.mr Austin D-vh, Ls Chairman and Professor o f MedMne w the University ~ Melbourne. A ]h,r medical appointnw,lts in the U.K. he went to the Universio, o f Otago in /952 as Senior Medical Research Officer. From 195" Io I Q66 he was First Assistant and Reader in dw Department o f Medicine at Melbourne, after which he n'ceived hi~ present appointment.
II II
2'+3 I
The Australian National Blood Pressure Study
order drug (alpl,at-mcth,.I d-pa. propranolol or pind,,l,,I), or i~qh. t,,cn: added %ub,,cqucntl}. third ohc'l drug, (hxdr.da l i n e o r ¢ l o n i d l n e ) ~ c r c A l t o n i| nec¢.~%tlx i n l l l a l h , t h e t~hlec: t~.~ t,, r e d u c e i ) B P tt~ ell mm Itg or It.,,. but :t[lt:r 2 ~.C;IP, the gtmi
~a,, Io~ercd to 8it mm I in.
A. E. Doyle"
P L l e c l ~ t t a b l e h , ~ c r t " i d e n t i c a l Ill ;tp~.',:lr-
Utliver+ily of .+lelhourne. Ih,parlmenl of ,th,dirm,., .,tl~ton II¢,Vtlltd. Ih'uh'lherg. ~0+~4|'l~ l,,ll,i, t u s / , . h a
+race to the a~'tit¢ tablet,, In ;In a l k ' n l p l h, athlete"
Inlrodtmllon
more were asked to return for a ,,¢etmd pilif
There is very strong evidence that even a minor degree of hYl~rtension leads to an increased risk of premature death from either stroke or e o r o n a ~ heart di,~a.~L Since the development of antihypertensive drugs 30 years ago. several reixlrts have confirmed that effective treatment of
of mcasurcmc.nts I - 2 ~cek,. l a k ' r ±%t thi,, Mags:. thc average of the h m r readings ~a.~ estimated and individuals x,~ith a~,erilge
readings bet~,een ~5 and I ~1~mm lie and in ~hom nt)exclusion factors Acre pn:,,cnt (Table I) became eligible to join the ,,ruth.
severe hypertension reduces both mortal- "lAlfl+l I l wlu~,,,n f.,ch,r~ i'y and the incidence of cardiovascular Vi',ll Ru.v, tm l,*r ~.-*.¢l:~,l+,n complications=: the Veterans administra()n trcatnlcnt t,,~ h,.pt'ryon study of patients with diastolic blood l:ir,,t ,,.cr¢cnlng ~.i',II lcnMon in pa~l ~ m+,nth,, pressures between 90 and 114 mm Hga Angina pt'c.',,ri,, h~ R,,',*: suggested that patients with less severe .~'o m d ~-n:cnlng t NI qUCM I~ ~n;ldirc ~a hypertension might aim benefit. This study tilth,n, ot m, ~alrdiai was comparatively small: the subjects were infarction in past three m, ml h~ all men, and the blood pressures had been Hl~lor.~ : )( ',l "okc taken in hospital. There was a high prevalPrcgnan,3 ence of pre-existing cardiovascular disea,~ Taking t.~-~.lr,gcn and in subjects entering the stud)'. The major p r o g t . ' , i l c n , n c in question left unanswered by these studies o~mhinalt +n A,,thma. di~ ~:tc~, gout was whether antihypertensive drug treatPrima~ cau. c of ment would reduce mortality and the pre- Clinic ~isit h.t tx:rtcn,, on valence of cardiovascular complications in k ~.idcncc of a population with mild hypertension free of ¢crcbro~,a~ " u l a r t.h~c ;.I,~..'. pre-existing hypertensive cardiovascular lran,~ient ~c r~hral i ~ h ; , c m i ~ . ".dl.|ck,.. ,tCUlC complications. A second and related quescoronal3 i v.utficicnc~. tion was to what extent failure to treat such plasma ct, atlnlnc "2 individuals would lead t o the premature mg dl ' development of deaths and complications Other ,~CrlOt ". of cardiovascular origin. ¢omplicathm~ of The Australian National Blood Pressure h.~tx'rtenqon F.('(i ¢~.ldcncc of Study ~ was designed to give answers t o m.x o c a r d l a l l~.'hacmia both these questions. The study was a An.~ potcnllall?, tatal placebo controlled therapeutic trial of di~;w2 antihypertensive therapy in 3427 men and Taking tric~dtc a n t i - d e prc~,%.lnt ,, women with defined mild hypertension, recruited from the general population by screening. Those with pre-existing Those volunteering its do so attended a cardiovascular disease were excluded. special clinie, at which a historx and ph~,,ical examination, eh.'ctrocardiogralph and Methods biochenlical examination of urine and Subjects were recruited from the general plasma w e r e |~2rfi~rlllett. population by screening by trained nonThose entering the trial ~ser¢ randoml.~ medical persomtel under standardized allocated either tO the active or thc placch) conditionss, using random zero sphyg- group. Randomization ~ as stratified !~ sex momanometers. Diastolic pressures pha,~ a n d t o t h r e e a g e g r o u p s . V (dim=ppearance of the Korotkoff sounds) Subjects in the active group were gixen (DBP) was used throughout the study. chlorothiazide 500 mg dail.~ as the first Individuals with a mean of two immedi- order drug. Thereafter. if control of blood ately consecutive DBP of 95 mm Hg or pressure was not achieved, the do.~ was incrca.~d to 500 mg twice daily or a second * On behalf of the Management Committee.
comparabh:
takin*, in b o t h
p,lth:m,,
groui~.
,d
tablct-
,m e,,tlanatc
+~,P,
nhld¢ o| the nunllx.r,, of ,ublcct,. ill the actitc" g r o u p llkeh !o n.-quirc ,inc. t++,~,,r n~llr~." d r u g , , t o l ) b h l l n lht.. th:,,IroJ h.'du+dlIt Ill
l~ bl,,~l pn.'+,,ur¢, in ,wc,,rdancc x+lth thi,,
t:,,timat¢, t~,,, in three el the plalceb,, Cr,,up ',~.erc r a n d o m l / c d t,~ the lir,,t order placcl~, tablet or.h. tx~t+ in nlA¢ |o I1;ltC ;.I ,,:c,,nd ,+rdcr tablet added and the lelnainlilg t,nLm nine In ha~c ,t tlurd ,,rdur tablet added later. SubJect,, attended the cllnic~ ;it 2-~cckh
mte~al,, during ,,tablll.,atu,n and then at 4-monthh intcr~al,,, or rnorc frequently, at the di,,cn:tion of the 'qlld~, c e n t r e dth.'tor~,. At each 4-monthh ~i,it. bh,M pre~,,ure t~as measured, tablet do%', t~cre adiu-ted if neccs,,ar,, and e~ick.nce h,r t~:eurrence of trial end point,, (TEP) (Table II) and treatment side effect,, x~cre ,,ought. Full clinical, biochemical and electrocardiograph examination,, t~en: made annualh. If at anx ~i',it DBP ~a,, 1 ll| mm Hg or more. or systolic bh~,d pressure (SBP) 20*~ mm lfg ,it more. ";irther xi',iIS were arranged at short int.'r+als. It at three ,,uch
,.ucces~ive visits ~ ithin a ~-~eek p~:riod the blood pressure remained a l ~ e the~: thresholds, dcfiniti;e anti-h.~pcrtem, isc treatment ~ a , given, lhe,,c .,ublcets ~crc classified as "pressure limits exceeded'. This - a s not a TEP and they," sub lech, remained in the stud~. I -~BII Ii l u.d ~.nd p,,mt,
Fatal l)c.tth Item an~ CatU-c(,.tu,~ ,,! ,l~;tth ,+x.mcd) { a ) {. ',l rdlo% a,~.ular" tb)t )lher
i ['lrolllbOlh.' e l h.|~'llh,t r~1,.igl,. ~.~:l,'bh+~,.l'.,~:ul,tl d|',.~.'.l,,c | I.IIIMCI)I ¢crcblal I'..C'101~'lllh." .ttt.t~k', t~ Ith o1"~'~2l', t.'tj lie Llft.'lO~h.'al ",l~ll ~,
M~,~:ardial Inf,th:lh,{1 D'. '~, tit ) ~,stcg,,r~ I ,,r II t ) t h c r i ' . , c h a c n l i c h v a f l d1~4.',1',.4.• l'~. r , , ' ~
qLiC'~tlOllfl,llfk'
ot d~.'fmcd ! C(.i ~ntcrt., {. "ongc'~ID, C cardhlc l.~dtl[,,.' |}l~,%'Clil)l~ .IOcUI"%MT) ~'| |hk' .Iofl.t Rt.'tin;il h;.icfllorthag¢,,. ~:~.tkl;.th.", Or r~,tl'qlh~.'dcnl,i
1t~ pcrlcnsiw cnccphal,,path.~ (h~,,ct of renal fiulurc ~ ith pla,.ma crcJlimn¢ clc~atcd abosc 2 mg dl * Cardio~ a~.'ulaf dealhs arc Imutcd to the,< cau~'d b~ the condition', li,~tcd under nt ,n-tital Tk P. ~:' Ll.~.,,ietN,~rth.floltand Ha,mcdz, al P:¢,'. I ' ~ l !il~. ~, r.l.l"
TIPS November 1981
294
-
TABLE IlL Comparabilityof activeand placebogroupscharacteristicsat entry Active Number Mean(SD) I oral subjects Age (years)by 10 yeargroups
Sex ScreeningDBP (ram Hg)
ScreeningSBP (mm Hg) SerumCholesterol level(rag dl- *) Smoking
30-39 40-49 5O--59 60-fi9 Meanage Male Female 95-99 100-104 10.T--109 Meanscreening DBP mm Hg <220 >220 Meanm8HI" Non-smoker Smokers
Placebo Number Mean($D)
1721
1706
229 546 653 293
223 514 680 289 50.4 (9,0)
50.5 (8.9) 1085 621 814 589 303
1085 636 799 589 332 100.5 (4.0) 157.7 (15.0)
100.4 (3.8) 157.1 (14.4)
691 1030
742 964 229.8 (44.0)
231.9 (44.5) 1303 4i8
12¢~7 439 5,5 (!.4)
Serum UricAcid(mg dl-') Myocardialinfarction prior to 3 months
5.5 (I ,4)
6
Any TEP which occurred subsequently was counted against the trial regimen to which they had been randomized originally, in effect therefore, the study was a comparison between 2 regimens relevant to medical practice. In one, subje~s were treated by pharmacological agents from the time of diagnosis of mild hypertension, while in the other, subjects were kept under observation (on placebo tablets) from the time of diagnosis and treated by pharmacological agents only if their blood pressure subsequently rose above the defined mild range. All subjects were given advi:-~ on weight, smoking and diet, regardless of the regimen to which they had been randomized. To maintain continued attendance, subjects missing appointments were contacted by telephone, letters and through their own
8
doctors The need to take tablets as prescribed was stressed and compliance encouraged by question and by residual tablet count at each visit. Detaiils of the methods of management, and the statistical analysis have previously been published'. Results Of 104,171 subjects screened, 3931 were randomized. In 504, pressures fell before tablets were due to be dispensed and never again reached the threshold to qualify them to start tablets (i.e. 95 mm Hg DBP or 200 mm Hg SBP). The number eligible to start ,:tblets previously defined as the 'trial population' was therefore 3427 which was 3.3% of those screened. The :tctive and placebo groups in the trial popula~tion were well matched at entry
TABLE IV Statusof the trial populationat end of study Active n
Continuingon regimen Trial end points No trialend points "ibta}
Placebo %
n
Total %
n
%
91 1047 1138
5.3 fi0.8 66.1
127 953 1080
7.4 55.9 63.3
218 2000 2218
6.4 58.4 64.7
Prematurely~toppedrel~imen Trial end points after ztopping No trial end points Lost to follow-up Total
47 494 42 583
2.7 28.7 2.4 33.9
41 539 46 626
2.4 31.6 2.7 3b.7
88 1033 88 1209
2.6 30.1 2.6 35.3
Grand total
172!
100
1706
100
3427
100
(Table !11), for length of time in the stud)' and person-years exposure. The status of the trial popt,lation at the end of the study is shown in Table IV. About one-third prematurely stopped the regimen to which they were randomized. Those who stopped did not differ in entry characteristics from those who continued on their regimens, except that they included a higher proportion of smokers (29% and 23% respectively) and a higher proportion of women (42% and 34% respectively). There were no significant differences in entry characteristics between the subjects of the active and the placebo groups who stopped prematurely. Thus, in subjects who prematurely stopped their regimen, the match between the active and placebo group in respect to entry characteristics, time of stopping, TEP rates, types of end points and reasons for stopping, makes it unlikely that factors associated with premature stopping biased the results of the trial in favour of the active group. There were 2218 subjects, 64.7% of the thai population, who continued on their trial regimen either until a TEP occurred or until the end of the study. The 'on treatment' analysis takes into account the experience of these subjects together with the experience, prior to stopping, of the ! 209 who prematurely stopped their regimens. The 'intention to treat' analysis takes into account the person-years exposure to risk of all 3427 subjects and the TEPs that occurred before or after stopping in the 3339 subjects whose status was known at the end of the trial. Trial end points In both the above modes of analysis, the rates of TEPs were lower in the active than in the placebo group (Table V). There were significant differences in both analyses for total TEPs and cardiovascular deaths. The differences for total deaths and non-fatal TEPs were significant only in the 'on treatment' analysis. The differences in rates wer~ such that by the 'on treatment' analysis there were seven fewer total TEPs including two fewer deaths per 1000 person-years in the active group. The numbers of TEPs in different diagnostic categories are shown in Table VI. Over two-thirds of all TEPs were due to ischaemic heart disease, predominantly non-fatal events, which occurred in similar numbers in the active and placebo groups. By both modes of analysis fewer cases of fatal ischaemic heart disease occurred in the active than in the placebo group; the numbers were small and the differences
295
TIPS - N o v e m b e r 1981
just short of significance in t h e ' o n treatment" analysis (P = 0.05 I). There were about half the number of total cerebrovascular events ih "he active compared with the placebo gro,~p and this was so for fatal strokes, for non-fatal strokes and for transient ischaemic attacks with observed neurological signs. The difference was significant for all events (P < 0.025) and for all non-fatal events (P < 0.05). Non-cardiovascular deaths were similarly distributed between the two groups. The cumulative occurrence of total TEPs and of all deaths for subjects continuing on their regimen is shown in Fig. 1. Differences between the groups emerged early in the trial and when analysed by Cox's technique were significant for all TEPs (P < 0.01) and for all deaths (P < 0.05). Blood pressure responses
The average of all DBPs recorded after commencing either active or placebo tablets has been estimated. The relationship of these average DBPs to the initial screening pressure is shown in Tables VII and VIII. It is clear that there was a general tendency in the placebo group for the average DBPs to he lower than the screening pressures, While the average fail in pressure was greater in those with higher screening pressures (Table VII), the numbers whose average DBP fell below 90 were smaller in those with the higher screening pressures, Table VIH. The relationship between the occurrence of TEP rates and average DBPs is shown in Table IX. It is clear that for each DBP class there is little difference between the occurrence of TEPs between the actively treated and the 130
120
...... ACTIVE PLACEBO
j
/
~
T A B L E V. Incidence of trial end
points(TEP)"
Intention io t.'eat Active Placebo n ~ 1721 a = 17116 No, Rate No, Rate Fatal T E P Cardiovascular Non-cardiov&scular Total fatal
g 17 25
I. ! 2.4 3.6
1lg 17 35
Non-fataITEP
113
16.2
133
All T E P
138
19.7
1614 24.5*
i
2.¢~g 2.5 5. I
4 5 9
19.4
I! 14 og
!~
1.7
i~
2% 12 3 7*
142
15.5
lU,~
2(! 8f
91
17.2
127
24.5§
" R a t e s per 1000 person-years exposure to risk; t p <0.()5; t P <0.025; §P <(p.OI. T A B L E VI. Numbers of trial cad points by diagmwtic categories
Ischaemic heart disease Fatal Non-fatal (a) Myocardial infarction (b) Others Total Cerebrovascular events Fatal Non-fatal (a) Haemorrhage or thron~bosis (b) Transie:tt cerebral ischacmic attacks Total Other fatal Aortic a n e u ~ s m
Non-cardiovascular (a) Neoplasm (b) Other Other non-fatal Retinopathy Congestive cardiac failure Renal failure Total
A
B
Intention to treat Active Placebo
O n treatment Active Placel,a~
in premature ithdrawals afler qoppmg ( A-B} Active placclx,J
5
II
2
8
.t
28 b5 98
22 76 109
t8 50 7(~
!~ 6,3 88
lO IS 2S
I 21
3
6
2
4
I
,"
i0
Ib
7
13
3
3
4 i7
'~ 3!
3 12
.~ 2.~
1 5
!
0
!
o
I
o
.
9 8
8 9
I 4
2 4
S 4
¢~ 5
2
5
!
4
I
i
3 i 138
3 2 108
2 i t)l
I 2 127
I 0 47
2 ~ 41
placebo group, and there is no clear support for the idea that factors other than DBP might be influencing the occurrence of TEPs between the active and the placebo group. Furthermore, in both the placebo ~0 80 "" and actively-treated groups TEPs occurred m 70 more frequently as the average DBP rose. An exception to this statement is the low occurrence of TEPs in the actively-treated ¢~Ou"40 6050 ~ / /ALLTEP group whose DBPs remained above 100 but the numbers of individuals in this group are so small as to cast doubt on the validity Z 30 ,i" of this figure. / 20 . . . . it appears from these data that the differences in occurrence of TEPs between ......... the active and placebo groups arc due 40O 8O0 1200 lt~0 2O0O mainly to the fact that in the activelytreated group 85% of the population DAYSINTRIAL attained DBPs of below 95 mm Hg, Fig. i. Cumulative incidence-oflrial' end poims.
110 10¢
On Ircatmunl At'tire placeh~ n -- 1721 n = 17(~ No. Rate No. Rate
whereas in the placebo group only 45% attained such levels, it appears that the incidence of TEPs rises gith average DBPs above g5 mm Hg. It needs to be emphasized that the figures in the placebo group have been partl.,, distorted by the fact that I t}8 of t h e ~ ,,ubjects began active treatment during the study because their DBPs n~se persistenth above 110 m m Hg. If the D B P o f t h e ~ subjects had been ~llowed to remain untreated there would undoubtedly have been a shift in the placebo group to the higher average DBPs. It is of interest that in both the active and placebo froups thc,se with higher screening blood pressures, irrespective of average DBP. had more TEPs (Table X). This change was less obvious in the active
TIPS November 1981
296
-
]-ABLE VII. Bloot~ pressure levels throughout the trial
Screening diastolic pre,~sure (mm Hg)
Number o(* subjects Active Placebo
95-99 ItH;-104 105-10t~ r~,tal
756 558 321~ 1(~33
Mean of average DBP m m Hg while on trial n:gimen Active Placebo
Mean of screening DBP mm fig Active Placch~
763 563 291 1¢~17
96.q 1019 1116,7 100.5
97.0 I01,9 Iik'~.7 1181.4
87.2 88.8 t111.2 88.3
92. I 94.5 97.5 93.t~
glean of fallt in DBP mm Hg Aclive Placebo
9.7 13.1 16.5 12.2
5.0 7.4 q.2 ¢~.¢~
* This table does not include the 176 subiects s~ho ttid not have "my blood pressure readir~gs after entry. ~'Difference between screening DBP and average DBP. "fABLE VIII. The number o r patients with DBP within specified :ar~:~,esafter active or placebo t,catment ~'recning DBP
I IHk- I t~,~
tpS-t~t~
Average DBP <90 91694 ~5-99 • liNt Total
Active 543(71.8) 144 (19.1)) 46 (6.1) 23 (3.0) 75h ( IIX))
Placclx~ 255(33.4) 244 (31,9) 183(24) 81(10.6) 7h311 Ill))
Active 335 (60.0) 142 (25.4) 48 (8.b) 33 (g.t)) 558 ( I(H))
105- IOt~
Placch~ 421 (21.5) i74 (30.')) 146(25.~) 122~21.7) 563 ( I!*01
Actiw: 166 (51.t)) 84126.31 49(15.3) 21 (~.6) 320 (lq~0)
Placeh~ 31 (lit.hi ~4122.01 83(28.5) 113(38.8) 2~ I ( I(H))
I:igures in parenthesis are percentages. ] A B L E IX. "lhc relationship between trial end point rates and average DBP values Aw.wage DBP n -~ '~)-q4 ,~5-nt~ --I~P ~otals
Population %
1044 370 143 77 1634
Active TEPs %
(63.8) (22.0) (8.8) 14.7)
53 23 12 3 ~1
5.07 6.22 8.39 3.89 5.57
'fABLE X. Sho~ing lhat subJeCtS with higher ~rcening blood pressure produced a higher percentage of fEI~,,
Scrccning BP L~5-9~J 10(~-i04 IO5-1ll9
n 756 558 32O
Active "HiPs % 37 32 22
4.t~ 5.7 6.~
n 763 563 2~1
Placebo TEPs % 53 45 2t~
6.t~ 8.0 t~.t~
than the placebo group. It may reflect in patti the presence of a greater incidence of pre-existing hypertensive vascular disea~ in tho~- with higher screening pressures, or ma.~ rcdect the fact (Table VIIi) that those with ldgher screening pressures had a greater tendency to retain higher average D:BPs. Dia:ussion This study has provided valuable information about the natura' histo~ of mild, m~complicated hypertension. The data confirm those obtained from Life Assurance svatistics, that even minor elevations of blood pressure induce an increased risk o[ cardiova~ular disea~, and that effec-
,
Population %
4O7 482 412 31tL 1~17
(25.1) (2tLS) (25.5) (1~.5)
Placeh~ TEPs % 23 26 32 46 127
5.65 5.39 7.76 14.5~ 7.85
tive control of blood pressure to below 94 m m Hg can be expected to leducc this risk. The data also indicate that in about half of the population identified as having mild hypertension, the blood pressure fell to below 95 mm Hg over a 4-year period, and that when this occurred spontaneously, the occurrence of vascular co~nplications was nluch the same as in t h o ~ whose pressures were reduced to this leveli by pharmacological hearts. Of the remaining subjects the blood pressure r o ~ above I:he mild range in about 12% of the total populu, ion, and remained between 95 an¢~ 109 n m Hg in about J,0% of the whok. popuiation. It appear~.~ from t h e ~ data that about half of the total population whosq: blood pressures did not fall could have b~een expected to have derived benefit from :.mtihypertensive drug tr=zatment. From the practical therapeutic point of view, ~hesc data allow two alternative approaches,. One would be to treat all those who are found to have DBPs above 95 mm Hg on several occasions. This i~ a simple ap0roach, which has the merit ef ensuring th~:t al!! patients likely to be at risk receive treatment. The second: approach, perhaps
more logical, and certainly cheaper, is to continue to review these patients but not to offer active treatment until it is clear that the blood pressure is rising or remaining high. The major practical difficulties in such an approach are to define the point at which a decision is to be taken and to avoid bias in blood pressure measurement. The study does offer some broad guidelines, since it appears that the higher the screening pressures the less probable is it that the pressure will fall, but in individual patients, the decision as to when to initiate treatment will remain a difficult one, usually only to be resolved by close observation over some time. The results of the study show a significant reduction in cardiova~ular deaths, and in the occurrence of stroke. Although the risk of these events appeared to be small in this population of mild uncomplicated hypertension, the benefit of treatment is clearcut. It is reassuring that serious side effects of treatment were extremely infrequent and that satisfactory control of blood pressure could be achieved easily in almost all patients. These factors, taken with the reduction in risk suggest that when there is doubt about the need for treatment, the risks of withholding drugs are probably g~eater than those of giving them.
Readinglist I Paul. O. ( I '-~71 ) Br, Heart J. (Sappl) I 16, I 16,- 12 I 2 Veterans Administration Co-operative Stud,,, on Antihypcrlensivc Agents (1967) J. Am. Med. A~soc. 202. 102t~-1034 3 Veterans Administration Co-operative Study on Antihypcrtcnsivc Agents (1~70) .I. Am. Med. Assoc. 213, 1143-1152 4 Managemt nt Committee ( I ~Stl) l.an('et i. 126 I 5 Abcrnath). J. D. (1~74) Med. J. ,4ust. I. 821-824
Profes.mr Austin D-vh, Ls Chairman and Professor o f MedMne w the University ~ Melbourne. A ]h,r medical appointnw,lts in the U.K. he went to the Universio, o f Otago in /952 as Senior Medical Research Officer. From 195" Io I Q66 he was First Assistant and Reader in dw Department o f Medicine at Melbourne, after which he n'ceived hi~ present appointment.