Document 6645

ACTION SERVICE 93'54 3%I (YIED)~2 . ?TH 15 :21 T. ;5 :23/'N0. 35?G13553o P
Cigarette smoking, tar yields, and non-fatal myocardial infarction :
14 000 cases and 32 000 controls in the United Kingdo m
S Parish, R Collins, R Peto, L Youagnan, J Barton, K Jayne, R Clarke,, P Appleby, V Lyon ,
S Cederholm-Williams, J Marshall, P Slight for the International Studies of Infarct Survival (ISIS)
Coliaborctor s
Obfecdeas-To sasses the effects of cigarette
B8F/rcami Rc
Gllnlol Tr l$ Service Unit
agd XOA.ealoloalal
Studio Unit, Naffuld
Depart mean ofC ha l
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CsrdLn Depar
, me r, john
Eadeli>feHoepitsl, Otdtsrd
OXI 9011
S Parrish, terser r+wmeh
R CoUina, Brivish Room
Fa9sdaias wniar rovarak
R Pcta,prvJrrror vfmdicd
xaasde and sprdrarfslear
LYourgman, wafer raeamh
tffa w
ltiiyuk swrctar os6,rpeisr*amr
R Cbrtss, rasach f lks ,
P Appleby, ,aws .rJ, fdlorrr
of Lpoa, "amok 1d1,n
P SldgfG prgi ;uur oetrina of
rmdivoa k'raadaors
Osfmd Bb-Research
Leboratary, Magdalen
Sdem*Pesb,, Oi&rd
Oxe 4GA
S t oderholin- ilhsmt,
1MarehaU, rare ci faao w
Contspoodcacr W :
Dr pm"
In countries such as the United Kingdom, wher e
smoking on the incidence of nonfatal myocardial
cigarettes have been used widely for several decades,
inf rudou, and to compare tar in different types of tobacco now accounts fat about 30% of All deaths in
mwmfacsmed dpreucs.
middle age, with lung cancer and coronary heart
Methodt-In the early 19906 responses to a postal disease the most common fatal conditions." Over the
queednnnalre were obtained from 13 926 survivors of pest few decades cigarettes have been altered in various
wyoe+sdiat laf>uctioa (tetra) recendy discharged
ways, reducing the to celled yields of tar and nicotine
from karpir:sls In the United Riagdom and 32369 of
when smoked in a standard way by a machine. Typical
British c,gareaes had tar yields of 25-3 S mg during the
their rdstlves (controls) . Blood had been obtained
hum cues soon after ad,at den for ebe index
1950s and 5-15 mg In 1990' Buy partly becsosc
myocardial infaretien and was also sought from the
the chief toxins in e{garere smoke are uneanin and
controls . 4923 eases and 6SSO cv nfrols were current partly because smokers may compensate for reduced
emokars of manufactured cigaratrer with known
yields (or other changes) by smoking cigarettes more
rear yields. Almost all tar yields were 7-9 or 12-15
actively,- the health aft= of 21r mores in cigarette
mgfciprette (mean 7•S mg for low tar (< 10 mg) and
manufacture arc unpredictable . Low rat cigarettes do
13 .3 for medium tar (a10 mg)) . The cited risk cruse substantial take of cancer and heart disease,
autos were standardised for are and sax and comalthough the risk of lung cancer is less than with high
paasd myocardial infarction rafts In current
tar cigarettes ."'-" For heart disease, however, thug
dsaret*a simwkan *ith those in non-smoker who
remains uncertainty"-" about whetter the rats he's
had nor ap+q)xd cigaremes regularly In the past
been decreased, increased, or not changed by alte
10 yearn .
:etti Composition oser the past few
ReedtrAt agd 30-49 die rases of nsi+oea dial
deeadee . Nato" heart disease mortality rarest and
.Qtiefi in makers were chant five times these In trends are fiat ififen7tative because ocher factors arse
ten-smokers (as deeaed) ; at ages 50-59 they were such large differences in coronary heart disease
thew times those in non-smokers, and even at ages between different populazovs and time periods .
60-79 they were twice as greet as in non-rockers Instead, concurrent epideauologicsl comparisons
(risk ratio 6 .3, 4-7,1-1, 2 .5, and 1 .9 at 30-19, 40-49,
within one population are needed.
50-59, 60.69, 70-79 respectively; each 21v<0.00001) .
But, although tobacco is a major cause of heart
Ater eamdardiasrion for age, eta, and amount disease, particularly among young and middle aged
emoksd, the rate of mm-fetal myocardial infsrcdon
adults, it 13 difficult for conventional prospective or
was 1d-40/6 (SD 5 .4) bigmer In medium tar *an In low retavspeUvc ewdks to compare the risks from diftar cigarette smoker, (2P•0.06) . This peaeenrage ferent types of cigarette . Only a narrow range of
was not egalSrsndy greater at ages 30-59 (16•ff,L cigarette tar yields is eoneutreedy available withic one
(7.1)) than at 60-79 (1.0'/. (S'S)) . In bade up ranges
population, and the tar yields of cigarettes smoked by
cite difference in risk between cigarette smokes and
people in 1990 might correlate poorly with the tat
netts-smokers was much larger than the difference
yields smoked by these people years earlier. Hence,
even large differences in dsk between prolougod use of
between one We of cigarette and another (risk ratio
low, medium„ and high at cigtrccces might produce
3 .39 end 3 .95 et ages 30-59 for smokers of similar
members of Saw and of medium nor ciger .we,, and only small dl$irvnces in risk between cgrrenr use of
risk ratio 2 .35 and 2.37 et ores 60-79) . Mum possible low and medium tar digarettes. At younger ages the
conAppadvRg facmfs dot could be rested for were proporoopal difff=cr id rated of eere:ury heart
similar in low and medium bar users, with no
disease between seokets and em1-smokers is pardatufgfalSotmt dl>seseaces in blood lipid or albtmmdn lady ewe, so any cffu t of cigarette type may also
be extreme . Thus, to minimise the chances of a false
negative result in a study of tar yields, the number of
Candxefove--The present study indicates that the
cases of myocardial iufarcoon in middle aged dgarecre
basmodrsent change of tar yields In the European Unions
srnolcers should be large--preferably scvail thousand
to comply with an upper limit of 12 mgfcigaretee will
not Increase (and may somewhat decrease) the -with at least as many controls . We achieved this
by studying subjects from the United Kingdom
facidmcc of myocardial imdarcdoo, ettlesa they
imb'ssedy help pc rpematc tobacco use . Seen low tar who patdeipated in the large ISIS (ratarnstional
Studies of infarct survival) vials of the vestment
agsratsee rem greedy Increase rates of myvcardiel
infierctlon, bowrsr, especiuw -m ovig people in of acute myocardial 41fatftioo,"0 by using Postal
their 30a, 409, and SOs, and far more risk is avoided
qucatlothaaires (copies available an request), rather
by not amoidng than by eheaging frees one typo of than inueviews, and by eimplifyicg blood collection
cigarette to anotlser .
19 AUausr 1995
47 1
;'itiED) 02 . J' 99 15 :21/ST. 15 :20/NO . 3586135585 P 3
Pa eacsaad urcdsoda
a a/ in a atodifteatioa for plasma of their uriaacr
radioimmunoaseay ." Rciv1 With this plaspha a}Uv
correlate closely with those with gas chromarogtaphr .Bcckrnatl CX-4 and CX-5 autosnalysers were used
for measuring concentrations of cholesterol and
albumin (both path Becl®sn reagents) and apolipoproteins At and B (suits Immune reagents) . To corms
for discoloration from haemolycis, an initial blank
reading was subs acted from the final reading. 5ampia
from a large plasma pool were included in each
analytical run, yielding coefficients of variation o f 2
for cholesterol and albumin and 46/6 for epolipopmrrins.
Cases were the survivors in the Uniird I(ingdom
aged 30-79 from the ISIS-3 or ISIS-4 trials who
completed an epidemiological qucadonnaire sent to
them a few months sfatx diet infarction . Those who
was asked to complex it were all Ole survivors from
ISM-3, but from 15154 only the survivors aged 30-59
who on adahissian to hospital were reported to be
ciareete ,molars. Thus, although only eases from
ISIS-3 can be used to compare smokers with nonsmekers, the ease from 1315-4 strengthen the analyses
of tar yields among cmakers shed 30-59. The ISIS-3
questionnaire asked the rases to identify all their
brothers, ilitas, and children aged at least 30
who were resident in the United Kingdom . A
similar "control" quesdonnaire was then seta to
such relatives, accompanied by a second copy, which
the rclnweu, if marred, were to ask their spouse to
complete- One reminder was seat to cases and relatives
who did not reply, and inconsimuclae or omissions
were queried once.
Of the 20 691 ISIS-3 patients in the U aired Kingdaem, 19065 who were oar known to be dead were
posted the ease questionnaire, of whore 1346 were
found to be dead and 13 969 (79% of presumed
survivors) completed it. The control questionnaire was
sent to 30 247 relatives of ISIS-3 cases, of whom 75
were found to be dead and 21995 (73% of presumed
survivors) and 14 245 of their spouses completed it.
Patients with a history of titrvke, gastointesdnal
bleeding, or ulcer tended not to have been recruited
into the ISIS-3 uial," and so pcoplc with such conditions were not digs'bJc aS c49e$ or controls . Of those
who completed questionnaires, 2002 cases and 3851
controls were excluded because they were under 30,
over 79, or of unknown age or because they had a self
reported history of "delralu stroke" or of "bleeding or
ulcer in (or near) the stomach . "
MS-4 patients in the United Kingdom aped 30-59
who were described at trial entry as current amokas
were also aeat the questionnaire . The response rest
for such patients was similar in both trials . Any of
theca ISIS-4 pagears whose questionnaire zcipoese
indicarod *et they were not cigarette smokers at the
pmt of their infarction were excluded . 1513-4 (and, to
some extent, ISIS-3) tended to exclude patchier with
chock or pervisaersr byparension,' but such exclusions
should not bias the epidemiological analyzes of tobacco
Information was sought on sex, age, batik- size
smoking, dcin1S1ng, past health, and relatives. Cease
were ,eked about their habits and hisboty jets before
their index myocardial infarction (because haring a
heart attack may ulcer a pedant's habits), while contzn{cr
were asked about their present habits . Kence, questions to cases often began, "Before your recent hospiai
admission. . . ." Roth cases and controls west asked
to lilt how many relatives of certain types then bar .
but only cases acre to provide contact details . In
other respects case and control queadomaicoa weze'
. ore was nenidcnrkaL The inc" history se
technical and recorded various conditions that mid
be assocismd with exclusion from the randomised trial
(see above) or that might affect, or be affected 17,
stroking. After the question of whether they had "env
smoked regularly Cie on meat days for at least a F=,~^
the rest of tau cigarette section was to be coeplent !
only by those who replied 'yes ." It dealt with the age az
which the subject hid first and last smoked regale==,
whether any cigarettes had been smoked in rte k.evious month, the number smoked per day wb.m 16 -subject had WE smoked cigarettes segsdady. and the
way in which ciguccres were smoked. People was to
rick against 137 derailed brand rimes the ace &e•,
what they Inc smoked, they usually smoked most eat, if it was not an the list, to write out its eaatu I-fY
(and, whenever possible, to enclose the peclbgiag of
that brand with she qucstionnsimr) . For the caw wso
listed more than One brand, the average of the yi&S
was taken- Ninety eight per cent of controls and 9°'' .
of cases who Currently stroked only mamtfscr>z-d
curettes with a )maim tar yield, and both :s tmt
using their corrects: brand for, an average, the parr 1i)
or 11 years .
.4015 [email protected]
Blood was to be taken froth p2tirm5 in ISIS-3
ismediately after randomisation but before the anal
Qeswents and eolleeeed in a 10 ml vecurainer conraining 0-I2 ml presarvative (15011 potassium EDTA
a+kfi aptmtimiss: 0 .34 mnlol/l: Becton Dickinson), on
reeurming their quecdonnsire, controls were sate an
identical container for their general practitioner to
collect blood . Case and control containers ware sent by
Scat class post m Oxford . Controls were sent one
reminder about giving a aapsple, A her a moan of two
days in the post the blood was centrifuged, the packed
ell volume was recorded, &Ad dhe plasma and huffy
coat were aficluoted for storage at -405C . Blood arrived
from 97% of ISIS-3 cases and 45% of controls, but
breakages or haemolysis rendered 5% of that samples
onusable . The present blood analysts involve only
correlations of smoking with blood biochemistry
results, and these analysed abould not be materially
blued by low response rates .
Respondents were daeifed as Current e4mraz z
(26% of the commas : those who had smok
cigarettes m the previous month, plus the few who
failed to answer ibis ym/ne queston but germ ad=
evidence of current cigarette use) ; other eobacoo testa
(3% : pipes, cigars, or smokeless tobacco in the px
year); or as not using tobacco Cllr/-: all oh=s)_ I-cable I these are further subdivided. Because of the
poapble confusion between those who vsapt
smoking ad" years ago and thou who never smokae,
the train compais si group was defined as rrcCr
smokers who had not used cigarettes regulary hi 1c
past 10 years.
Plasma eodnine concentration was measured in
controls who were current cigarette smykeas, and in
a 3% sample of oontroIs who repotted no current use
of tobacco, by means of antibodies developed by Knight
The tfnktsd Kingdom's government chc%6~v% eve
ducts surveys of common cigarette brands, .. . -s
tar, aleoleme, and carbon moddiddt yieIdsy,twfiee a
(R We,, personal communication) . Duiitn to Um
19809 the apaual dusts in sales weighted yids
about 2-30/. for tar, 1-29/6 for nicotine, and gnu 7th
carbon mofOZide (j Renteul, personal coI
don) .' Most 1313-3 cases replied in 1990 eb ez t
.cccsr 1°95
BMJ voL(Ji4n 311 19 .
;WED) 02. 13'991 15 : 22/ST. 15 : 2J,'NC. 358C ,13558t ?
inyararrlisl ln&redon (wain Ante of
ittiltredort! Pebrnaty 1990), most controls replied in
1990-1(meam November 1990), and mostlSLS-4 -see
replied in I992-3 (mean date of infarction : July 1992) .
To avoid secular treads in yields introducing minor
biases, the slid-199O sun, results for each cigarette
brand were used (R Waller' . personal comunlcatlan) .
If a brand was assayed only earlier or later then midL990, yidda flvm die dvscet survey were eatrapoiamrd
eo meld-1990 by animal dcacases of 2 .5% in tar and
1 .5%. in nicodne .
a8ST RVSY O? COM7lO .! A P2w YuARS LATan
To diode mepredt eibllity, about 2000 co ols
who originally returned both qu€stionaalre and blood
sample (and whose replies indicated no previous
vascular disease) were scut the same gnettiooneis and
blood kit spa about 2-3 ytats lira. To avoid over.
sampling yunng cononIs, the random sample wa s
'god with reap= r to vex and age in groups of an
yeas. Severity per cent (1388/1996) tealwrned the
qucidmaaire, 95% (1324(1388) of whom Save blood.
LTATl4TiuaL agrwODS
The anslyvee are ell tla2matcbed-hat is, they
compare cases with all controls, not just with their own
r alseva--6nd. for tar yield analyses among male"
tha console are as relevant to ISI5 4 as to ISIS-3 cases .
All analysts of myocardial in&redon rates were stratified either for r and five year age poup or for
three factors and amount smoked (five categories; see
below). Calculaioas of risk rado*-or, equisaleady,
relative vials--erlta0ed soma lad stratified Iogisdc
is Tars (famed by uaomditional muimum like!!hood), with ova cans ra177r included for eaclt st2avrm .
Risk ratios pee often worn with 95'/0 confidence
iatervala. Tana aided probability thirds (2P) are used.
ran 1-R0eY BY mnoetr u t PR Ad moon am= #dy .
(g Aspeedd deny AWA,v t av (d4% epwrid 20 par jp' .
s,dd'57ia lepmmd 10-3W. (6) Taryiddras 1950 ofdas bamdt r4wrmd
do, of (a) the reported number smoked per 44y and (b)
the e:dmated 1990 of yield. Self repoeoed 4p0ette
constunpdan was caegaeiaed a 1-9, eaectly 10, 11-19,
eseeriy 20, and 2121 agerenes a day; 85% reported
smoldng 10.30 ogarecua a day. The tar yields show a
bimodal distribution, with contmoneet values 7-9 or
12 .15 tng/cjpxr e . Tar yields of 10 mg were rare,
which manses this a natural point of subdivision,
unaffected by stay slight difc men in data of a3e and
coutrol responses, to ddnle two mak camgorissi low
:ar (< 10 w& mean 7-5 sslg) and medium tan (s 10111&
mean 13-3 mg) . Meditrall tar is :Omenmen split imrm 1012,13, and 14 iddprette. This dellnidoa of low tar
is also used by tits Depaaeat of Keith (R Wailer,
personal omemunimtion)! Twenty fm per amt of the
smokers in figure lb use low at cigarettes, as in [bit
nsmonslly representative survey in 1990 . !most al l
FMQvm4crDLYrp.u moMaofsr4Q1Gy4Ogoofi s
Table r shorts the numbed of controls 2nd cases in
various categories of tobacco use subdivided by vat and
by ate. The ace range of ditefrdevance to the tar yield
analyses is 30-59, andaa:tong controls in this tangs 25%
beds of moo. sad of women were alarm dpreae
smokes, is dose ag eepent with pappnlly rcpreecuunfm e, hmarviewa administered arrays is the arly
1990x .+ Twenty two per cent of that cresols were
cum= usara of mam&wntred eipfemes only with
knows mr yields.
Figure I tivm for controls who cutretady used
nraoa gwssd. dprvtn only, the frequency disuibw?AaiaF-Tu6
gar it ems mdemmu4 . ed!O-? cad Inudmmaku nowned
Cm,mr da -Me>•+nlm
Noe ai as aaeb,ee s
adarmbe m
.l oi~gv+a~ Ae
-6mm 70-79
Mw 6001
wwso 60
1m7 awsc
$a 70-7+
00104 90•@1
O ahe
.4 ,
3111 5502
fill 2010
o®R 30 •m 163
laeeeeopI dpma. +wo ks
a dvirxaaaa
Mw 60-79
wove 40-79
218 gas
Ma 70-19 1117
468 1566
447 676
r gNi s
434 647
NO 47
977 1266
272 226
4192 7779
411 4
14 2
-C+matmen std a0ames.
RMI voWM16 3 L 1 19 Avctser 1995
47 3
In Satire 2b the mean eoonine values wsse aboin a
third higher ametog the controls who emoked medissas
tar dermas (low tar 217 ng/mI v mcdhuo tar
292 ngtml) . But the smokcm of low tar dgarcrtm
rtpoeed smoking 15.8 elgareaes a day compared with
19-7 a day for those in the modium w group . Afro
standardisation )br age, act, sod amount stroked,
however, t))c mean Plasma cunel c coaeennkvOn was
suf 19% higba with medium tar ciprettes . This
difference in w ire is sdU highly 9iptg5Cant
(2P <0.00001), which helps validdatt the aregtlewadon
of tar yield based on the qutseionnaite . Bat it is less
ocLtee than The d&rencc of aver 506/r in the nicodms
yldd Per cigarette measured by machine (0 .73 mg and
1 .18 rpg) . This may be partly because the cazcgorisatioa of - yields is impeded, and partly because
smoke's of low yield cigarettes compensate by sa y
490-1 (b)
C.Caolvrr arise dpb'rilr~r
l~u .~p(~~ryCdai~we w.W r-yi,id
in mete smoke per cigarette . Buts dncc this caregnrisa
iron predkrs highly ng stream biechcmicii differences
in blood taken months laces (figtac 2b), it Me some
Cab Uft
esvwhatred drrems
o1Jy (or - Tabaan)
wrJ: .Y,va aleeukesl6f
Jim., '
a4vZ17aodZ9]ri e4amine
gts®s adq .ar JS4d
Je•7,andMU= ' Qrpw
gk_w, .-,. 7.4asdJ3.3 wt
370, 0.734wd J-Jd art rais,dar,
.4ee 4 JS.O iget2(aid '4oe
rr6da 151osdarm odtw sa
Lew nr
6LfYY(4 rjaj~r r, 9/es►
quanxNakiv, Nadia 1
20 Md
ble&taiadavlaroli lea u
emmmmim (pp- 2oa wp4p
kdicead souse t6ias6p tier
0203 No owrrnttobaae (3%21l051$
Tar y (nwft rrra)
TAMS v-Nwrfaas1 eyo,-U i daIdow: £es'nwadt 0100 4(tmatc toe in PWk midi av Xm y uJ
>Regw MropldlPie asa,elaEa~tYrerFe
Llalml GZWW d
A. bras) C . OMMON
Nmaadcew7sw --PJm
ds•ara a6ampaa l0 y,M„
W-4 .1010 1195%
r-s eoanDL mrMwD mdoel
Arts 6-35(441e6.91) 24
4306 4 .66 6Vtm3-6o 15-1
2701 3.10 66 .3.49) 13-7
I1lLD }es CHI w4•343 221
2299 436 (216 W 2 9p 1) 4
362 1-92(14302-ft 44
9241 207 (200w2•72) 12-1
•3arhr r ns .rd6t,a s.r aaaadrdir00 ear eau red res.
When those using maaufacmred cigarettes only
were compared with ==-mlokcts who had not smoked
agarettey regularly in the past 10 yews (eaehlding w
both cases those using any otbar type Of Tebaoco), the
relative risks for non-&W myocardial inft+etion in
people With no precious neoplaetic or maw vascular
diseaso depended strongly on age (rablt IX, fig 3) . As is
the cane for mortality from eeronary 'heart diwase,' 1
the risk ratio ce, i aring smokers with n0A'makers
was grow a younger ages, reinforcing the need for
the role w,ce of tar yields to be eoasidered saparately at
younger and older ases .
InfOtmauon about the ralcvanct ofear yield . comm .
from cum= users of mamlifacenred Cigarettes 0sno . Of
these, much the moat mfo=ative pre the 9000 aged
30 .59, lather than the 3000 aged 40 .79. Tltisis not only
bccaalse the aumbxit are Inger but also because the
risk r ado whm 6mokers m compared with non-
Mroaeriei inbreo m std elglratra migkag•
12 0(10 mw sM 32 ODD cw&vl s
f$we .draea.d' '- br+d>~d6lracttaeartrrlibdi><en9ramnw.
used filtcod bands (100% of the low tat group, 9694
of the medium nr pup), so Slurs accounted for lisle
of the di$cace in ylelda betweee low grid mcdinm tar
aiparaacs in 1990 .
3tt(ATION VZrWzor QU2frIDNr•3Avm AND wrnn2
&au-igh of r6RI UN
Ales maid by lrrloldra
3. I
Figure 2 shows the relation between plena c opine
eances=tlonf and (a) reported daily ciprczra file and
(b) tot yield for conuols reporting use t f manufacruad
cigarettes only or no current tobacco use . The man
eorminc couccutredon was very low in the self reponed
non-zmoketa, which helps validau both quesdonnoire
and laborawsy avuhD. Among dpmtte smokxw then
was a swag Z&6 0A between cot one mncennJtlun
and dig ga oust reposed to be smoked, which spin
helps validpte the guecriotraaire. The downward
ruvantrc It figure 2a sllggees that those who smalls
mote dgarnctes may absorb lets nicotine from each one
or that those reporting Imp numbers include duproporvonarely many who overrepme4 cite both . Hoge
way, self repotted cigarette consumpdon prow dot only
appro 'CUM information about The rsal dosds of
ulconne and of other sobsTaacda.
~' 4
33.9 4Wl 50 .9 1 70-9
AV W79
abk reap 383 &,k , 237
too 3--Cwsarama and not-!d xveaftw ijpr at efipe tease
Ad ,eon or vs,.wt earn Ronde n3 MOO aa* sspnvbw 11ipe.y of
MW eagpla m lsQadto &1061. 304 FU roe . It Aw,oas16ad for
as and /br gwgaaavame of egg eeld aarWWW diver mutt WWWA.oeo avy MA 46M arrr ors Mae aa,.rrbr we
. OW
nold ple
wMBV sad had Mar halls rrtwlor dpi .dM an6Rst a MY Mod w AO
P" JO jeavL Rid coin u thins ad i garb rolrao . (A, all WO
MR&O dJr ,,1SIF-4 so" ataradr ol5Ya16 dwftt+r salbat Q6w
r .byrdISJS3)
SAIJ vowxa 311 l9 Atzt=1999
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TAers ,,,, IV n m,fid rotes n a .nov imaAe7r df nTorw and hen tar semester
l•vgw9mo,awes .NWAl mot
60 ¢snsW6vahem 1990
R.b. of wm .6ed 'a,aeIdML ;a ametlaa
Ord"= tar samoken efles,
(aith h7u c naarnre .tend aid dp,tr6ma)
SCadadbcd for
ere.-Nan d
crasser 'CesW4t Grade 5enda Lae diet mm&wseeee&
mh,edses 1a611e6de (n . 'n.d-dh tithe nspc,*,, ,
5%4 1534 ta£ .ewea) stesa4szom, wnewatmaoed dicoset
1203 1 .166 1 073
(1961 .1•x64) (t•O25w.1 .324) (09cwwt•zi7 )
)26 5
416 e
1P.-0004 3PQ-az ~1+>0 L
AP 6&79,
A,e s0-7v:
170 1
1400 1.019 1 .010
(0.590001 .230) (0.3761 1 .191) (0177L to L-325)
21Oae-1 2PeO .1 aP3'. e . 1
1 .142 1 .104 14Y35
(I'034 m i •255) (0998 e .1-2227 (0-910 0o 1 .173)
W.500! ZP.O-06 2070• 7
e d omeer drMUlor ur yWd o IM 133-11 ffte,
slee.rdus .yen . oft N A rdd , t muet .dt f~ od no
..d) 1000 (Sb Oby )).
trw cw0asabm OUR R a oft irda.e ar yktda, ted.aaet et)ne .ae .ids seine per. aesplasea as sea .
dies. a,., wll omdax es m-Ll b ..d Mype,a(Tir. d. crma.n.
TMS2 tw-.4naieees bd- --).v kaki, ad 1&.d rived m..rn.eaowv. Ydwr .>, suonr CS$)
Gme:we aw
C,arost . to w Non-rrsekerwkss
CWWv*o rtWd
dms.&ea .=d aadp e e .,e
dpnorenly iapaniar .t Lowow Mcdlamor
(_1156) (0.3123) SipaaMeee (0.295) (o.942) Stsaaaee
Lipidma owuncm
r holeleeel (a e .Yq 5-02 (095) 341 th•02) Ns 6-01 (946) 6-05 (ads) Na
AP°CP°P1O . At (dA 1 .277 (0006) 1`185 (9.094) 2F=0.03 1 266(0013) 1-x64(0007) N3
Apoapepeewbll ()01) 1 .354(0 .009) 1 .165 (0005) 29.01004 1422(0014) t-226 (e 009)9
Tealiv-AVrVd-N-ty e(f Nt90ikf
Rmpome warIAN1 gae,deemiee
e mre.9,De"lbsav
Ret9.ate msepmt
goaeocmwim 4d,sus lsett
~t..,odv •,ipuOa,, .,y
Pemw eipteetr m,.ie.r.
Not mtiaa :oeaao
6103aea s l0, .,
was much larger dean the differrnce between one type
of cigarette and another the risk ratios were 3,39 and
3 .95 for smokers of similar numbers of low and of
medium tar ciVt,ntcs at sgcs 30-59 and wt arc 2 .55 and
2 .37 at saes 60-79_ (Table I i shows that results Were
similes when these compariso))s wee : based on the
sma lee numbers of cigarette smokers with no Sported
history of neoplasne or mifor vascular disease . ) DacOMCIORa
Table [V relates smoldog to blood lipid eonc dntradons among ISIS-3 cases entering the trial tsfthin 0-4
hours of pain onset whose blood spent only one or two
days In die pos , and among one randomly chosen
control per case (matched for age, sex, and days sample
spent in the post)- Apolipoprotein Al was 1-a%lower
and apolipoprotein B 24% higher in smokers than in
non-Smokes llVr Cuss` di=c" sr wo small to
aeea,alc for much of the excess risk among smoltets .
There netts no significant differences in blood lipid
concentrations (Or albumin concentration, data not
shown) between smokers of law and of medium tar
cigarettes, either overall or in these aged 30-59 (dsz
nor shown) . For many factors theft wan likewise
no significant dldbre ces between smokers of low
and medium tar eigareaes. These include self
repulsed height, weight, loneliness, depression ,
wt)rry, insomnia, teenage acre, tell consumption,
alcohol coaatrmpds , and whether living with a
apotlse. For a few &-on, however, there Wee definite
diffareecea even after stands di,aden for age sad sae .
(Multivariate adjustment for these observed differences would make little difference, but these
differences point to the powlbllity of others adorns.)
Those who smoked low tar dgarrttea were, on average,
almost six months olds when they left full time
educedon (Mean Leaving ape 15-9 pars for low ta r
group o 15 .5 years for 1Dcdlalm tat), was more likely to
ivy that they had matured physically 'law than
"ero de" (13 .4% . 10 5%), had "so&sr hands the
rw average" (14.40/0 a, 11 .00/.), had been regular drinkers
of cofee (75% u670/#), were older when they faerrCd to
smoke (18,9 a 17 .9 yon old), and had changed to their
1 es 7 3 3 current brand more recently (7.9 v 10 .1 years pre29 1s 50 rl o viousiy) . Thew suggest a general tendency for thos e
who smoke medium tar dprevrea to include a slightly
tte,e~ 2 10 r 374 is larger proportion Of manual workers, and to have
.Nes f s a >9l skigtly less education . (Likt:wtae, unpublished
"mww any net ee lad rs,o.01s91sId an beds egslew (6S d.,)6ed . in un w as41e<tArm w
1.6r. 21 w 1e. d.ea Is. a m medLm e.o 1.., 5,, b . do= abalhw) .
smokers Is more elttrame in middle than in old ago
As there was no aignkilant difference between the tar
yields of cases aged 30-59 in MS-3 and in 1515-4
(table m), the groups were combined.
Table La provides age-set standardised comparison, of aaa-5►mi atyocerdial Infarction in smokers of
low tar vases smokers of medium tar cigarettes .
Overall, there were only slight effeees of the air yield .
The mm daffy ml-be of tenures smoked *aa
dighrly higher in the medium tar than in the law nr
Cigarette smokers (19 .0 v 17.1). When standardised
not just for age and sus: but also for the daily dumber of
(dgasetra smoked, the incidence of myocardial inlhee
don was 10 .06 (SD 5.4) higher in medium than in low
tar dgaltutc smokers (zPao•o6) . This di&renee was
non-> alllaatty geeeecr at ages 30-59 (16 .0% (7.1)
higher 2P=0.02) than as 60-79 (1 .04/. (S-5) higher,
2P>0-1) (fig 4) . As threes two "auks are no
t hil y dArenc fiom eask other, they do not prove tha t
tar yield, in of pew peCpornodll itltpottannce to tba
eardibtaacity of cigarettes in middle than in old age,
especially since the smoker versos non-smoker risk
ratios are low ewetteme in old age . In both age ranges the
difference between cigarette smokers and non-smokers
B11Q VIOLU es 311 19 tumors 1995
analyses by M Jarvis of the 1990 and 1992 general
household surveys in the United Kingdom fotlad
eignillda,etly higher "indices of depre eton" in user;,
of medieuse than of law tar eipretres .)
A total of 1388 controls repeated the questionnaire t
few years lacer, and table V compares their two replies .
When subdivided three ways (men ilIcni ed cigercucs
only, ocher tobacco or a -atests smol9a c to year5i
resesainder), 900/, r+ealained in the same axgog of the
97 who smoked pnly menufactgred cigarettes with tar
known on both occasions, 890/. bad continued to smoiae
medium or low at cigarettes as originally . Overall,
there was a 56/4 shift towards the low tar calagory, in
line with national osuda, and the coarelsdon eoeJiSc ienr between the two assessments of err yield was
0-71 .
When cigarette amolters are compared with non-
smoker the risk ratio for m7umrdiel infarction is
mulch mote e)e,seme in early adult lift than in old age
The numbers eomtributing to figure 3 are unusually
loge (12000 eases and 32000 controls) and so the
pattern of seedily ineseasing risk ratio with younge r
47 5
: E9132. J' 9 15 :214/ST. i 5 : 2- 0, 31H0135586, P
age is put cularly reliably demonstrated, as are the
hazzrds at the extremes of the age range of 30-79 . The
risk ratio is twofold at ages 74-79, but It is almost
fourfold at ag , 30-59 (dsroefoid at 50-59 but 5 ►cfold If
30-49), }burn these large differesees hew probably
beep somewhat dllutcd by the tniselsssi}leanon of some
smokers or non-smokers. Had it been possible, with no
claaificat on errors, to Compare p tangent agamte
smokers with lifelong non-smokers then the risk ratios
would probably have been still mots extreme than
those in figure 3, and would have been at least Wurfcid
at ages 30-59 . As moat ofthe excess risk associated with
smoking is caused by smoking," this fourfold risk
redo implies that about three quarters of he
myocardial bfarcdons among c1prstte smokers aged
50-'59 wtxe caused by tobacco (two L A at ages 50-59,
but four fifflu at ages 30-49) .
Any di;ffetenees In the risk of heart disease between
those who are smoking differcat types of cigarette must
be mach la-se earente than the diffeatnces between
smakert and ionrsmokere so especially large studies
are needed to assess them. Moreover, epidemiological
media that were undertaken when tar yields below
15 mg were still uacnmmon (N j Wild er al, tutpublished data)- are of limited contemporary
relevance in countries such as the United Kingdom
where tar yields above 15 mg have already virtually
disappeared (fig Ib) and where a European United
upper limit of 12 rag is soon to be eefoered . As no other
line recent studies ace aveilabla, our current lfndings
stand aloneFor me yields the rested finding is that sf smndardisedon for age, tax, and number of ggarettcs,
the incidence of a,on-atal aryocardial infarction
seemed m be about 10% greater with medium tar then
with low tar cigsrttms (95% confidence interval 0 to
an ., time UJJ .1gvra If this toy. difference was highly
staristical(y significant (which it is not 211-0-06) ye
would call not be epidemiologically secure. It is
uncertain )tow much sdeed .e empbuis to put on the
data at ages 30-59 as opposed to thou at 60-79, how
much seleeelve emphasis to put on the die from people
with no previous disease, and how much to empheeie e
Nlreetrde In kWoa and d ur Pd
ta+ or (<10 mg mine 75 mg )
nedlua or (>lo mg mw 133 too
Ik4% (SD 7.t)
more irduttr.
br .maWna
1.0% (so 0-b)
moat siV .
ALa 36,9 Asa 60-79
PKr or yield, a,d rvi it no»~r! r 4w,Jim _q-Pfi Atired for use, ts, led macaws -AU 4 mntyansu at
aim 10-1/ &-r- .r that wma-f ayo .a ^'m a"
1-166 (SD 0071) roan Serra macaw sradawt rant mrasar loseerr
aem®i mwmlarr (SP-O'01; mabk L . TA* sera tv"d•&Mj
mmparuear at yw 60-99 - 1 .010 M-OAS) (NS) . Thee An
amts (1-1 d6 asd l'Ol Q) wr atnotuwd aide cis . F&k rvwot y3*31
and 2.3? .r d,swet, Weak", va,w a aaae.Aw all ) to AW ON
rid riots P1AX fro ae.tdt•r of lot. madrrsd6na rm ajvmra 3 39 std
3 9S s qsw 10,T9+vt 0- 75 e,d7 .37x taw 6479
ICQy masavpee
• Non-fatal myocardial infarction rates are five
times as great among cigarette smoitas as among
non-smokers at ages 30-49, three thncs as great
at ages 50-59, and twice as great or age 60 .79
• Among cigarette smokers four fifths of
myocardial lnfarctions at ages 30-49 were caused
by tobacco, two thirds at ages 50-59, and half at
ages 60.79
a The risks seem to be ll%lttly greater with
medium tar than with low tar cigarettes, but this
difference is not definit e
• Didrrences in risk between cigarette smokers
and son-smokcre are far greater than any differvncca ip risk between one We of cigarette and
• Far More myocardial infarctions could be
avoided by not smoking than by changing from
one type of cigarette to another
analyses that tee staadirdiaed for the amount smoked .
(Those using low tar cigarettes reported smokes
slinky fewer than those smoking medium tar
cigarettes, and if lower daily consumption is chiefly a
consequence of tower yields of tar, nicotine, and other
smoke components then it should not be standardised for.) Hence, table III reports several' diferent
comparisons of disease rates in smokers and in non
smoltcrs, wit1 h, differences that are somedmee more and
sometimes leas than [0%. Also, there was a slight
geodency fur tar yields to be inversely related to
education sod eg various other aspects of toast tat . It
is di£=ulr to see how :case of these uncertainties can be
resolved: large scale eandomissidon is impracticable,
and even if the present study could have been much
larger, thereby narrowing the confidence intervals, the
possibility of confounding would rtmlain .
Despite these uncertainties, however, the present
results provide some reassurance to those in government or in iadusay who could direct decreases in
cigarette to yields to reduce cancer iAejde tee .''h" .
They indicate diet such changes will not subsrrntisily
increase the incidence of myocardial jujigetfon and
miy well decrease it. Tlhus, the limit of 12 mgrcigarstte
an tar yields that is now bed introduced in the
European Union should help limit the number of
premature deaths from tobacco, unless govcmmcm3 or
smokers come to retard reduadons in tar yield as
substitutes fur she avoidance of ageretras, for in
developed crannies tobacco remains much the most
impostamr rinse of premature death. T W ii pardeulsdy so for mere, with toboeoo now causing about a
third of all deeths in middle aged men- But where
women lave been smoking cigarettes for some decades
(as, fior example, in the Ualred Kingdom or the United
Surer) tobacco also already causes about 3 quarter of
all the deaths in middle aged women,'
For the general population, therefore, the most
important finding is not the slight and rsnratsia
difference in figure 4 bow= out type of cigarette and
anathes but the lard and definite difference in fgtme
3 between cigarette smokers and doe-smokers,
particuujady in early middle age IrrecpeCdve Of
whether low or medium tar cigarettes are used, about
due quarters of the smokers who bavt la heart stuck
in their 30e, 40a, or 501 need not have done so, and far
more heart attacks eoeld be prevented by not ,molting
than by reducing cigarette tar yields .
The Aid ockaowledgmmt is to erne patients and fib t
476 EM vor nsor 31 t 19 AUGUST 199 5
FROM B_DSC URGEN ACTION SERVICE 019375"'r-321 (WED) 022 . 1'T 99 15 :24,iST . 1.5 :2ci/NO. 35810135585 P 8
rtIadraa wh6 m(kbor red in this amdy, and ro ft 1nOdisl
Lod unrdq I from more than 100 hapir&L id rite United
Kln tom tared in the IS 1S report ." It We pardcutidy dunk
Peers Faogiyatt, Cheryl Sweep, and Rob= Waff of the
Indgmdedi Scimtifie Comeaieree on Sawiml6 and lialfb,
De rams of Kellett ; Keith Dahill 6f the I b6ratOty of the
Gtl.anlamc Chemia* M2cdn Jail of the rmpastal cancer
Resserh Fugdi and Kaldip Bhamee, (entail Borg . Lee
Beelal)shsm, Macy B,atnn, Sarah Clark, Sarah, Edward,,
Shrill Foster, Heaters Halls, Maya Kies, Keen Kaarril lay
Clultdoe Maraden, Gale Mad, Kavtp Murphy Muds
Radler, and Karl Wa11rndeays of rite Qzbrd ClFoicol Trial
Service Unit and Fpida, i616pal Studiy Unit .
Faadlne The ISIS dials end epidaatiolopfeal awdiu wee
9oppQrrd by the daanurcatas of the study dap"" and by
the Bridah Heft Foutldedoa, Imperial Cancer Raeat&
Fund. Mcdicx) Research Council, and Tobacco Produen
Roeatch Tttaat of the Independenr Sdefldfic Commlmee on
Smoidng and Hce1tl., Deparg0pen( Of Hid,,
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Hfdd,)90Z 113-7.
(Aaaad 7SA,6,II)
A 2S year follow up of mortality among women who smoked during
Paula Rentekllilio, Em Isari, Max** Kcwsnon
Ol f,etiae-To iavatigure 16pg term mortality
atitaa' wmil7dn who smoked daring preoancy and
dew who mopped Umoldog.
Detigo-A fdlldw up of a geographirQy 4Rfinird
cohost from 1961 through to im .
3,4/tctfi--11994 wemm is oer wn FisLnd
aq scsed t o deliver in 1966, cA®ptisiog 9Q/. of all
woman giving birth In the wee during that year.
Smoking habits were reeonded during pregnancy but
not later.
RcOth QSeisaas mind
hula; ehysfOulu,
s4pilde 1, FIN-0120
oats, Flabmd
P:vla RrvJ atlio, yrrlfErmr
Bea Lyana, Mot o
Harlot KniTmee .
epAuniorf *differ
C6nefpcmdmu WC
Dc Rallrzbliio.
8MJ vari'.4fi 311
Mawr oatcoms rndoaure-3Kartelit7 by cause (571
diode) .
Ria iLto-T a mortality reds ad uetad the age,
plw of raW nee, yeas of edncado and marital
MEW war 2.3 (9Sa/4 coa$dencd lacdtvai 1-d to 1-3) for
the weslien who soeok>ed during pregnancy and 1 .6
(1 .1 to 2.1) for those *ho stopped nolring before the
mend moats of pregnant , both eou plead with
tan-smolcves . Among the oetd!!s the r save
mortality sae higher for typical disease* related to
tobacco intake, Butch u respiratory and oesophageal
aefscer and discasrs of the cardiovascular and
digestic orbs and ahu for acddumt: and suicides.
Conclusion-The risk of premature death oecem a
19 Atmurr 1995
to be hfOuer in women who emeriti dnriyag prepaney
than to other wonaet7a who smoke. This stay be
explained either by the low proportion of those who
O11op laser and the high proportion of heavy emoks3s
or by odor rhaaaaaa4adcs of these aabjecta that
hMW"se the rink .
The o®sequencee for the child of marexaal unitin g
during pregnancy have been well documented,' but
less interest has been directed towards the morherLprogrlosis. We analyse here 28 yew mortality data on ;L
geagaphirally defined population of women who
smoke during prt:wsaucy; many background vanables
were recorded pr-pee vely .
Pop,det m -The cohort eonaileed of 12 CIS 5
pre®naut women (13 of them delivering twice) in the
two most norcherD provinces In 1?ialaad, OWu sad
Lapland, whose expected dam of delivery fell in 1966
and when the pregnancy Iriulced in a birth . The cohort
covered 96'h of all delfveties in the rq;ion in 1960 Th e