Saturday 23 November 1991
ORIGINAL ARTICLES
Morbidity and mortality in the Swedish Trial in Old
Patients with Hypertension (STOP-Hypertension)
Although the benefits of
antihypertensive
treatment in "young" elderly (under 70 years)
hypertensive patients are well established, the value
of treatment in older patients (70-84 years) is less
clear. The Swedish Trial in Old Patients with
Hypertension (STOP-Hypertension) was
prospective, randomised, double-blind, intervention
study set up to compare the effects of active
antihypertensive therapy (three &bgr;-blockers and one
diuretic) and placebo on the frequency of fatal and
non-fatal stroke and myocardial infarction and other
cardiovascular death in hypertensive Swedish men
and women aged 70-84 years.
We recruited 1627 patients at 116 health centres
throughout Sweden, who were willing to participate,
and who met the entry criteria of three separate
recordings during a 1-month placebo run-in period of
systolic blood pressure between 180 and 230 mm Hg
with a diastolic pressure of at least 90 mm Hg, or a
diastolic pressure between 105 and 120 mm Hg
irrespective of the systolic pressure. The total duration
of the study was 65 months and the average time in
the study was 25 months. 812 patients were randomly
allocated active treatment and 815 placebo. The mean
difference in supine blood pressure between the
active treatment and placebo groups at the last
follow-up before an endpoint, death, or study
termination was 19·5/8·1 mm Hg. Compared with
placebo, active treatment significantly reduced the
number of primary endpoints (94 vs 58; p=0·0031)
and stroke morbidity and mortality (53 vs 29;
p=0·0081). Although we did not set out to study an
effect on total mortality, we also noted a significantly
reduced number of deaths in the active treatment
group (63 vs 36; p=0·0079). The benefits of
treatment were discernible up to age 84 years.
No 8778
We conclude that antihypertensive treatment in
hypertensive men and women aged 70-84 confers
highly significant and clinically relevant reductions in
cardiovascular morbidity and mortality as well as in
total mortality.
a
Introduction
Arterial hypertension is common in all industrialised
countries, and in the elderly the prevalence approaches or
even exceeds 50%.1 Associated with this disorder is a
pronounced increase in the risk of cardiovascular disease and
death, especially in patients aged 60-74 years;Z-5 the risks in
hypertensive patients aged 75 and over are much less
clear.2,6,7
In "young" elderly patients (ie, up to the age of 70
years) the value of antihypertensive treatment is well
established.8-11 Two studies have also suggested that
antihypertensive treatment might be beneficial in patients
older than 70 years ("old" elderly),8,9 but in intention-to-
treat analysis of mortality in a European trial 12 the benefits of
treatment declined with age and could not be recorded
above age 75. One of the studies that found a therapeutic
effect in the age range 70-74 years was an open trial without
placebo control,9 and the other lost a large number of
patients from follow-up.8 For these reasons we believed it
was important to confirm the value of antihypertensive
treatment in people aged 70-74 years and to expand the
database up to the age of 84 years, since old elderly
hypertensive patients form a substantial part of the
ADDRESSES Department of Medicine, University of Göteborg,
Östra Hospital, Göteborg (B. Dahlöf, MD, L Hansson, MD); Health
Sciences Centre, University of Lund, Dalby (L. H. Lindholm, MD,
Prof B. Scherstén, MD, T. Ekbom, MD); and Department of Medicine,
University of Umeå, University Hospital, Umeå, Sweden (Prof
P-O. Wester, MD). Correspondence to Dr Lennart Hansson, Department
of Medicine, University of Goteborg, Ostra Hospital, S-416 85 Göteborg,
Sweden.
 1282

hypertensive population. The Swedish Hypertension TABLE I-BASELINE CHARACTERISTICS OF PATIENTS BY

TREATMENT GROUPP
Society set up a study to evaluate the usefulness of
antihypertensive treatment in the age group 70-84 years, the
Swedish Trial in Old Patients with Hypertension (STOP-
Hypertension). Recruitment of patients started in
November, 1985. The aim was to investigate whether the
frequency of fatal and non-fatal stroke, fatal and non-fatal
myocardial infarction, and other cardiovascular death was
affected by antihypertensive treatment in this age group.

Patients and methods

The design of the study and results from the pilot study (1985-86)
have been reported previously. &bgr;-iS Briefly, this multicentre study was
carried out at 116 health centres (out of 846) throughout Sweden, and
hypertensive men and women aged 70-84 years were randomly
allocated double-blind administration of active hypertensive therapy
or placebo. Patients were included consecutively if they were willing
to participate (and gave written consent) and had untreated or treated
essential hypertension. The entry criteria were that on three separate *Less than 6 months before run-m period
BMI body-mass Index
occasions the systolic pressure was 180 mm Hg or above with a
diastolic pressure of at least 90 mm Hg, or that the diastolic pressure
was above 105 mm Hg irrespective of the systolic pressure during a (retrosternal), lasting longer than 15 min and with onset within the
1-month placebo run-in phase in previously untreated patients. The preceding 48 h, or pulmonary oedema in the absence of known
valvular disease or syncope without hypovolaemia/intoxication; (b)
run-in phase was preceded by a 1-6-month wash-out period in
previously treated patients. changes on electrocardiography (diminished R-wave amplitude
Reasons for exclusion were supine blood pressure above and/or pathological Q-waves); (c) temporary rises in serum
230 mm Hg systolic and/or 120 mm Hg diastolic; isolated systolic aspartate aminotransferase activity (two or more results above the
reference value) with a maximum 24 h after the onset of symptoms
hypertension (180 mm Hg or higher with diastolic below 90 mm or changes in serum alanine aminotransferase activity, lactate
Hg); orthostatic hypotension (more than 30 mm Hg fall in systolic
blood pressure on standing); contraindications to any of the drugs; dehydrogenase isoenzyme pattern, or creatine kinase activity. The
myocardial infarction or a stroke during the previous 12 months; diagnoses of stroke or myocardial infarction could also be made at
necropsy. Other cardiovascular death included sudden death
angina pectoris requiring treatment with drugs other than glyceryl
trinitrate; other severe or incapacitating illnesses; or unwillingness (unexpected death within 1 h of onset of symptoms and without
obvious cause), fatal congestive heart failure, and fatal
to take part.
cardiovascular events not covered by the above definitions (eg,
Blood pressure was measured, by the same observer (nurse or
doctor) for each patient throughout the study, after 5 min of ruptured aortic aneurysm).
Recruitment took place between Nov 14,1985, and Oct 31,1990.
recumbent rest and after 1 min of standing, by means of a mercury
1627 patients were recruited-812 were randomly allocated active
sphygmomanometer. The standard cuff bladder measured 12 x 35 treatment and 815 placebo (table i). The average follow-up time
cm, but larger (15 x 43 cm) or smaller (9 x 25 cm) cuffs were used in
when primary endpoints were considered was 25 months. The
patients with arm circumferences above 32 cm or below 22 cm,
respectively. Disappearance of the Korotkoff sounds was recorded Safety Committee operated under the stopping rules recommended
as the diastolic blood pressure. The average value of two recordings by Friedman et al.6 The study was terminated on April 8,1991, on
in the supine position, measured to the nearest 2 mm Hg, was the the advice of the Safety Committee; investigators were advised that
main blood pressure variable upon which inclusion, changes in all blinded medication should be discontinued. All surviving
dosage, and so on, were determined. patients were recalled and examined at the end of the study. No
All drugs were given once daily. Treatment consisted of atenolol patient was lost to follow-up.
50 mg, hydrochlorothiazide 25 mg plus amiloride 2-5 mg,
The study was approved by all ethical committees in Sweden and
the National Board of Health and Social Welfare. It was carried out
metoprolol 100 mg, or pindolol 5 mg. The drugs chosen were those in accordance with the Declaration of Helsinki.
that at the start of the study were the most widely used in Sweden. If
the supine blood pressure, as defined above, was 160 mm Hg
Statistics
systolic and/or 95 mm Hg diastolic or above after at least 2 months
of treatment or at any later point during the study, the diuretic was We assumed that 30% of strokes and myocardial infarctions
added to any of the p-blockers or vice versa. Each centre was free to would be fatal, that the risk reduction would be 1 75% per mm Hg
choose any of the four basic regimens, which then had to be reduction in systolic blood pressure, and that active treatment
maintained throughout the study. Placebo tablets were identical in would lower systolic blood pressure by 20 mm Hg more than would
shape, taste, and colour to the active medication. If supine blood placebo: based on Swedish mortality statistics we calculated that
pressure exceeded 230/120 mm Hg (and/or) on two subsequent 6000 patient-years would be needed to show a significant reduction
visits the patient was changed to open antihypertensive treatment. in primary endpoints with a statistical power of 90% at the
After a non-fatal endpoint, a patient could continue on double-blind significance level of005 (by a two-tailed test). 13
treatment.
Endpoints were evaluated by an independent endpoint TABLE II-SUPINE SYSTOLIC AND DIASTOLIC BLOOD
committee, unaware of treatment given or blood pressure. Their PRESSURE BY TREATMENT GROUP AND YEAR OF FOLLOW-UP
evaluation was based on medical records, death certificates, and
necropsy reports, as appropriate. For an event to be accepted as an
endpoint, agreement of the independent evaluations of the two
committee members was required.
Primary endpoints were stroke, myocardial infarction, and other
cardiovascular death. Stroke was defined as a persisting (longer than
24 h) neurological deficit with sudden onset (excluding non-
vascular causes). Myocardial infarction was defined by the presence
of at least two of the following three criteria: (a) chest pain
 1283

TABLE III-PRIMARY ENDPOINTS AND MORTALITY BY

TREATMENT GROUP P

*Only the first endpoint to happen

tlncludmg sudden death.
irrespective of preceding non-fatal primary endpomt
§All causes.
MI = myocardial infarction, CV = cardiovascular

In the analysis, the intention-to-treat principle was used. The

analysis of total primary endpoints was made on the first endpoint
that happened in an individual patient. If the first endpoint was not
fatal, the patient could later undergo a fatal event, which would then
be included in the analysis of mortality. 14 patients underwent both
a non-fatal and a later fatal event.

Comparisons of the risk of primary endpoints, stroke as a primary

endpoint, and death before study termination, were made by means
of Mantels test. Age was used as a time variable and sensoring was
done at death and/or at the occurrence of primary endpoints.
Confidence intervals for risk ratios were determined by means of the
optimum test for comparison of two Poisson distributions17 and the
duality between tests and confidence sets.
The survival functions (probability of escaping events) were
estimated by the maximum likelihood method, assuming constant
hazard functions within 6-month periods. A Poisson model,18
including treatment group, present age, and time since entry, was
applied to calculate the risk ratio as a function of age and the
corresponding 95% confidence intervals (CI). All tests were
two-sided.
All centres were visited regularly by study monitors. In addition,
data auditing in accordance with the recommendations of the US
Food and Drug Administration was carried out at randomly
selected health centres by an independent reviewer. Ten different
centres were visited and the results of these visits formed the basis of
a written report. The survey found no deviations from the protocol
of a kind that could affect the main purpose of the trial and that the
study had been carried out in a scientifically correct manner, so its
final result should be reliable.
Time (yr)
Fig 1-Percentages of patients who have escaped a primary
endpoint (A), fatal or non-fatal stroke (B), or death (C) during
4 years of treatment.
Survival functions estimated by maximum likelihood method assuming
constant hazard functions within 6-monthperiods. P values apply to total
study period.
apparent early in the study and became more pronounced
with time.
During the study 172 secondary endpoints occurred, 132
in the placebo group and 40 in the actively treated group
(p < 0-001). These endpoints were congestive heart failure
(39 vs 19), hypertension (above 230/120 mm Hg; 75 vs 10),
transient ischaemic attacks (9 vs 3), and angina pectoris (9 vs
8). The beneficial effects of active antihypertensive
treatment were clear at all ages studied (fig 2).

Results
Active treatment reduced blood pressure significantly
more than did placebo (table II). At the last follow-up before
a primary endpoint/death or study termination, supine
blood pressure 186/96 (SD 22/10) mm Hg in the
was

placebo group and 167/87 (SD 21/9) mm Hg in the actively

treated group (difference 19-5/8-1 mm Hg). At that time
77% of the placebo group and 84% of the actively treated
group were still taking the study medication. Two-thirds of
the actively treated patients received combined treatment.
The effects of active treatment and placebo on primary
endpoints and mortality are given in table III. By life-table Fig 2-Risk ratio (and 95% CI) of a study endpoint in active vs
analysis it was evident that patients receiving active placebo group as a function of age, determined by a Poisson
treatment had significantly fewer primary endpoints, lower model.
morbidity and mortality from stroke, and lower total Risk ratio lower than 1 0 means a greater effect for active than placebo
mortality than those on placebo (fig 1) ; these effects were treatment.
 1284
No unexpected, serious, or previously unknown side-
effectswere evident during the study. 58 patients on active
treatment and 47 on placebo discontinued randomised
treatment because of subjective side-effects not classified as
any specific clinical event (difference not significant).
Discussion
Our findings show that administration of active
hypertensive therapy reduced supine blood pressure
substantially in comparison with placebo in hypertensive
patients aged 70-84 years. Associated with the fall in blood
pressure were highly significant reductions in the number of
primary endpoints, stroke morbidity and mortality, and
cardiovascular and total mortality. These results are at least
as positive as those of previous intervention trials in young
and middle-aged hypertensive patients.19.20 As well as
supporting previous positive results of antihypertensive
therapy in young elderly populations,8,9 our study shows
antihypertensive treatment can be beneficial in old elderly
hypertensive patients.
In many previous intervention trials against various
cardiovascular risk factors, there have been positive effects
of treatment on particular endpoints such as stroke
morbidity or mortality, without significant effects on total
mortality. Since a reduction in total mortality is as desirable
a goal as an effect on individual endpoints, the highly
significant reduction in total mortality obtained with active
hypertensive treatment is important. Perhaps equally
important is the substantial decline in morbidity.
The eligibility of most of the patients (61%) was defined
by their systolic blood pressure, though they all had diastolic
pressures of at least 90 mm Hg. Thus, although patients
with isolated systolic hypertension were excluded from the
study, it seems that elderly patients with substantially raised
systolic blood pressure and a less striking rise in diastolic
blood pressure benefit from antihypertensive therapy. In
this respect our findings accord with those of the Systolic
Hypertension in the Elderly Program (SHEP) study, in
which patients with isolated systolic hypertension (160 or
above/less than 90 mm Hg) benefited from antihypertensive
treatment-in particular, stroke, mortality and morbidity
were lower.21 In practical terms, this is important
information, since systolic blood pressure is higher in many
elderly hypertensive patients than in young and middle-
aged hypertensive patients.1.22 Several secondary endpoints
also showed abeneficial effect of active treatment.
Furthermore, there was no significant difference between
placebo and active treatment in the rate of dropouts for
side-effects.
The clinical implication of this study is that high arterial
pressure in men and women aged 70-84 years should be
treated with antihypertensive drugs. The benefits of such
treatment are at least as striking in elderly patients as in
young and middle-aged hypertensive patients.
This study was supported by Astra/Hassle, ICI Pharma, Merck Sharpe &
Dohme (Sweden), Sandoz, and the Swedish County Councils.
Study organisation
Steering committee: Dr B. Dahlof, Dr L. Hansson, Dr L. H. Lindholm,
Dr B. Schersten, Prof P-0. Wester, and Dr T. Ekbom, with associated
members Ms G. Eneroth (MSD), Mr P-E. Homkvist (ICI), Mr H.
Kohlmark (Sandoz), and Mr C. Larsson (Astra/Hassle). Working Party Dr
B. Dahiof, Dr L. H. Lindholm, Mr J. Wemgren, Mr A. Nordenhem, Mr C.
Larsson, Mr N-B. Nilsson, Ms A. Hotmner. Safety committee Dr L.
Wilhelmsen, Dr H. Wedel, Dr A. Kagerud, Dr M. Danielson, and Dr M.
Ribacke. Endpoint committee: Dr L. Erhardt, Dr C. Helmers, and Dr U. de
Faire. Coordinating centre: Department of Medicine, Ostra Hospital,
University of Goteborg. Statistician. Anders Od&eacute;n. Data audlt.- Dr 0.
Samuelsson. Monitors. T. Danhill, P-O. Gustafsson, H. Kvist, U.
Lundberg, N-B. Nilsson, A. Nordenhem, J-H. Wenslow, J. Wemgren.
Investigators: J. Aagaard, N. G. Ahlen, B. Alenius, U. Ahlstrom, D.
Andersson, N. Andreasen, L. Banke, C. Berglund, S. Bergman, J. Bjerkeryd,
B. Bjorktund, T. Bjorklund, A. Blom, 0. Borgholst, M. Brian, G. Brostrom,
J. Brunner, M. Carlberg, H. Christensen, A. Dahl, B. Dahlen, S. Einarsson,
G. Ekblad, S. Ekesrydh, H. Ekstrom, J. Elliot, M. Enekvist-Widell, S.
Engstrom, 1. Enstrom, P. Encsson, C. Fabian, G. Femlund, 0. Fjelkeg&aring;rd,
G. Forsberg, G. Frenckner, L. Fries, G. Fronaeus, L. Froberg, 0. Garmen,
N. G. Gisslen, H. Glingert, U. Glitterstam, C. Gunnarsson, G. Gustafsson,
S. Gustavsson, P. Guterstam, C. Hallendahl, L. Hallerback, C. H. Hallgren,
F. H. Hansen, C. Hegen, T. Hegle, T. Hermansson. U. Hollertz, B.
Jacobson, 1. Jacobson-Marklund, E. Jaensson, B. Jansson, R. Jansson, P.
Jemfeldt, 1. Johannesson, H. Johansen, H. Jones, L. Jonsson, R. Jonsson.B.
Jordin, S. de Joussineau, G. Jonsson, R. G. Jonsson, H. J. Jorgensen, S.
Kalin, M. Kallioinen, C. Karkow, D. K)ellstr&ograve;m, H. Kallqvist, K. Klinga, L.
Kvist, A. Landin, R. E. Lmdbergh, U. Lindblad, 0. Lindekranz, K.
Lindstrom, B. Littorin, L. Ljungstr&oacute;m, S. Lundmark, T. Lundstrom, B.
Lonner, B. Low-Larsen, P. Malm, K. Malmgren, B. Malmros, R.
Malmstr&ouml;m, P. Mattsson, H. Mikkelsen, G. Moser, C. M. Molstad, B.
Moren, T. Morck, M. Nadal, R. Nandorf, A. Nelvig, P. Nicol, H. J. Nielsen,
A. Niklasson, A. Nilsson, C. Nordenhall, K. Nordmark, I. Nygard, M.
Oldner, H. Ohlsson, J. E. Olsson, K. Olsson, P. Ohlsson, G. Persson, L. G.
Persson, 0. Persson, R. Peste, C. Petersson, S. Pihl, L.Rommer, F. Rost, M.
Rotstein, S. Rudholm, M. Sandor, H. Sandstrom, J. Schnaider, A.
Segerstedt, A. M. Sil&eacute;n, L. Sjoberg, A. Sjostrand, C. von Segebaden, S.
Skeat, P. Skoog, B. Smitterberg, G. Somansson, A. Stein, S. Strid, 0.
Stromstedt, S. Sundeman, C. H. Sundin, G. Sundin, C. A. Svanberg, R.
Svartholm, M. Svennebring, B. Sorqvist, B. Thoren, B. Tilling, E. Tivell, T.
Tovi, H. Unnegard, G. Wahlberg, G. Wallberg, V. Wallenberg, R.
Wahlstr&ouml;m, R. Wentzel, A. Werkelius, T. Wessman, N. Wikstrom, L.
Viktorsson, K. Valdal, J. Zadig, B. &Aring;kerstr&oacute;m, H. Odling, L. E. Okvist, and
H. Ortoft.
REFERENCES
1. Sorensen K, Hilden T. Increased total mortality and decreased functional
capacity are associated with low systolic blood pressure among elderly
women. Scand J Prim Health Care 1988; 6: 105-10.
2. Holme I, Waaler T. Five-year mortality in the city of Bergen, Norway,
according to age, sex and blood pressure. Acta Med Scand 1976; 200:
229-39.
3. Agner E. Predictive value of arterial blood pressure in old age. Acta Med
Scand 1983; 214: 285-94.
4. Landahl S, Lernfelt B, Sundh V. Blood pressure and mortality in old age:
eleven years follow-up of a 70-year-old population. J Hypertens 1987;
5: 745-48.
5. Kannel W, Gordon T. Evaluation of cardiovascular risk in the elderly: the
Framingham study. Bull NY Acad Med 1978; 54: 573-91.
6. Fry J. Natural history of hypertension: a case for selective non-treatment.
Lancet 1974; ii: 431-33.
7. Mattila K, Haaristo M, Rajala S, Heikinheino R. Blood pressure and
five-year survival in the very old. Br Med J 1988; 296: 887-89.
8. Amery A, Brixko P, Clement D, et al. Mortality and morbidity results
from the European Working Party on High Blood Pressure in the
Elderly trial. Lancet 1985; i: 1349-54.
9. Coope J, Warrender T. Randomized trial of treatment of hypertension in
the elderly patients in primary health care. Br Med J1986; 293:
1145-51.
10. Hypertension Detection and Follow-up Program Cooperative study:
Five-year findings of the HDFP, 1: reduction in mortality of persons
with high blood pressure including mild hypertension, 2: mortality by
race, sex and age. JAMA 1979; 242: 2562-79.
11. The Management Committee. Treatment of mild hypertension in the
elderly: a study initiated and administered by the National Heart
Foundation of Australia. Med J Aust 1981; ii: 398-402.
12. Amery A, Birkenhager W, Brixko R, et al. Efficacy of antihypertension
drug treatment according to age, sex, blood pressure, and previous
cardiovascular disease in patients over the age of 60. Lancet 1986; ii:
589-92.
13. DahlofB, Hansson L, Lindholm L, R&aring;stam L, Scherst&eacute;n B, Wester P-O.
STOP-Hypertension: Swedish Trial in Old Patients with
Hypertension. J Hypertens 1986; 4: 511-13.
14. Dahlof B, Hansson L, Lindholm L, Scherst&eacute;n B, Wester P-O.
STOP-Hypertension: preliminary communication from the pilot
study of the Swedish Trial in Old Patients with Hypertension.
J Hypertens 1987 5 (suppl 5): S607-10.

15. Hansson L, Dahl&ouml;f B, Ekbom T, Lindholm L, Scherst&eacute;n B, Wester P-O.
Key learnings from the STOP-Hypertension study: an update on the
progress of the ongoing Swedish study of antihypertensive treatment in
the elderly. Cardiovasc Drug Ther 1990; 4: 1253-56.
16. Friedman LM, Furberg CD, DeMets DL, eds. Fundamentals of clinical
trials. Littleton, MA: PSG Publishing, 1985: 213-39.
17. Lehman EL. Testing statistical hypotheses. New York: Wiley, 1959:
140-42.
18. Breslow NE, Day NE. Statistical methods in cancer research, vol II.
Lyon: IARC Scientific Publications, no 32, 1987: 131-35.
19. Veterans Administration Cooperative Study Group on Antihypertensive
Agents. Effects of treatment on morbidity in hypertension: results in
Prevention of travellers diarrhoea by oral
B-subunit/whole-cell cholera vaccine
B-subunit/whole-cell cholera vaccine (BS-WC)
has been shown to give Bangladeshi mothers and
children only 3 months protection against severe
diarrhoea due to enterotoxigenic Escherichia coli
(ETEC). Since a long-lasting effect is not necessary
for protection against travellers diarrhoea, a
prospective double-blind study was conducted
among tourists who went to Morocco from Finland.
307 tourists received two oral doses of BS-WC,
whereas 308 controls received a placebo before
departure. A research team went out with tourists
and a laboratory for enteric pathogens was set up on
location. A faecal specimen was taken from 100
randomly selected subjects before departure, from all
travellers with diarrhoea, and routinely after return.
Enteropathogenic bacteria were not isolated from
any of the pre-departure specimens but were present
during or after the holiday in 47% of tourists with
travellers diarrhoea, and in 14% of those without
diarrhoea. BS-WC induced a 52% protection
(p=0&middot;013) against diarrhoea caused by ETEC. The
protection was better for mixed infections (65%,
p=0&middot;016). The protective efficacy against a
combination of ETEC and any other pathogen was
71% (p=0&middot;02), and that against ETEC plus
Salmonella enterica even better at 82% (p=0&middot;01).
Partial protection against travellers diarrhoea is
thus obtainable by active immunisation with
BS-WC.
Introduction
Travellers diarrhoea affects 30-50%12 of the 18-20
million persons a year who travel from industrialised to
developing countries.2 34% of Finnish travellers to North
Africa have been reported to fall ill with diarrhoea.3
Prophylactic drug therapy always carries disadvantages,
especially when it concerns large numbers of people.
Therefore there is a need for immunoprophylaxis that is
safe, easy to administer, and effective. The finding that,
world wide, enterotoxigenic Escherichia coli (ETEC) seems
to be the commonest single cause of travellers diarrhoeal,2,"
1285
patients with diastolic blood pressure averaging 115 through 129 mm
Hg. JAMA 1967; 202: 1028-34.
20. Veterans Administration Cooperative Study Group on Antihypertensive
Agents. Effects of treatment on morbidity in hypertension, II: results in
patients with diastolic blood pressure averaging 90 through 114 mm
Hg. JAMA 1970; 213: 1143-52.
21. SHEP Cooperative Research Group. Prevention of stroke by
antihypertensive drug treatment in older persons with isolated systolic
hypertension: final results of the systolic hypertension in the elderly
program. JAMA 1991; 265: 3255-64.
22. Hansson L. Isolated systolic hypertension. Curr Opin Cardiol 1987; 2
(suppl 1): S15-19.
gives some hope for progress. The action of the heat-labile
toxin (LT) excreted by ETEC on the intestinal epithelium is
identical to that of cholera toxin, and the two toxins are
antigenically closely related.7-9
Short-term protection against cholera has been achieved
with an oral whole-cell vaccine supplemented with the
B-subunit of cholera toxin (BS- WC).lO-12 The possibility of
using BS-WC against travellers diarrhoea became realistic
when its cross-protection against diarrhoea caused by
LT-ETEC was shown in a large field trial in Bangladesh:
BS-WC induced 86% protection against severe diarrhoea
due to LT-ETEC when given to mothers and 2-15-year-
old children.13 This cross-protection lasted only 3 months,
so wide use of BS-WC against E coli diarrhoea in the
endemic areas was not thought to be worth while. However,
duration of protection is not so important a consideration in
travellers diarrhoea. We describe here a prospective
randomised study to investigate the effect of BS-WC on
travellers diarrhoea.
Subjects and methods
Participants and study design
The study was organised along the lines of a pilot study done 8
months earlier.s In short, after approval of the protocol by the
National Board of Health and the ethics committee of the National
Public Health Institute, three travel agencies sent a letter to clients
(adults only) who had booked to go to Agadir, Morocco, between
Oct 24 and Nov 21, 1989, asking them to participate in the project.
Morocco was chosen as a target because it is one of the risk areas for
travellers diarrhoea3.14 to which Finnair operates regular winter
charter flights. In 1989, the winter season flights started on Oct 24.
A month before departure date those agreeing to take part
received from the study organisers a more detailed letter with
code-labelled vaccine or placebo, instructions, a reaction follow-up
sheet, and a vial for a pre-departure faecal specimen. The reaction
forms and the specimens were collected at the airport.
ADDRESSES: National Public Health Institute, Helsinki, Finland
(H Peltola, MD, A. Siitonen, PhLic, M J Kataja, Tech D); Childrens
Hospital, University of Helsinki, Helsinki (H. Peltola); Aurora
Hospital, Helsinki (H Kyr&ouml;nseppa, MD); Jorvi Hospital, Espoo (I
Simula, MD); 1st Department of Medicine, Helsinki University
Hospital, Helsinki (L. Mattila, MD); Finnair, Helsinki (P Oksanen,
MD); and Pasteur M&eacute;rieux Serums et Vaccins, Marnes la
Coquette, France (M Cadoz, MD) Correspondence to Dr H. Peltola,
Childrens Hospital, University of Helsinki, 11 Stenback Street, SF-00290
Helsinki, Finland.