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Ove K Andersson a Department of Medicine, Sahlgrenska
University Hospital, S-413 45 Gothenburg, Sweden, b Department of Medicine, Section of Nephrology, Sahlgrenska
University Hospital, c Department of Clinical
Pharmacology, Sahlgrenska University Hospital, d Institute
of Heart and Lung Diseases, Section of Preventive Cardiology,
Sahlgrenska University Hospital
Correspondence to: Dr Andersson
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Abstract |
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Objective: To compare survival and cause
specific mortality in hypertensive men with non-hypertensive men
derived from the same random population, and to study mortality and
morbidity from cardiovascular diseases in the hypertensive men in
relation to effects on cardiovascular risk factors during 22-23 years
of follow up.
Design: Prospective, population based observational
study.
Subjects and methods: 686 hypertensive men aged 47-55 at screening compared with 6810 non-hypertensive men. The hypertensive
men were having stepped care treatment with either
adrenergic
blocking drugs, thiazide diuretics, or combination treatment.
Mortality, morbidity, and adverse effects were registered at yearly
examinations and from death certificates.
Main outcome measures: All cause mortality and cause
specific mortality.
Results: Treated hypertensive men had significantly
impaired probability of total survival as well as survival from
coronary heart disease and stroke. All cause mortality as well as
coronary heart disease and stroke mortality were very similar in
hypertensive men and normotensive men during the first decade, but
increased steadily thereafter despite continuous good blood pressure
control. Smoking, signs of target organ damage, and high serum
cholesterol levels, but not blood pressure at screening, were
significantly related to the incidence of coronary heart disease during
follow up. In time dependent Cox's regression analysis, the incidence
of coronary heart disease was significantly related only to serum
cholesterol concentrations in the study. Cancer mortality was almost
similar in treated hypertensive men (61/686, 8.9%) and
non-hypertensive men (732/6810, 10.8%).
Conclusion: Treated hypertensive men had impaired
survival and increased mortality from cardiovascular disease compared
with non-hypertensive men of similar age. These differences were
observed during the second decade of follow up. During an observation
period of 22-23 years
about 15 000 patient years
hypertensive men
receiving diuretics and
blockers had no increased risk of cancer or
non-cardiovascular disease.
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Key messages
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Introduction |
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Treatment of hypertension prolongs life and prevents or delays congestive heart failure and nephrosclerosis and reduces the incidence of stroke.1-5 Antihypertensive treatment has, however, been less effective in preventing coronary heart disease.6 It is not clear whether this is due to inadequate blood pressure control, inadequate intervention of other risk factors, negative effects on the risk of cardiovascular disease from antihypertensive drugs, intervention being too late to affect atherosclerosis, or inadequate effect of present drugs on atherosclerosis.
Previous controlled trials on chronic hypertensive disease have been limited by their duration (about 5 years) as a better therapeutic effect has been suggested at later stages of treatment. 7 8 If so, important information could be gained from prospective studies of long duration, which would also allow the evaluation of patient characteristics of prognostic importance.
Our population based, prospective study of more than 20 years aimed to analyse the long term mortality in treated hypertensive men compared with non-hypertensive men taking part in the same prevention programme, and to analyse the effects of treatment on mortality from cancer and non-cardiovascular diseases.
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Subjects and methods |
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Subjects
The multifactor primary prevention trial started in Gothenburg in
1970. The trial aimed to study whether intervention against smoking,
hypercholesterolaemia, and hypertension could reduce the incidence of
and mortality from cardiovascular diseases.9 The study
comprised one third of all men born between 1915 and 1925 except those
born in 1922 and 1923. The intervention group comprised 9998 men and
two control groups of 10 000 men each. The control groups will not be
discussed further. The first screening took place between January 1970 and March 1973. Overall, 7495 men took part in the screening
(participation rate 75%).
Methods
Intervention on risk factors was based upon the concept of
multiple risk. For the practical intervention programme it was found
feasible, however, to select a discrete cut off point for intervention
against each of the risk factors of elevated serum cholesterol
concentration, elevated blood pressure, and tobacco smoking,
irrespective of the values of the other risk factors in the patient.
The Gothenburg blood pressure clinic
The outpatient blood pressure clinic in Gothenburg was set up in
1970 to care for hypertensive patients from the ongoing prevention
study,9 and to help general practitioners with severely
hypertensive patients or those resistant to treatment.10
At the first clinic visit a detailed patient history was taken and a
physical examination and standardised laboratory tests performed. Blood
pressure was measured after 5 minutes of supine rest and after standing
for 1 minute. During the study two nurses recorded about 90% of the
blood pressures.
adrenoceptor blocking agent or a
thiazide diuretic was adapted for each patient's needs. If necessary
these two drugs were combined to achieve the target blood pressure of
<160/95 mm Hg. In 1988 the target blood pressure was revised to a
diastolic blood pressure <90 mm Hg owing to international
recommendations. If further drugs were needed to achieve the target
blood pressure, a stepped care regimen was followed without a strict
protocol. Hence, hydralazine or other drugs, or both were added if
necessary. After 10 years, 64% (368/575) of all patients were
receiving a
adrenoceptor blocking agent; 74/575 (13%) took this
drug alone as single drug treatment. After 15 years the corresponding
frequencies were 68% (311/457) and 18% (81/457). Thiazide diuretics
were used in 58% (n=334) of all patients after 10 years, with 6%
(n=35) having this drug as single drug treatment. After 15 years the
corresponding treatment was 62% (283/457) and 8% (n=37).
All hypertensive patients had at least one annual check up. The patient
history concerning cardiovascular disease morbidity was updated, and
blood pressure measurements and laboratory test data were obtained.
Patients who did not keep an appointment were given a new one.
During the first year of follow up 25 (3.6%) of the hypertensive men
had stopped attending the clinic, but thereafter the annual withdrawal
rate was less than 1%. No patient in the treated hypertensive group
was lost to follow up for mortality and morbidity.
Statistical methods
The data were analysed using PC-SAS (version 6.12, SAS
Institute, Cary, NC).
14 15
Standard summary statistics
were used to illustrate results.
diastolic blood pressure, serum cholesterol concentration,
smoking, and target organ damage based on criteria of the World Health
Organisation
were included for analysis. When variables with updated
measurements were tested (blood pressure, serum cholesterol
concentration, and smoking) the updated covariates proportional hazards
model was used.17 This model is also known as Cox's time
dependent regression model.
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Results |
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Table 1 shows the patients' characteristics on entry to the study, and table 2 shows the risk factor changes. Blood pressures were reduced after the first year of follow up, and a further reduction was observed after 5 years. After 10 and 15 years the mean blood pressure was 149/89 mm Hg and 145/89 mm Hg respectively. Serum cholesterol concentrations were reduced and the proportion of smokers decreased from 34% at baseline to 17% after 15 years of follow up. Of the 686 hypertensive men, 257 (37.4%) had a significantly higher all cause mortality compared with non-hypertensive men (1992/6810, 29.2%) (table 3 and fig 1). The odds ratio for mortality was 1.6 (95% confidence interval 1.4 to 2.1). This increased mortality in hypertensive men was due to a higher incidence of cardiovascular disease (27.6% versus 14.2%) dominated by coronary heart disease (20.1% versus 10.3%; odds ratio 1.9, 1.6 to 2.3) (fig 2). Mortality from stroke was also higher, 4.4% and 1.8% respectively (2.1, 1.4 to 2.7). An important observation was that all cause mortality as well as coronary heart disease mortality were similar in hypertensive and normotensive men during the first decade, but this increased steadily despite continuously good blood pressure control.
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Mortality from cancer in hypertensive and non-hypertensive men was 8.9% and 10.8% respectively. Mortality from all other causes was lower in hypertensive men (0.9% versus 4.1%) (table 3).
In multivariate regression analysis the incidence of coronary heart disease was independently associated with target organ damage (WHO stage 2-3), smoking, and serum cholesterol concentration (table 4). In time dependent Cox's regression analysis only serum cholesterol concentration was significantly predictive of coronary heart disease (table 4).
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Discussion |
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Our population based study differs from controlled trials of antihypertensive treatment as it has a much longer duration of over 20 years. This study shows that hypertensive men treated long term with the same drugs have an increased mortality compared with non-hypertensive men. This was predominantly observed during the latter part of follow up despite good blood pressure control.
The higher total mortality rate in treated hypertensive men was due to cardiovascular complications, while mortality from non-cardiovascular causes was lower among treated hypertensive men compared with non-hypertensive men. A carefully structured interventional programme with defined blood pressure targets, regular follow up, and a limited drop out rate does not therefore allow a complete normalisation of cardiovascular risk.
On the basis of the difference in risk factor profile at entry between hypertensive and normotensive men, a certain proportion of hypertensive patients probably already had advanced atherosclerosis and hypertensive target organ damage at the start of follow up. The outcome was therefore not unexpected. The strong association between target organ damage at entry to the study and the incidence of ischaemic heart disease underlies the importance to prognosis of cardiovascular abnormalities present before treatment.
With the exception of target organ damage and smoking at entry to the study, the strongest association with ischaemic heart disease in treated hypertensive men was baseline cholesterol and achieved cholesterol concentrations. Our programme of lifestyle modifications to control hyperlipidaemia was not, however, very effective. Only the lipid lowering agent cholestyramine was available for the major duration of follow up, and it was only prescribed to patients with serum cholesterol concentrations >7.0 mmol/l. The modest reduction of serum cholesterol concentration to about 6.2 mmol/l seems therefore suboptimal for a substantial positive effect on coronary atherosclerosis. More recently developed pharmacological methods with the use of statins should have a superior preventive effect. 18 19
There are several possible explanations for the high long term cardiovascular mortality in the hypertensive men. To what extent this was a consequence of failure to reduce blood pressure to normal is difficult to evaluate. Hence, both systolic and diastolic blood pressures were reduced by 15-20%. If a diastolic blood pressure reduction of about 6 mm Hg results in a 36% reduction of stroke and a 16% reduction of expected coronary heart disease over about 5 years,6 it is conceivable that the blood pressure control achieved in the present study would also be beneficial. However, the reduction in blood pressure did not bring all the patients to strict normotension, and a majority of the treated patients remained in the right part of the total blood pressure distribution curve. Coronary heart disease incidence was not related to achieved blood pressure.
It has been suggested that antihypertensive treatment with
blockers
and thiazide diuretics may increase cardiovascular risk because of
induced impairment of metabolism of lipids and
glucose.20-22 These drugs were used as first line
treatment in the present study because they were available when
treatment was started in the early 1970s. Calcium antagonists of the
dihydropyridine type were introduced during the later part of follow up
as replacement for hydralazine, and angiotensin converting enzyme
inhibitors were only used to a minor extent. Drugs related to
metabolism have been previously analysed in the present patient series,
but there was no evidence of increased risk of complications from
elevated triglyceride concentrations or impaired glucose tolerance
induced by treatment.23 The treatment in our study may
seen outdated, but it should be emphasised that newer treatment with
calcium blockers and angiotensin converting enzyme inhibitors
became increasingly more common only during the later part of follow
up. It was during this period, however, that the increased morbidity
among the hypertensive men was most evident. To date no study has shown
the effects of more modern treatment on hard end
points.
An association between high blood pressure and several metabolic variables, as well as disturbances of the fibrinolytic system, is well known.24-26 These abnormalities, which have important prognostic importance in the general population, are not favourably influenced by the antihypertensive drugs available at the time of the present study. Several of these abnormalities, in addition to high blood pressure, may be caused by a common mechanism that is not influenced by such treatment. Whether newer drugs with other modes of action will be superior is presently not known.
It is possible that the preventive effect of lowering blood pressure was less than expected because treatment was started too late, especially as target organ damage (WHO stage 2-3 at the start of intervention) strongly increased the risk of ischaemic heart disease.
Conclusion
Our study of a representative group of hypertensive men showed
that despite treatment they had a significantly higher long term
mortality from cardiovascular diseases than normotensive men. Part of
the risk is irreducible with the treatment regimens available at the
time of the study, and may be related to cardiovascular damage and risk
factors present before established hypertension was diagnosed. During
treatment only an elevated serum cholesterol concentration was
predictive of coronary heart disease, and high blood pressure levels
were associated with an increased risk of stroke.
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Acknowledgments |
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Contributors: The primary prevention trial in Gothenburg was initiated and designed by LW and Professor Gösta Tibblin. LW was responsible for the study. The present study was designed, conducted, and supervised in all parts by OKA, who will also act as guarantor for the paper. The other authors took an active part in the analyses and interpretation of the data and in writing the paper. We also thank professor Göran Berglund for his previous efforts when initially organising the outpatient clinic for hypertension management at Sahlgrenska University Hospital and our head nurse Ann-Louise Eriksson who followed the patients from the start of the study.
Funding: The Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Bank of Sweden tercentenary fund, the Knut and Alice Wallenberg Foundation, and the Gothenburg Medical Association.
Conflict of interest: None.
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References |
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are they of prognostic importance?
BMJ
1996;
313:
660-663(Accepted 30 March 1998)
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