Fifteen-Year Survival of Patients Beginning Treatment
with Methyldopa Between 1962 and 1966
COLIN T. DOLLERY, KERSTIN HARTLEY, PAULINE F. BULPITT, MARGOT DAYMOND, AND
CHRISTOPHER J. BULPITT
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SUMMARY The 15-year survival of a group of 205 patients who started treatment in the period
1962 through 1966 and who received methyldopa for two-thirds or more of the time has been
investigated. At entry these patients had severe hypertension with an average pretreatment pressure
of 216/126 mm Hg. Twenty-one percent had retinal hemorrhages, cotton-wool spots, or papilledema.
Blood pressure showed a large fall in the first year, followed by a small, progressive, further fall up to
the sixth year. After 5 years of treatment the blood pressure averaged 144/90 mm Hg in men and 151/
91 mm Hg in women. The average daily dose of methyldopa was approximately 1500 mg and changed
little over the 15-year period. Survival was analyzed by life tables. Approximately 81% of men and
women aged 30 to 49.9 years at entry were still alive 10 years later. In the age group 60 to 69.9 years,
53.8% of men and 63.2% of women were still alive 10 years later. Seventy-nine of the patients died
during the follow-up period, 89% from cardiovascular or renal disease. Ischemic heart disease (40%)
was the major cause of death, followed by stroke (19%). No patients died from drug toxicity.
(Hypertension 6 (Suppl II): II-82-II-86, 1984)
KEY WORDS • hypertension
• methyldopa
• survival
T
• ischemic heart disease
tients whose treatment began in the period 1962
through 1966. This period was selected because it
marked the beginning of the modern era of antihypertensive therapy, after use of ganglionic-blocking drugs
had declined and before /3-blocking drugs came into
widespread use. The principal drugs used during this
time were thiazide diuretics, methyldopa, and the
adrenergic neuron-blocking drugs bethanidine and
guanethidine. This report is mainly concerned with the
outcome of treatment in those patients in whom methyldopa was the principal therapeutic agent used
throughout most of the treatment period.
HE Hammersmith Hospital Hypertension Clinic was set up in 1951 to 1952 shortly after the
introduction of the quaternary ammonium
ganglion-blocking drugs into therapeutics. Since that
time the clinic has maintained complete registers, initially manually and for the last 12 years on a digital
computer, which enable all patients in whom antihypertensive treatment was initiated to be identified.
Most patients in whom treatment is undertaken are
followed up indefinitely, at intervals that depend on
their blood pressure control. Patients in whom blood
pressure has been good for 3 to 5 years are seen in the
clinic only once or twice a year. In the interval between
visits the patients are under the care of their family
doctor. Those who are not under good control are seen
at more frequent intervals.
A number of studies of long-term survival have been
made that use the clinic records as a starting point. The
great majority of the patients are registered with the
Office of Population Censuses and Surveys (OPCS),
which ensures that a copy of their death certificate (if
they die in the UK) is forwarded to the clinic clerks
within a few weeks of death. The present study forms
part of a larger investigation of the outcome for pa-
Methods
All the patients whose names were recorded in the
clinic log books from 1962 through 1966 were included in this study. Six-hundred-and-sixty patients were
identified and the records of 646 were recovered from
the hospital files. Forty-nine were not considered further, either because blood pressure subsided without
antihypertensive therapy or the patients were resident
abroad at the time they were seen and only short-term
follow-up was possible. The remaining 597 patients
were registered with the OPCS. Eighty patients who
had been lost to follow-up from the clinic could not be
traced by the OPCS, but other enquiries revealed that
18 were dead and 11 were still living at the end of the
selected study period. This left 51 patients (8.5%) who
could not be traced.
From Che Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W12 OHS, England.
Address for reprints: C. T. Dollery, Department of Clinical Pharmacology, Royal Postgraduate Medical School, London WI2
OHS, England.
11-82
FIFTEEN YEARS ON METHYLDOPA/Do//ery et al.
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The study follow-up period terminated in July 1981
when the last patients to have been recruited would
have completed 15 years' treatment if they were still
alive. The hypertension clinic case records were very
carefully scrutinized and information was extracted
from the initial referral up to July 1981. The information obtained included age, sex, race, untreated blood
pressure, smoking habits, family history of hypertension, retinal appearances, weight, and biochemical
data at presentation. The data were not complete, for
example, 31% of patients were already on treatment at
presentation so that pretreatment blood pressures were
not available.
Follow-up information was also extracted and included all blood pressure readings with their dates, full
details of all antihypertensive therapy, and all measurements of potassium, urea, creatinine, cholesterol,
uric acid and hemoglobin levels. Details of complications such as nonfatal myocardial infarction and stroke
also were recorded. The patients were defined as having been treated with methyldopa if they had received
this drug for at least two-thirds of their total follow-up
period; 205 patients fulfilled this definition.
Statistical Methods
Survival was analyzed with standard life-table techniques. When groups were compared for characteristics other than survival the unpaired /-test, analysis of
variance, or chi-square test was used as appropriate.
To determine the effect of different variables on survival, the Cox regression model was used.
Results
The average age of the patients when treatment was
started was 49.9 ± 11.7 years and the average untreated blood pressure was 216/126 mm Hg. Data for men
and women are given separately in Table 1. Fortythree patients who had papilledema or retinal cottonwool spots fell within the definition of accelerated
TABLE I. Characteristics of the Methyldopa-Treated Patients at
Presentation (mean ± so)
Men
Number of patients
Average age
Smokers (%)
Black race (9c)
Lying systolic blood pressure
(mm Hg)
Lying diastolic blood pressure
(mm Hg)
Blood urea levels (mmol)
Serum cholesterol levels
(mmol)
Body weight (kg)
Malignant hypertension (9fc)
Accelerated hypertension (%)
94
49.2 ± 10.4
57.8
4.3
Women
III
50.3± 12.8
42.2
13.5
2I3±29
219±29
I29±I5
6.6±4.6
123±14
5.5 ±1.5
6.5±l.3
76.5 ±14.5
7.0±l.3
69.9±15.6
6.4
2.7
23.4
10.8
11-83
hypertension. Thus, by current standards, the patients
included in the study were severely hypertensive.
Nearly two-thirds of the men smoked tobacco and
more than one-third of the women were smokers.
The most commonly used drugs after 1 year of treatment were thiazide diuretics (60%-70%), followed by
methyldopa (50%-60%), bethanidine (20%), and
guanethidine (6%). Very few patients were ever given
high-ceiling diuretics or potassium-conserving diuretics. Later in the follow-up period an increasing number of patients were treated with propranolol. The
average dose of methyldopa increased from 1230 mg
daily to 1575 mg daily in men over the period of
follow-up. Average doses in women were approximately 100 mg/day less (Figure 1).
Avaraga doaa of Mattiyldopa
mmmmmi
V**r* of tr*atm*nt
FIGURE I. Mean daily dose of methyldopa prescribed at the
end of each of the first 10 years of treatment.
Blood pressure control showed a progressive improvement during the first 5-year period of follow-up
and a small further fall between 5 and 10 years (Figure
2A, B). The blood pressure at the fifth year of followup averaged 144/90 mm Hg in men and 151/91 mm Hg
in women treated with methyldopa.
Length of Survival
Survival was analyzed by means of life tables. Data
for three age ranges in men and women are given in
Table 2. Patients aged 30 to 59.9 years have been
combined in Figure 3. There were too few patients
under age 30 or over 69.9 years at the start of treatment
to make analyzing them as separate groups worthwhile. The numbers in each of the three age groups
analyzed in Table 2 are not large and there are some
anomalies, for example, women aged 50 to 59.9 years
at entry had a better survival than those 10 years
younger. The general pattern, however, is clear. Approximately 81% of men and women aged 30 to 49.9
years at entry were still alive 10 years later. In the age
group 60 to 69.9 years, 53.8% of men and 63.2% of
women were still alive after 10 years of treatment,
when the mean age of this group had reached 75 years.
11-84
HYPERTENSION
SUPPL II VOL 6, No 5, SEPTEMBER-OCTOBER 1984
B.P. Control In Man
B.P. Control In Woman
"i
E
e »
N
- . V
»
*
j.
I
•
•
Yaara of Traatmant
Yaara of Traatmant
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FIGURE 2. Average systolic (*) and diastolic <O) blood pressure of men (A) and women (B) during the first 10
years of treatment. Note the gradual improvement in blood pressure (B.P.) control for years I through 6.
They were then at an age at which there is substantial
mortality among the general population of England
and Wales. The mortality of the treated group was
somewhat higher than that of the general population,
particularly at the younger ages; for example, the 10year mortality of a 42-year-old man or woman in the
population at large is only 2% to 3%, compared with
19% among the treated patients. The survival of the
60- to 69.9-year-old patients, however, was only
slightly worse than that of the general population of the
same age and sex.
Causes of Death
The underlying causes of death given on the death
certificates are listed in Table 3. Eighty-nine percent of
TABLE 2.
the deaths were due to cardiovascular or renal disease;
only 10% were from cancer. Ischemic heart disease
was the most frequent cause of death (40%), followed
by stroke (19%). There were only two patients whose
death was certified as being due to renal disease. None
died from drug toxicity.
The patients who died had higher pressures at presentation and were more likely to be male and to smoke
cigarettes than were those who survived (Table 4). The
concentration of urea in the plasma during treatment
was, on average, higher in those who died than in those
who lived. There was no association between serum
potassium levels during treatment and outcome. The
serum cholesterol was not a useful predictor of survival
but it did correlate with the cause of death: Patients
Life Tables of Survival of Patients Treated with Methyldopa (percent surviving vs year of follow-up)
Men: Age (number)
Year
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
30-49.9
(39)
97.4
94.7
94.7
89.2
83.8
81.1
81.1
81.1
81.1
81.1
78.4
72.9
72.9
72.9
70.1
50-59.9
(38)
97.4
92.1
89.5
89.5
86.8
81.6
76.3
71.0
71.0
71.0
65.8
52.6
50.0
47.4
39.5
Women: Age (number)
60-69.9
(13)
100
100
100
100
84.6
76.9
69.2
69.2
53.8
53.8
53.8
46.1
38.5
30.8
23.1
30-49.9
(40)
97.5
95.0
95.0
89 5
86.8
86.8
84.1
84.1
81.4
81.4
76.0
76.0
73.3
70.6
67.8
50-59.9
(41)
100
100
100
100
100
100
97.5
97.5
97.5
95.0
95.0
92.5
90.0
85.0
82.4
60-69.9
(19)
100
94.7
73.7
73.7
73.7
68.4
68.4
68.4
68 4
63.2
57.9
52.6
52.6
52.6
52.6
FIFTEEN YEARS ON METHYLDOPA/Do/terv et al.
Survival of Patlanta agad 3 0 — 6 0 Yaare
Yaara of Traatmant
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FIGURE 3. Life table of survnnl ofpatients aged 30-59.9 years
at entry for thefirst16 years oftreatment. • = Men;0 = women.
who died of ischemic heart disease had higher levels of
cholesterol; those who died of cancer had lower-thanaverage levels. Body weight was not a useful predictor
of survival.
Smokers had a higher mortality than nonsmokers;
the excess mortality was caused by ischemic heart disease, stroke, and cancer.
Discussion
Antihypertensive therapy may be used continuously
for a substantial fraction of a patient's life span. Although clinical trials provide the only conclusive evidence of the efficacy of treatment, they are usually of
only 3- to 5-years' duration. Both the efficacy and the
safety of drugs may differ over long periods of treatment from the results found in medium-term clinical
trials. Clinic records can provide a means of filling this
gap provided certain conditions are met. These conditions include adequate documentation of the patient at
the initiation of treatment, follow-up information on
U-85
blood pressure control, and information about the
cause of death — with only a small proportion of
patients untraced. All these conditions were met in this
study, which records treatment over a period of at least
15 years in each patient who survived.
Our data showed a satisfactory survival of the patients when compared with untreated series, such as
data reported by Smirk and his colleagues from New
Zealand1 and by Bulpitt.2 Without a randomly allocated control group it is impossible to prove that these
patients' long survival was due to specific antihypertensive therapy, although this explanation seems likely. Another approach is to compare the patients' survival with the general population of the same age and
sex.1 The results of doing so are, at first sight, surprising.
For the oldest age group the survival of the treated
patients was only slightly worse than that of the general population of the same age. The expected 10-year
survival of a man aged 63 years is 57%, and the observed 10-year survival of the treated male hypertensive patients aged 60 to 69 was 54%. The corresponding figures for women of the same ages were 74% in
the general population and 63% in the treated patients.
These are relatively small differences. The pattern in
the younger patients was less favorable: among the
patients aged 30 to 49 years at the outset the 10-year
survival was 81% in both women and men. The expected 10-year survival of men and women of this age
is 96% to 98%. Thus, although the survival was relatively good, mortality was substantially greater than in
the general population.
The blood pressure control achieved after 5 years of
treatment was fairly satisfactory even by contemporary
standards — an average of 147/92 mm Hg. This level
of diastolic blood pressure was associated with very
little increase in risk among patients in the Framingham study.4 The reason for the slow improvement
in control for the first 5 years is not entirely clear.
TABLE 4. Determinants of Survival in Methyldopa-Trealed
Patients
Men
TABLE 3. Causes of Death in 79 Patients Treated with Methyldopa for Two-thirds or More of the Follow-up Period
Cause of death
Code
Men (%)
Women (%)
4 (11.4)
Hypertensive disease
400-405
5 (11.4)
410-414 17 (38.6)
15 (42.9)
Ischemic heart disease
Cerebrovascular disease 430-438
8 (22.9)
7 (15.9)
Other cardiovascular
390-459
disease
2 (4.5)
3 (8.6)
580-599
Renal disease
—
2 (4.5)
Lung cancer
162
1 (2.9)
1 (2.3)
140-208 4 (9.1)
2 (5.7)
Other cancer
1 (2.9)
460-519
Respiratory disease
6 (13.6)
—
1 (2.9)
Other causes
44
Total
35
Average results
Alive
50
Number of patients
Systolic blood pressure
(mm Hg) at presentation 208
Diastolic blood pressure
(mm Hg) at presentation 125
3
Malignant hypertension
8
Accelerated hypertension
18
Smoker at presentation
Plasma urea levels (mmol)
5.9
at presentation
Body weight (kg)
78.5
Serum cholesterol levels
6.4
(mmol) at presentation
Black race
3
Women
Dead
Alive
Dead
44
76
35
219
214
228
132
120
128
3
2
1
13
5
7
29
18
14
6.4
5.3
5.6
74.3
70.6
68.5
6.6
7.1
1
9
6.9
5
11-86
HYPERTENSION
SUPPL II VOL 6, No 5, SEPTEMBER-OCTOBER 1984
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Progressive small changes in drug therapy may have
played a part, although the upward adjustment of
methyldopa dose over this period was, on average,
very small. Reversal of cardiovascular hypertrophy
may also have been important. Whatever the reason it
is gratifying that blood pressure control tended to improve, even though in untreated patients with high
blood pressure levels an upward trend is common.
Deaths were predominantly from cardiovascular and
renal causes. Thus, the mortality pattern still reflected
that expected in hypertensive patients rather than in the
general population. There were no deaths from liver
disease, carcinoma of the biliary tree, hemolytic anemia,5 6 or any other cause that might have raised suspicion of drug toxicity.
These patients with severe hypertension treated predominantly with methyldopa had a remarkably long
survival but, especially at the younger ages, they still
had a higher mortality than that of the general population of the same age and sex. This rinding was not
particular to methyldopa, because patients treated predominantly with bethanidine and guanethidine showed
the same pattern. One possible explanation for the
similarity of the older patients' survival to that of the
general population might be that hypertension, treated
or untreated, has only a minor effect on survival in
older patients; however, this is not in accord with epidemiologic evidence. 7 Another possible explanation
may be that treatment is particularly effective in the
older patients.
The less favorable effect on mortality in younger
patients is also difficult to explain. Secondary hyper-
tension is somewhat more common in younger patients, and excess deaths from chronic renal disease
(which itself caused the hypertension), could provide
an explanation. Both deaths from chronic renal disease
occurred in patients who were under 30 years old at
entry but there were too few renal deaths to invoke this
as the whole explanation. Another possibility is that
atheromatous vascular disease caused by hypertension
could not be reversed by blood pressure control. If,
however, this hypothesis was true, the same, or greater, effect should be seen in the elderly and it was not.
At present no entirely satisfactory explanation is possible but the data do draw attention to the problems of
moderately severe hypertension in younger patients.
While much progress has been achieved, a normal life
expectancy has not yet been attained.
References
1. Smirk FH, Veale AMO, Alstad KS. Basal and supplemental
blood pressures in relationship to life expectancy and hypertension symptomatology. NZ Med J 1959;58:711-735
2. BulpittCJ. Prognosis of treated hypertension 1951-1981. B r J
Clin Pharmacol 1982;13(l):73-79
3. Holme I, Waaler H. Five-year mortality in the city of Bergen,
Norway, according to age, sex, and blood pressure. Acta Med
Scand 1976:200:229-239
4. Anderson TW. Re-examination of some of the Framingham
blood-pressure data. Lancet 1978:2(8132): 1139-1141
5. Worlledge SM. Carstairs KC, Dacie JV. Autoimmune haemolytic anaemia associated with a-methyldopa therapy. Lancet
1977:2:135-137
6. Hoyumpa AM, Connell AM. Methyldopa hepatitis. Am J Dig
Dis 1973:18:213-222
7. Miall WE, Chinn S. Screening for hypertension: some epidemiological observations. Br Med J 1974:1:595-600
Fifteen-year survival of patients beginning treatment with methyldopa between 1962 and
1966.
C T Dollery, K Hartley, P F Bulpitt, M Daymond and C J Bulpitt
Hypertension. 1984;6:II82
doi: 10.1161/01.HYP.6.5_Pt_2.II82
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