Download Labile Hypertension: A Faulty Concept?

Labile Hypertension: A Faulty Concept?
The Framingham Study
W. B. KANNEL, M.D., PAUL SORLIE, M.S.,
AND
TAVIA GORDON
SUMMARY Labile blood pressure elevation is believed to have less clinical significance than "fixed
hypertension." This assertion was examined in the Framingham cohort of 5209 men and women followed for
20 years for the development of cardiovascular events in relation to three routinely measured blood pressures at
each of 10 biennial examinations.
Variability of pressure judged from the standard deviation about the mean of three pressures was not a consistent characteristic of subjects from one examination to the next (r = 0.07). Higher pressures were more
labile than low ones, so that "fixed hypertensives" actually had more labile pressures than did so-called labile
hypertensives. Lability also increased with age.
Labile hypertension, determined during a 1-hour period of observation, adds nothing to the ability of the
mean blood pressure to predict cardiovascular disease. The mean, minimum and maximum of three pressures
measured during an examination were equally efficient predictors of cardiovascular disease. In multivariate
analysis, for any given average pressure, risk of cardiovascular events was unaffected by the degree of
variability of the pressure. It is recommended that the average of a series of pressures be used to determine
risk, preferably over more than one examination.
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LABILE HYPERTENSION is regarded as a
relatively innocuous antecedent of "fixed" hypertension.1 As such, it is common clinical practice to consider labile hypertension unworthy of treatment.2
The purpose of this report is to examine the concept
of labile hypertension and its role in the development
of cardiovascular disease in the Framingham Study.
This cohort has been followed over 20 years for the
development of cardiovascular disease in relation to
three routinely obtained biennial blood pressures. The
lability of pressure is calculated from these readings
and its net effect on risk of cardiovascular disease,
taking the average level of pressure into account, is
ascertained.
Methods
The Framingham cohort consists of 2336 men and
2873 women ages 30-62 years at entry to the study in
1948-1952. They received a standardized, routine
reexamination for the development of cardiovascular
disease every 2 years. Cardiovascular events and mortality that occurred in the 20 years of follow-up were
ascertained by means of these biennial cardiovascular
examinations and surveillance of hospital admissions
and deaths. Criteria for cardiovascular end points
have been given elsewhere.3
The examination procedures, sampling, type of
follow-up and response rates have been described in
detail previously.4 The examination procedure includes blood pressure measurements, an ECG, a carFrom the Framingham Heart Disease Epidemiology Study,
Framingham, Massachusetts, the Boston University School of
Medicine, Evans Memorial Research Foundation, Department of
Medicine, Boston, Massachusetts, and the Biometrics Research
Branch, NHLBI, NIH, Bethesda, Maryland.
Address for correspondence: Paul D. Sorlie, National Institutes
of Health, 7550 Wisconsin Avenue, Room 2A06, Bethesda,
Maryland 20205.
Received April 25, 1979; revision accepted November 30, 1979.
Circulation 61, No. 6, 1980.
1183
diovascular physical examination and history, a
cigarette history and a variety of blood chemistries, including cholesterol, lipoproteins and blood sugar.3
Systolic and diastolic pressures were obtained using
a mercury sphygmomanometer with a 14-cm cuff long
enough to fit the most obese arm. The subject was
seated and the left arm was used. Recommendations
of the American and British Heart Associations were
followed.5 Palpation was used to check auscultatory
findings. Diastolic pressure was read at the fifth
Korotkoff phase. Readings were made to the nearest
even number. Beginning in 1950, three pressures were
obtained routinely on each subject: one by the nurse
and two by the examining physician - one at the start
of the exam, the other at the end of the interview after
the blood specimen was obtained.
The relation of the various components of pressure
under consideration - the mean, minimum, maximum and variability - to subsequent appearance of
cardiovascular disease was evaluated by estimating a
logistic function using the methods of WalkerDuncan6 and Truett-Cornfield.7 These evaluations use
a person-exams approach in which blood pressures at
all 10 exams are considered. Thus, the assessment of
cardiovascular risk is based on all available blood
pressures and not on a single initial reading.
The within-person standard deviation was used to
assess the variability of the pressure. Because only two
or three blood pressures were used to estimate this
variability, the standard deviation was adjusted for the
bias caused by small numbers.8 9 When two blood
pressures are available, the standard deviation is the
absolute difference of the two measurements multiplied by a constant. Thus, in some analyses, the absolute difference between the blood pressures is used
as a description of within-person variability.
Hypertension was designated when two pressure
determinations exceeded 160/95 mm Hg, normotension was indicated by pressures consistently below
140/90 mm Hg, and intermediate pressures were
designated "borderline."3
CIRCULATION
1184
Results
Variability
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Blood pressure is acknowledged to be a measurement that fluctuates physiologically in response to
changes in physical activity, emotion, mood,
wakefulness and other demands for greater tissue perfusion. Therefore, pressures under office conditions
are sometimes variable. This has engendered skepticism about the value of a single blood pressure
reading.
However, it is difficult to discern what most
physicians or texts mean by the term "labile hypertension." Presumably it means that, using some arbitrary
definition of "hypertension," the pressure measurement, when repeated, is below this arbitrary level and
in the borderline or normal range.
When examined in this way, 35% of male and 27%
of female hypertensives on one biennial examination
were borderline or normotensive on the next (table 1).
By this criterion, those subsequently found to be normotensive might be judged very labile, and those
borderline moderately so.
However, this concept of "lability" is confounded
by the statistical phenomenon of regression toward the
mean. A subgroup selected because it is above average
pressure and then remeasured, will be closer to the
mean for the entire sample and hence lower on the
second measurement.
One indication of the lability of the blood pressure
is the standard deviation about the mean of a series of
pressures obtained over an hour on a particular biennial examination. An approximation of this standard
deviation for two measurements is the absolute
difference between the measurements. About 65% of
those examined had differences in two systolic
measurements, made by a physician, of less than 10
mm Hg; for diastolic, 81% had a difference less than
10 mm Hg. Differences greater than 20 mm Hg occurred in less than 10% of persons for systolic and in
only 2% for diastolic (table 2).
The variation of blood pressure during the 1-hour
exam did not appear to be a repeatable characteristic
of a subject. The variation at one moment was unrelated to variation at another. While the blood
pressures themselves were highly correlated in a subject from one exam to the next (table 3), the correlation of standard deviations of blood pressure from one
examination to another is extremely low whether 2
years or 18 years apart (0.08 and 0.04, respectively).
Analysis of subjects who had all 10 examinations
shows that extreme variability of systolic blood presTABLE 1. Hypertensive Status at Examination 3 vs Examination 4: Men and Women Ages 30-62 Years at Entry. Framingham Study
Pressure status at exam 3
Normotensive
Borderline
High
Percent hypertensive
at exam 4
Men
Women
3%
2%
21%
21%
65%
73%
VOL 61, No 6, JUNE 1980
TABLE 2. Distribution of Differences Between Two Physicianmeasured Blood Pressures at One Examination: Framingham
Study, Examination 3, Men and Women Ages 34-66 Years
Percent with specified difference
Differences
Systolic
Diastolic
Men
Women
Men
Women
(mm Hg)
65
82
0-9
65
80
10-19
26
26
16
18
20-29
7
6
2
2
> 30
2
2
0.2
0.2
TABLE 3. Correlation of Blood Pressures Between Initial
and Later Examinations: Framingham Study, Men and Women
Ages 30-62 Years at Entry
Systolic
Later exam
Exam 2 (2 yrs
later)
Exam 10 (18 yrs
later)
Diastolic
Women
Men
Women
Men
0.67
0.80
0.60
0.69
0.47
0.55
0.38
0.43
sure repeated on many examinations is a rare finding
(table 4). In comparing the number of persons
with high variability with that expected from the
binomial function, there are slightly more subjects
observed than expected in those categories with the
more frequent occurrences (three or more exams with
high variability). This is consistent with the small but
positive correlation coefficient described earlier.
However, the magnitude is very small. If four or more
occurrences of high variability may be thought to indicate an individual with "characteristically high
variability," there are only 12 more individuals so
observed than expected out of a population of 1785.
Thus, although pressures do vary some during an
office examination (table 1), there is little evidence to
support the contention that there are actually identifiable persons in a population who characteristically
TABLE 4. Number of Subjects with High Variability (HV)*
of Systolic Blood Pressure on 10 Framingham Examinations:
Observed and Expected
Number of Framingham exams
with high within-person variability
No. of exams with HV
1 of 10
2 of 10
3 of 10
4 of 10
5of 10
6oflO
7 or more
Number of subjects
with HV
Observed Expectedt
857
777
574
674
240
263
92
61
17
9
3
1
2
0
0
0
1785
1785
*High variability means difference > 20 mm Hg between
systolic pressures taken by two examiners.
tExpected is based on binom-iial function with an overall
probability of HV of 0.07983.
LABILE HYPERTENSION/Kannel et al.
TABLE 5. Within-person Variation of Systolic Blood Pressure
by Age and Sex, Framingham Heart Study. Examination 3
Average withinNumber of
person standard
persons measured
deviation
Age
Men Women
Men
Women
(years)
405
35-39
367
5.68
6.74
453
365
6.65
40-44
6.74
407
317
45-49
6.94
7.13
367
261
7.99
7.61
50-54
55-59
8.40
332
275
8.52
254
205
10.32
8.74
60-64
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have unusually labile pressures on a number of cclxaminations. However, systolic blood pressuire
variability is related to age, with the older subje(cts
having higher variability, at least in the age ranige
35-64 years (table 5). Furthermore, all pressures aire
to some extent labile, and high pressures are actua,lly
more labile than low ones. Even after adjusting ifor
age, within-person variability increases with increasing systolic pressure (fig. 1). Hence, pressures 1far
above the arbitrary dividing line between "hypertee,nsion" and normal or borderline pressures, commornly
regarded as "fixed hypertension," are actually mc:re
labile than those close to this arbitrary boundary aLnd
usually regarded as labile.
Lability and Risk
"Basal" pressures have been considered the boest
basis for judging the need for treatment.1 2 Those rlot
elevated under basal conditions were often in the p;ast
judged innocuous and thought not to require trelatment. As an extension of this concept, physicians haive
tended to use the lowest pressure recorded on a paticent
as the most valid for evaluating risk.
In the Framingham cohort, the lowest presstare
X
s
----
z
Men
Women
0
Fe
5
-L'
11.0
9.0
a
z
7.0
0
cc
LAJ
CL
m
5.0 l110
110-119
120-129
130-139
140-149
_j
150+
SYSTOLIC BLOOD PRESSURE (MM-Hg)
FIGURE 1. Age-adjusted, within-person variation of
systolic blood pressure (mm Hg) according to level, examination 3. Men and
women
ages 35-64 years.
1185
TABLE 6. Regression of Incidence of Cardiovascular Disease
on Three Blood Pressures: Men and Women Ages 45-74 Years.
Framingham Study 20-Year Follow-up
Regression coefficients for SBP
(independent variables: SBP, age)
Measurement
Women
Men
of three pressures
0.0204
0.0177
Minimum
0.0210
0.0178
Mean
0.0195
0.0163
Maximum
Abbreviation: SBP = systolic blood pressure.
TABLE 7. Incidence of Cardiovascular Disease at Borderline
Pressures in Men Ages 45-74 Years: Framingham Study
20-year Follow-up
2-year
Classification of
age-adjusted
systolic pressure
Population No. of incidence rate
(mm Hg) on three
(%)
cases
at risk
readings
Maximum > 140;
3.7
56
1497
mean < 140
Mean > 140;
5.3
48
893
minimum < 140
Minimum, mean,
6.0
177
2723
maximum > 140
Normotensive
(maximum <
2.6
111
4520
140)
recorded during an office visit was not a better predictor than the average pressure. The mean, minimum
and maximum of three pressures taken during an
office examina+:jn are, judging from the regression of
incidence of cardiovascular disease on them, virtually
indistinguishable predictors of cardiovascular disease
(table 6). The similarity of the regression coefficients
in table 6 indicates that the relative risk is similar for
the three measures of blood pressure. For example, if
the blood pressure were to differ by 20 mm Hg, the approximate relative risk for the minimum, mean and
maximum would be, respectively, 1.43, 1.43 and 1.39
for men.
However, because of the relationship among the
minimum, the mean and the maximum pressures, the
absolute risks are different (table 7). If only the maximum of three readings is over 140 mm Hg, the other
readings will be lower, resulting in a lower risk of cardiovascular disease in this group. This risk is still 42%
higher than that for normotensives. If the minimum is
high, this reflects a higher average pressure, which
results in a higher risk - more than twice that of normotensives.
Thus, there is no question that persistently elevated
basal pressures are associated with a high risk of cardiovascular disease. The lowest pressure obtained in
the office is, when elevated, clearly associated with a
high risk (fig. 2). Also, at any level of pressure the risk
is greater when it is the lowest than when it is the
highest of a series of pressures. This is merely a reflection of the higher average pressure of the former. In
any event, the converse is not true. It is not safe to disregard patients whose pressures fail to be persistently
1186
TABLE 9. Cardiovascular Disease vs Systolic Level, Lability
and Age: Framingham Study 20-year Follow-up, Ages 4574 Years
Standardized multiple logistic coefficients
Men
Women
cc
4
us
0
12%
- Minimum of 3 readings
Mean of 3 readings,
-- Maximum of
cc
4
VOL 61, No 6, JUNE 1980
CIRCULATION
C,,
IL
(.5
8%
0
z
c0
Lu
C,,
0
LA.
Lu
4%
,
z
W
a
SBP lability
SBP level
Age
p <0.001.
Abbreviation: SBP =
-_. ,,
a
a
a-
0.027
0.357*
0.303*
0.080
0.420*
0.458*
systolic blood pressure.
z
74- 110- 120- 130- 140- 150- 160- 170- 180- 190+
109 119 129 139 149 159 169 179 189
SYSTOLIC BLOOD PRESSURE
FIGURE 2. Fitted incidence of cardiovascular disease by
level of systolic blood pressure (minimum, mean or maximum of three readings). Men ages 45-74 years, age-adjusted
incidence. Framingham Heart Study.
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elevated on every determination if the average
pressure is high.
It would seem that the best indicator of risk is the
average of a series of office pressures rather than the
lowest reading. Though all measures demonstrate
nearly equal relative risks, the average of a series
would yield a more precise estimate of a person's
blood pressure.
Whereas the risk of cardiovascular disease is best
judged from the average of a series of pressures, the
risk is unaffected by the variability of these pressures
about the mean. Patients whose pressures are more
"labile" have no lower risk of cardiovascular events
than those whose pressures were less variable. In fact,
taken alone, the risk of cardiovascular disease actually
increases with the degree of variability in pressure
(table 8). However, this reflects only the higher
average pressure of those with more variable values.
When this is adjusted for the mean level of pressure by
computing coefficients of variation, there is no relation of variability to risk.
TABLE 8. Cardiovascular Disease by Pressure Variability
in Men Ages 45-74 Years: Framinyham Study 20-year Followup
Unadjusted for
average pressure
Standard
deviation
of pressure
(mm Hg)
0-4
5-9
10-14
15+
2-year
incidence
rate (%)
3.7
4.0
4.5
5.7
Adjusted for
average pressure
Coefficient of
variation
2-year
incidence
(*
rate (%)
4.2
2.6
3.5
4.5
0-0.9
1.0-1.9
2.0-2.9
3.0+
Standardized
slope
0.129
0.051
2.74
Age-adjusted
1.02
*Coefficient of variation is the within-person standard
deviation of pressure divided by within-person mean pressure.
A surer way of disentangling the effects of lability
from the pressure level is to compute multivariate
regression coefficients, allowing an interpretation of
the net effect of each component of the pressure. This
shows coefficients for lability that are neither substantial nor statistically significant and they are not
negative (table 9). Thus, there is no indication of a
lesser risk in relation to lability, taking the level of
pressure into account. In fact, there is no suggestion of
any influence of lability, one way or the other, on risk
of cardiovascular sequelae of hypertension.
Discussion
Blood pressure is a dominant contributor to the
major cardiovascular diseases, particularly for stroke
and cardiac failure.'0' 11 Epidemiologic data have
clearly shown that casual office pressures are highly
predictive of subsequent incidence of cardiovascular
disease. Physicians appear convinced that they can improve on this by attention to the lability, systolic and
diastolic components, repeated measurements over a
period of observation and basal pressures.
Casual pressures can be obtained more reproducibly by standardizing the measurement situation,
making sure that the subject is tranquil and rested,
and by acclimatization through repeated measurements."' 12 Whether this is a more appropriate measurement for evaluating risk is uncertain. It can be
argued that a casual measurement is more representative and relevant.9' 10 The initial examination blood
pressure measurement at Framingham was somewhat
higher on average than on later exams, presumably
due to the novelty of the procedure, and predicted cardiovascular disease at least as well as pressures on
later exams.9
Variation in blood pressure has been examined
previously, but its significance in evaluating risk has
not been clearly determined.'13-5 The lack of precision
in the diagnosis of "hypertension" is surprising, considering that it is a prevalent and powerful contributor
to cardiovascular disease. Over the years, hypertension has been subdivided into malignant and benign
and labile and fixed varieties in an attempt to distinguish severe from mild forms of the disease process.
The malignant or accelerated variety appears to be
a distinct entity with a unique vascular pathology - a
necrotizing, fibrinoid arteriolar process. Labile
hypertension has no such distinguishing features. In
fact, almost all normotensive persons occasionally
LABILE HYPERTENSION/Kannel
have pressures above the arbitrary normal limits.'6' '7
Likewise, almost all patients with so called fixed
hypertension occasionally have pressures below the
conventionally designated hypertensive limits.
Perhaps a useful characterization of lability could be
arrived at by responses to standard stimuli or by
analysis of long-term chronobiological fluctuations.'8
By current definitions, however, and by short-term
observations, the entity does not appear to be a persistent individual characteristic or to have clinical
significance.
Clinical Implications
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As assessed by repeated 1-hour clinic visits, no
support can be found for the concept that there is a
discrete subgroup of the population with characteristically labile pressures. However, there are other definitions and descriptions of labile blood pressures.
Many distraught patients will have an elevated
pressure in the physician's office but will later exhibit
what is considered a nonhypertensive pressure.
Recognition of this appears to be responsible for the
traditional concept of fixed and labile hypertension.'9' 20 Those who accept this distinction as valid
have concluded that "basal" blood pressures are more
reliable determinants of the prognosis in hypertension
than are casual pressures.2"22 While this may seem
reasonable on a priori grounds, given the known
variability of blood pressure, casual pressures predict
outcomes surprisingly well. In regard to cardiovascular sequelae, it appears that the only reason that
fixed hypertension is associated with a higher risk than
labile hypertension and basal pressure elevations carry
a higher risk is that the average pressure of basal or
fixed hypertension is higher. It would therefore appear
more logical to rely on the average pressure rather
than on such ambiguous indicators as basal or fixed
states of hypertension. It is not safe to rely on the
lowest pressure recorded on a patient as an indicator
of the need for treatment.
Caldwell et al.23 found that near-basal pressures
were no more accurate as indicators of cardiorenal
manifestations of hypertension than were casual
pressures.
It may be unwise to label a patient hypertensive on
the basis of a single office blood pressure. It does not
appear to be good practice to place such patients, who
may have been transiently emotionally upset, on a
lifetime of antihypertensive therapy on the basis of
one office blood pressure reading. However, it would
appear equally unwise to conclude that the patient
who occasionally has a nonhypertensive blood
pressure is in no jeopardy.
Greater attention to diastolic than systolic casual
office pressures, contrary to widely held belief, adds
nothing to the precision of risk estimates.'011
Disregarding those with isolated systolic elevations is
also a mistake.'0 More important in assessing the
gravity of the average blood pressure is the height of
the systolic pressure, the number of associated cardiovascular risk factors and whether or not there is
target organ involvement.' This is true whether the
pressure elevation is labile or fixed.
1187
et al.
References
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2. Freis ED: VA cooperative study on anti-hypertensive agents:
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T. Washington DC, US Government Printing Office, 1974
4. Gordon T, Kannel WB: The Framingham Massachusetts Study
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Labile hypertension: a faulty concept? The Framingham study.
W B Kannel, P Sorlie and T Gordon
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Circulation. 1980;61:1183-1187
doi: 10.1161/01.CIR.61.6.1183
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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