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ORIGINAL INVESTIGATION
Headache in Mild-to-Moderate Hypertension
and Its Reduction by Irbesartan Therapy
Lennart Hansson, MD; David H. G. Smith, MD; Richard Reeves, MD; Pablo Lapuerta, MD
Background: Although it is generally acknowledged to
be a problem in severe hypertension, headache has not
been consistently associated with mild-to-moderate hypertension.
Patients and Methods: In 7 randomized, double-
blind, placebo-controlled trials, which included 2673
patients with mild-to-moderate hypertension (defined as
seated diastolic blood pressure of 95-110 mm Hg),
patients were randomized to receive once-daily treatment with irbesartan, an angiotensin II receptor blocker
(n = 1987), or placebo (n = 686). The data were pooled
and analyzed retrospectively to determine whether the
level of hypertension was associated with headache and
H
From the Division of Clinical
Hypertension Research,
Institute for Geriatrics, Uppsala
Universitët, Uppsala, Sweden
(Dr Hansson); Memorial
Research Medical Clinic, Long
Beach, Calif (Dr Smith); and
Pharmaceuticals Research
Institute, Bristol-Myers Squibb
Co, Princeton, NJ (Drs Reeves
and Lapuerta).
whether antihypertensive therapy reduced the incidence
of headache.
Results: Factors found to be predictive of headache incidence were diastolic blood pressure, sex (female), and
age (,50 years). In comparison with placebo, the use of
irbesartan was associated with a significant reduction in
the incidence of headache (P =.003).
Conclusions: These data suggest that mild-tomoderate hypertension is not asymptomatic and that the
incidence of headache can be reduced by antihypertensive treatment with a favorable adverse effect profile.
Arch Intern Med. 2000;160:1654-1658
EADACHE MAY be the most
frequently mentioned
complaint that accompanies hypertension. As
early as 1913, in a review of more than 7800 patients, Janeway1
concluded that headache was the most
common of the various symptoms reported by patients with hypertension, a position supported by other investigators.2,3 In a study of 400 patients with
hypertension (diastolic blood pressure
[BP] $110 mm Hg), 55% of patients reported headache as a consequence of their
hypertension.4 For diastolic BP between 95
and 125 mm Hg, the incidence of headache has been reported to be between 15%
and 20% in patients with hypertension
who are untreated.5
Despite the early recognition of an association, the link between headache and
hypertension has often been attributed to
anger, anxiety, or the adverse effects of
drug therapy. Indeed, the reporting of
headache has been used in an “anger scale”
that predicted hypertension in the
Framingham Study.6 According to another report, anxiety-induced hyperventilation has been considered a common
cause of headache in hypertension.7 Other
investigators have attributed the develop-
(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 12, 2000
1654
ment of headache in hypertension to the
adverse effect of diuretics, calcium channel blockers, and angiotensin-converting
enzyme (ACE) inhibitors.8-10 Confounding the situation further, pain of any cause,
including headache, may elevate BP.
Some reports have indicated that the
treatment of hypertension reduces the frequency of headache.11-14 Additional indirect evidence was provided by Cooper et al,5
who found that headache frequency increased following drug withdrawal from all
classes of antihypertensive agents except calcium channel blockers, indicating that BP
control with well-tolerated agents may reduce the frequency of headache. The recently developed angiotensin II receptor
blockers (ARBs) may reduce BP as effectively as other antihypertensive medications, while providing a tolerability profile
similar to that of placebo,15-20 thus offering
the means to test the hypothesis as to
whether the reduction of BP without the
imposition of adverse events reduces the
frequency of headache in hypertension.
Irbesartan is an angiotensin II receptor antagonist; in an integrated analysis,
it was shown to possess a clear dose
response in antihypertensive effectiveness for both diastolic and systolic BP.21
Furthermore, this integrated analysis of 9
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PATIENTS AND METHODS
Patients were men or women (surgically sterile or postmenopausal) 18 years or older (irbesartan therapy, n=1987;
placebo, n= 686). All patients had newly discovered or established mild-to-moderate hypertension (defined as seated
diastolic BP of 95-110 mm Hg) and were randomly assigned to a treatment or placebo group in each of the 7 studies. (Reports on 6 of these studies have been previously published.25-29) Exclusion criteria were related to specific
concomitant diseases that would present safety hazards or
to concomitant medications that might interfere with the
assessment of safety or efficacy of irbesartan and were highly
consistent across all studies. Each study was approved by
an institutional review committee, and each patient gave
informed consent before study enrollment. There were no
statistically significant differences in baseline characteristics between the irbesartan therapy and placebo groups. Most
patients (80%) were white, and more than half (63%) were
men, with a median age of 53 years and mean baseline BP
of 154/101 mm Hg.
hydrochlorothiazide combination therapy; these patients
and groups were excluded from this analysis.) Blood pressure was measured with a standard, calibrated mercury
sphygmomanometer and analyzed according to standardized protocol. Blood pressure was determined by calculating the mean of 3 to 5 measurements taken 1 minute apart,
following 5 to 10 minutes of rest in the seated position at
24 ± 3 hours after the previous day’s morning dose. Only
the baseline (end of placebo lead-in period) and final BP
measurements at the completion of the double-blind period were used in the current analysis.
Safety monitoring at each clinic visit (every 2-6
weeks) included evaluation by open-ended questioning regarding health status. Investigators recorded any change
in health status as well as specific information on onset,
severity, cause, treatment required, and resolution of any
adverse event on a standardized case-report form. Accordingly, headache was detected by spontaneous adverse event
reporting and relied on patient recall. Furthermore, reporting of headache as an adverse event captured data on
new or worsening headache only; data on stable headache
were not captured. Physical examinations, electrocardiograms, and tests on blood and urine samples were also performed individually.
CONTRIBUTING STUDIES
STATISTICAL ANALYSIS
All 7 studies began with a 4- to 5-week single-blind
placebo lead-in period. Following the lead-in period, eligible patients were randomized to receive placebo or irbesartan in fixed doses, ranging from 1 mg to 900 mg for a
period of 8 or 12 weeks. (These studies also included an
extension period26 or randomization arms28,29 in which
patients could receive hydrochlorothiazide or irbesartan-
In this pooled analysis, the relationship between headache and age, sex, baseline diastolic and systolic BP, last
recorded diastolic and systolic BP, and active drug treatment was analyzed by logistic regression. A backward elimination method was employed to determine the relative
importance of each factor to headache incidence. P,.05
was considered statistically significant.
PATIENTS
placebo-controlled, 4- to 12-week studies of irbesartan
monotherapy (irbesartan, n = 1965; placebo, n = 641)
found that irbesartan was associated with tolerability
comparable with placebo at all clinical doses and that
the incidence of headache among patients receiving irbesartan was significantly lower than that of patients
receiving placebo (12.3% vs 16.7%; P=.005). The safety
profile was consistent regardless of age, sex, or disease
severity.
Based on the excellent safety and efficacy profile of
irbesartan and recent data indicating that aggressive BP
control may improve the quality of life for patients with
hypertension,22,23 we analyzed pooled data from 7 randomized, double-blind, 8- to 12-week, placebo-controlled trials to investigate whether mild-to-moderate hypertension
is associated with headache and whether effective treatment with irbesartan might be associated with a reduction in the incidence of headache. A preliminary report
of these data has previously been published.24
RESULTS
Among patients who received placebo alone, sex (female) and last measured diastolic BP were significant predictors of headache incidence during the double-blind
period. Figure 1 shows the cumulative incidence of new
or worsening headache in men (18%) and women (29%)
(P,.001 vs men in logistic regression). The last diastolic BP measurement of less than 90 mm Hg, 90 to 99
mm Hg, and 100 mm Hg or greater was associated with
headache in 19%, 21%, and 27% of cases, respectively
(P=.03 in logistic regression) (Figure 2). There was no
observed relationship between the last systolic BP measurement and headache incidence. There was a statistically significant trend toward decreasing frequency of headache with increasing age (P=.02 in logistic regression)
(Figure 3). Table 1 summarizes odds ratios for headache among patients who received placebo by age, sex, and
last diastolic BP measurement. Similar trends were also seen
among patients who were treated with irbesartan.
In both the placebo and irbesartan groups combined, the mean BP after randomization was 142/92
mm Hg and the baseline BP was 154/101 mm Hg. When
all patients were analyzed, the same factors remained predictive of headache incidence, namely sex (female) and
the last diastolic BP measurement. Increasing age was also
significantly correlated with a decreasing incidence of
headache (Table 2). Active drug treatment was a significant independent predictor of decreased headache. Patients receiving irbesartan had a significantly lower incidence of headache compared with patients receiving
placebo (17% vs 22%; P=.003).
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29%
30
Table 1. Results of Logistic Regression Analysis
for Patients With Hypertension Who Received
Placebo (n = 686)*
Headache Incidence, %
25
20
Variable
18%
Age (years)
Female
Last diastolic blood pressure measurement,
(mm Hg)
15
10
Odds Ratio
P†
0.98
2.05
1.02
.02
,.001
.03
*The last systolic blood pressure measurement did not enter the logistic
regression model as a significant predictor of headache ( P=.30).
†From logistic regression analysis adjusting for age, sex, and the last
diastolic blood pressure measurement.
5
0
Men
Women
Figure 1. Sex (female) was significantly predictive of headache incidence
among patients who received placebo ( P,.001 vs men).
Table 2. Results of Logistic Regression Analysis
for Patients With Hypertension Who Received
Irbesartan or Placebo (n = 2673)*
30
27%
Variable
Odds Ratio
P†
0.79
0.98
1.74
1.02
.04
,.001
,.001
,.001
25
Irbesartan treatment
Age (years)
Female
Last diastolic blood pressure measurement,
(mm Hg)
Headache Incidence, %
21%
20
19%
15
10
*The last systolic blood pressure measurement did not enter the logistic
regression model as a significant predictor of headache ( P=.80).
†From logistic regression analysis adjusting for age, sex, and the last
diastolic blood pressure measurement.
5
0
<90
≥100
90-99
Last Diastolic Blood Pressure Measurement, mm Hg
Figure 2. The last diastolic blood pressure measurement was significantly
predictive of headache incidence among patients who received placebo
( P =.03 for trend).
Headache Incidence, %
25%
24%
20
18%
15
10
5
0
<50
Similarly, the 15th edition of The Merck Manual of
Diagnosis and Therapy states that:
Primary hypertension is asymptomatic until complications develop . . . Dizziness, flushed facies, headache, fatigue, epistaxis, and nervousness are not caused by uncomplicated hypertension . . . 31
30
25
larly considered a symptom of elevated arterial pressure, headache is characteristic only of severe hypertension . . . 30
≥60
50-59
Age, y
Figure 3. The incidence of headache by age among patients who received
placebo ( P =.02).
COMMENT
The following statements from the 14th edition of Harrison’s Principles of Internal Medicine succinctly present
the “classic” opinion about the relationship between mildto-moderate hypertension and headache:
Most patients with hypertension have no specific symptoms referable to their blood pressure elevation . . . Though popu-
There are findings, however, including those from
the current analysis, that indicate a more direct association between headache and hypertension, ie, that patients with hypertension who receive treatment have a
lower incidence of headache than those who do not receive treatment.11,12 In the present analysis, patients with
mild-to-moderate hypertension (diastolic BP, 95-110
mm Hg) who were treated with irbesartan had a significantly reduced incidence of headache compared with patients receiving placebo (17% vs 22%; P =.04 in logistic
regression). In fact, the magnitude of the effect could be
greater since the studies were not designed to capture
headache specifically. Additionally, a potentially greater
effect from treatment might be realized at doses higher
than the 75- to 150-mg oral dose of irbesartan that was
used in most of the 7 studies.
In the current analysis, the incidence of headache was
related to diastolic but not to systolic BP. However, our
analysis used only the last recorded BP measurement. More
comprehensive measurements, such as ambulatory BP data,
could be more effective in identifying an independent relationship between systolic BP and headache.
(REPRINTED) ARCH INTERN MED/ VOL 160, JUNE 12, 2000
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The findings of the current analysis agree with the
findings of other studies, indicating that a pharmacologic reduction in BP may result in improved quality of
life and a reduced incidence of headache. Cooper et al5
studied 11710 patients with newly diagnosed or poorly
controlled hypertension (seated diastolic BP of 95-120
mm Hg). Following a 2-week washout period, patients
received treatment with an ACE inhibitor. Prior to treatment with the ACE inhibitor, the highest prevalence of
headache was noted in the previously untreated group,
which also had the highest BP at baseline. Throughout
the trial, headache incidence was related to increasing
levels of BP for both diastolic and systolic BP. During treatment with the ACE inhibitor, the overall frequency of
reports of headache was lower, but the same relationship was observed. The Treatment of Mild Hypertension Study (TOMHS),22 which included 902 men and
women with borderline hypertension (average baseline
BP of 140/91 mm Hg), found a nonsignificant trend toward a reduction in the incidence of headache among patients receiving treatment compared with those receiving placebo.
More recently, the Hypertension Optimal Treatment (HOT) Study32 found that intensive BP lowering
was associated with improved quality of life. Despite the
aggressive use of antihypertensive agents, a substudy of
patients participating in the HOT Study (n = 610) demonstrated that intensive BP lowering improved quality of
life and significantly reduced the incidence of headache.23 Furthermore, 2 self-administered questionnaires—
the Psychological General Well-Being Index and the Subjective Symptoms Assessment Profile—indicated that the
lower the diastolic BP achieved, the greater the improvement in well-being reported by patients. More intensive
antihypertensive therapy was also associated with a significant reduction in the incidence of headache. In the
HOT Study, 18 790 patients with hypertension (mean diastolic BP of 105 mm Hg) were randomized to 1 of 3 target BP groups (#90, #85, and #80 mm Hg). In the HOT
Study, the incidence of headache was reduced in all target groups (P,.001) and was associated with an elevated BP rather than with adverse events resulting from
treatment. Although the findings of the current study are
generally consistent with the overall results of the HOT
Study and TOMHS, it included additional analyses of the
relationship between BP and headache. It used a multivariate method to control for the effects of age and sex,
it differentiated diastolic and systolic BP in terms of their
ability to predict the incidence of headache, and it identified a significant relationship between diastolic BP while
receiving treatment and new or worsening headache in
patients receiving placebo only.
In the current studies, the relationship between headache and BP may have been more easily identified because of the excellent tolerability profile of irbesartan
therapy. Irbesartan therapy has been shown to have a tolerability profile that is comparable with placebo, with no
relationship between irbesartan dose and the overall incidence of adverse events or adverse drug events.33 With
other agents, a more confusing picture may emerge in
analyzing adverse event reports, and the adverse effects
of hypertension may be difficult to separate from the ad-
verse effects of the antihypertensive agent, particularly
as the doses are likely to be higher among patients with
higher levels of BP.
The reduction in the incidence of headache with irbesartan therapy may have important implications for the
clinical use of ARBs. Classes of antihypertensive agents that
are thought to be more tolerable, such as ACE inhibitors,
are associated with lower rates of discontinuation from
therapy compared with agents that are thought to be less
tolerable, such as calcium channel blockers and diuretics.34,35 Although long-term, large-scale, comparative studies evaluating discontinuation rates with ARBs are lacking, the superior tolerability of these agents may translate
into improved quality of life and, consequently, into improved compliance and long-term BP control.
CONCLUSIONS
In this pooled analysis of 7 double-blind, placebocontrolled trials of irbesartan therapy, the incidence of
headache was directly associated with the level of attained diastolic BP. Factors predictive of increased headache incidence were sex (female), younger age, and receiving placebo. These data indicate that treatment with
irbesartan lowered the incidence of headache. Thus, mildto-moderate hypertension may not be an asymptomatic
condition; furthermore, reduction of BP with irbesartan
therapy is associated with a reduced incidence of headache. The results of the analysis suggest that physicians
should take patient reports of headache seriously and take
steps to aggressively reduce BP, preferably with agents
that have superior tolerability profiles, to improve overall quality of life.
Accepted for publication November 4, 1999.
Dr Smith has been an investigator in clinical trials sponsored by Bristol-Myers Squibb Co, Princeton, NJ, and Dr
Hansson has been a consultant to Bristol-Myers Squibb Co.
Corresponding author: Lennart Hansson, MD, University of Uppsala, Division of Clinical Hypertension Research, Institute for Geriatrics, Uppsala, Sweden 75125.
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