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Headaches and the Treatment of Blood Pressure: Results From a Meta-Analysis

of 94 Randomized Placebo-Controlled Trials With 24 000 Participants


Malcolm Law, Joan K. Morris, Rachel Jordan and Nicholas Wald
Circulation 2005;112;2301-2306
DOI: 10.1161/CIRCULATIONAHA.104.529628
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Hypertension

Headaches and the Treatment of Blood Pressure


Results From a Meta-Analysis of 94 Randomized Placebo-Controlled
Trials With 24 000 Participants
Malcolm Law, FRCP; Joan K. Morris, PhD; Rachel Jordan, MPH; Nicholas Wald, FRS

Background—Uncertainty exists over whether blood pressure–lowering drugs prevent headache.


Methods and Results—A meta-analysis was carried out of the 94 randomized placebo-controlled trials of 4 different
classes of blood pressure–lowering drugs (thiazides, ␤-blockers, ACE inhibitors, and angiotensin II receptor antagonists)
in fixed doses in which data on headache were reported. There were 17 641 participants who were allocated blood
pressure–lowering drugs and 6603 who were allocated placebo. Treatment lowered systolic and diastolic blood pressures
by 9.4 and 5.5 mm Hg, respectively, on average. One third fewer people on average reported headache in the treated
groups (8.0%) than the placebo groups (12.4%) (odds ratio, 0.67; 95% CI, 0.61 to 0.74; P⬍0.001). About 1 in 30 treated
persons benefited by having headache prevented. The prevalence of headache was reduced (P⬍0.001) in trials of each
of the 4 classes of drugs.
Conclusions—Our results show that blood pressure–lowering drugs prevent a significant proportion of headaches. That this
effect is seen with pharmacologically unrelated classes of drugs indicates that it is likely to be due to the reduction in
blood pressure per se, the only recognized action that the drugs have in common. This in turn indicates that high blood
pressure is a cause of headache, but this conclusion is not supported by observational studies of blood pressure and
headache. The uncertainty over whether high blood pressure causes headache does not, however, detract from the
practical benefits of the use of blood pressure–lowering drugs in preventing headaches and cardiovascular disease.
(Circulation. 2005;112:2301-2306.)
Key Words: blood pressure 䡲 headache 䡲 hypertension

T he classic “hypertensive headache,” present on waking,


throbbing in nature, and wearing off during the morning,
was described 90 years ago by Janeway.1 His patients
is no link with headache22 or that, if there is, the headaches
are attributable to anxiety and tension induced by being told
one has “hypertension.”23 Recently, an editorial asked, “Why
described it “so commonly that I have almost come to look on does the hypertension headache myth persist?”24
it as a typical hypertensive symptom.”1 Similar reports Against this negative observational data, it is striking that
followed; about half of patients reported headaches.2 published intervention studies have suggested that blood
Janeway’s view, however, was rejected in favor of an pressure–lowering drugs prevent headache. Data from 7
interpretation that the headache was “a socio-psychological randomized double-blind trials of 1 blood pressure–lowering
disorder precipitated by the recognition of the hypertension.”2 drug, irbesartan, showed that it prevented headache25; a large
This followed the demonstration 50 years ago on 200 con- randomized controlled trial (not double blind) of doctors
secutive patients with hypertension that headache was com- using any drug to lower blood pressure showed fewer
mon (74%) in 96 patients who had been told that they had headaches in treated patients26; and 2 nonrandomized inter-
high blood pressure but uncommon (16%) in 104 patients vention studies showed that when patients diagnosed as
who had not (the 2 groups were comparable in blood pressure hypertensive received treatment, headache became less prev-
and other factors)3; that finding was confirmed later in a alent.7,27 The randomized double-blind trial data, however,
larger (n⫽3858) study.4 Subsequent explanations were that relate to only 1 drug,25 and the other results are susceptible to
anger- or anxiety-induced hyperventilation may both cause bias.
headache and raise blood pressure.5,6 Cross-sectional studies To assess whether blood pressure–lowering drugs prevent
have generally shown no association between blood pressure headache, we report here a meta-analysis of 94 randomized
and headache,4,7–21 reinforcing the prevailing view that there placebo controlled trials of 4 classes of blood pressure–

Received December 15, 2004; revision received July 25, 2005; accepted July 29, 2005.
From the Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts, and the London Queen Mary’s School
of Medicine and Dentistry, London, UK.
The online-only Data Supplement can be found at http://circ.ahajournals.org/cgi/content/full/112/15/2301/DC1.
Correspondence to Malcolm Law, Professor of Epidemiology, London Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London
EC1M 6BQ, UK. E-mail m.r.law@qmul.ac.uk
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.104.529628

2301
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2302 Circulation October 11, 2005

lowering drugs in which data on the prevalence of headache TABLE 1. Details of the 94 Trials of Blood Pressure–Lowering
were reported. Drugs Included in the Analysis
Trial design, n
Methods Parallel group 84
The analysis was adapted from our previously reported systematic
review of 354 randomized placebo-controlled trials of 5 classes of Crossover 10
blood pressure–lowering drugs in fixed doses28,29 in which we Trial characteristics (median; 90% range)
assessed their efficacy in lowering blood pressure and the prevalence
Participants per trial, n 123 (24–1440)
of adverse effects according to dose.28 In this analysis, we excluded
trials of calcium channel blockers because they can cause headache Age, y 53 (43–77)
(through vasodilation). Duration, wk 8 (2–14)
The analysis was based on a systematic review of all randomized
Total participants, n 23 599
placebo controlled trials of any drug in 4 classes of blood pressure–
lowering drugs (thiazides, ␤-blockers, ACE inhibitors, and angio- Placebo groups, n 94
tensin II receptor antagonists) in fixed doses that were published Randomized treatment arms testing different 112
from 1966 to 2001. We used MEDLINE but also searched the classes of drug,* n
Cochrane Controlled Trials Register and the Web of Science
database, examined citations in the reports of the trials identified and *Sixteen trials had 2 such arms; 1 trial had 3.
in review articles, and asked pharmaceutical companies to identify
trials of drugs that they manufactured. We used Medical Subject
Headings (MeSH) terms that included trials (clinical trial, controlled combined. On average, across the 94 trials, treatment lowered
clinical trial, randomized controlled trial, random allocation, double-
blind method) and blood pressure–lowering drugs (antihypertensive systolic and diastolic blood pressures by 9.4 and 5.5 mm Hg,
agents; hypertension; blood pressure; diuretics; thiazide; adrenergic respectively, adjusted for the change in the placebo groups.
␤-antagonists; ACE inhibitors; receptors, angiotensin/antagonists One third fewer people reported headache in the treated group
and inhibitors; tetrazoles or the generic and trade names of individual than in the placebo group (odds ratio, 0.67; 95% CI, 0.61 to
drugs in the 4 classes). We also searched for studies containing the
0.74; P⬍0.001). There was also a statistically highly signif-
text words randomized or randomised or the generic or trade names
of the individual drugs. icant (P⬍0.001) reduction in the prevalence of headache in
We included all double-blind trials of ⱖ2-week duration in adults trials of each of the 4 classes of blood pressure–lowering
(ⱖ18 years of age). We excluded trials with no placebo group, with drug.
⬍2-week duration, with dose titration (so that different patients Separate analysis of trials of parallel-group and crossover
received different doses), or in which some control patients were
treated. We also excluded trials testing drugs only in combination design showed statistically significant reductions in the preva-
with other drugs, crossover trials with nonrandomized order of lence of headache in the treated groups compared with placebo
treatment and placebo periods, and trials recruiting patients with in both. In the 84 parallel-group trials, 33% fewer treated than
heart failure or acute myocardial infarction (but otherwise included placebo participants reported headache on average (95% CI, 26
trials regardless of diseases of the participants).28 Trials were not to 39; P⬍0.001), and in the 10 crossover trials, 45% fewer
excluded if similar proportions of treated and placebo participants
took other blood pressure–lowering drugs besides the test drug, participants reported headache (95% CI, 5% to 68%; P⫽0.03).
although in almost all trials this did not happen. In trials in which the There was no statistically significant difference between the 2,
numbers of treated and placebo participants reporting headache over validating a combined statistical analysis.
the duration of the trial were published, we recorded these data. We The Figure summarizes the individual trial data. For each
also recorded the reductions in systolic and diastolic blood pressures
of the 4 classes of blood pressure–lowering drugs (thiazides,
as the change in sitting or supine blood pressure in the treated group
minus that in the placebo group (in crossover trials, end-treatment ␤-blockers, ACE inhibitors, angiotensin II receptor antago-
minus end-placebo blood pressure). nists), there is a separate data point for each of the larger trials
The data were analyzed with STATA statistical software. Parallel- (⬎10 participants reporting headache); smaller trials are
group trials and crossover trials yielded similar results, so we combined into a single data point. That figure shows that
combined them. Results were analyzed on an intention-to-treat basis.
The estimates from each trial of the ratio of the odds of developing almost all the individual trials recorded a directionally lower
headache among participants allocated active treatment to that prevalence of headaches in persons allocated blood pressure–
among participants allocated placebo were combined through the use lowering drugs than placebo. In 17 individual trials, headache
of a random-effects model based on the method of DerSimonian and was statistically significantly less prevalent in treated than
Laird.30 We tested for heterogeneity using the I2 test statistic
placebo groups (identifiable in the Figure as those in which
proposed by Higgins and Thompson.31
We performed 2 additional searches of the databases. To identify the 95% CI does not cross the line of unity); in only 1 trial
randomized placebo controlled trials of the preventive effect of the was headache significantly less prevalent in the placebo
blood pressure–lowering drugs in patients with migraine, we com- groups. These results and the numbers with headaches in each
bined the names of individual drugs or of the classes of drugs with trial (see Figure) show that the overall association does not
migraine, all as MeSH terms or text words. To identify observational
studies of the association between blood pressure and headache, we
arise from a small number of trials. Omitting the few trials
combined the terms hypertension or blood pressure with headache. with the most extreme results from sensitivity analyses had
trivial effects.
Results There was a statistically significant dose-response relation
Table 1 summarizes details of the 94 trials identified. Table 2 across trials for diastolic blood pressure (ie, a greater reduc-
shows the reduction in blood pressure and prevalence of tion in headaches in trials producing a greater reduction in
headaches according to the class of blood pressure–lowering diastolic blood pressure). On average, the reduction in the
drug, with summary estimates for the 4 classes of drug prevalence of headaches was 13% greater (95% CI, 5% to 20%;
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Law et al Headaches and Blood Pressure–Lowering Drugs 2303

TABLE 2. Reduction in Blood Pressure and Prevalence of Headaches According to the Class of Blood Pressure–Lowering Drug:
Meta-Analysis of 94 Randomized Placebo Controlled Trials
Mean Blood Reduction in Blood Pressure
Pressure in Placebo (Treated Minus Placebo), mean Participants Reporting
Participants, n Group, mm Hg (95% CI), mm Hg Headache, n

Class of Drug Trials, n Treated Placebo Systolic Diastolic Systolic Diastolic Treated Placebo
Thiazide 26 2662 1432 153 95 8.7 (7.7–9.7) 4.4 (3.8–4.9) 193 (7.3) 163 (11.4)
␤-Blocker 19 2080 938 156 98 8.4 (7.1–9.7) 6.9 (5.9–7.9) 106 (5.1) 112 (11.9)
ACE inhibitor 39 4172 2429 155 99 9.6 (8.5–10.6) 5.4 (4.8–5.9) 409 (9.8) 290 (11.9)
Angiotensin II receptor antagonist 28 8727 2988 149 97 10.0 (9.2–10.9) 5.7 (5.2–6.2) 708 (8.1) 401 (13.4)

Any of the 4 94* 17 641 6603* 151 97 9.4 (8.9–9.9) 5.5 (5.2–5.8) 1416 (8.0) 818* (12.4)
*These totals are less than the sum of the numbers in the individual drug categories (112 trials, 7787 placebo participants of whom 966 have headache) because
some trials include ⱖ2 treatment groups testing different drugs and they share the same placebo group.

P⫽0.01) in a trial with a 5-mm Hg-greater diastolic blood caused by the drugs or did not record symptoms. In the 94
pressure reduction, but this association depended on the trials in which headache was reported, those data were among
influence of a single trial with an outlying result and was tabulated data on several common symptoms; there was no
weaker with this trial omitted (reduction in headaches 8% special focus on headaches or on the fact that they were less
greater; 95% CI, 0 to 17%; P⫽0.06). There was no relation common in the treated group. There was no indication of
with systolic blood pressure. The analysis, however, lacked publication bias on inspection of funnel plots for asymmetry
the statistical power to demonstrate a dose-response relation- or on performing Egger’s test,32 although these tests, based on
ship because all the trials tested a single blood pressure– showing that smaller trials are more likely to be positive, are
lowering drug against placebo, so there was little variation relatively insensitive.
across trials in the blood pressure reduction attained. Therefore, this meta-analysis shows that blood pressure–
There was significant heterogeneity between trials in the lowering drugs prevent headache. Interestingly, it is already
proportional reduction of headaches in the treated groups acknowledged that 1 form of headache, namely migraine, is
(␹293⫽124; P⫽0.01). This may reflect in part the above prevented by blood pressure–lowering drugs. Randomized
tendency to a greater reduction in headaches with a greater placebo controlled trials conducted in patients with migraine
reduction in diastolic blood pressure. In addition, there was a testing ␤-blockers,33–36 ACE inhibitors,37 angiotensin II re-
suggestion of heterogeneity across the 4 classes of blood ceptor antagonists,38 and calcium channel blockers39 – 41 (we
pressure–lowering drug (␹23⫽7.4; P⫽0.06), reflecting a found no randomized trials of thiazides) all show statistically
greater effect of ␤-blockers than the other 3 classes of drug highly significant reductions in frequency of migraine attacks
(see the Figure). The reduction in headache with blood in the treated groups. Our result from the 94 trials that blood
pressure lowering was unrelated to age. pressure–lowering agents have a general effect in preventing
The absolute difference in the proportion of people report- headache extends the prophylactic effect beyond the preven-
ing headache between the treated and control groups was tion of migraine alone.
3.5% on average (95% CI, 2.8 to 4.1; P⬍0.001); ie, treatment Whether the prevention of headache is attributable to the
prevented headache in 3.5%, or about 1 person in 30. blood pressure reduction or to separate pharmacological
However, the absolute difference in prevalence between the actions of the drugs other than lowering blood pressure is
treated and placebo groups increased with prevalence in the unresolved. It would appear likely that the effect is due to the
placebo group (r⫽0.66, P⬍0.001). The relative reduction (of blood pressure reduction because the reduction in headaches
one third) reported above has the advantage of being inde- was statistically significant (P⬍0.001) for each of the 4
pendent of the prevalence of headache in the placebo group classes of blood pressure–lowering drugs. ACE inhibitors and
(blood pressure reduction tended to reduce headaches by a angiotensin II receptor antagonists have related actions, but
constant proportion of their existing prevalence). these 2 classes of drugs together, thiazides, and ␤-blockers
have no identifiable actions in common by which they might
Discussion prevent headache other than blood pressure reduction (eg, no
The 94 randomized placebo controlled trials show that blood recognized analgesic effect). One would need to postulate
pressure–lowering drugs reduce the prevalence of headache that each prevented headaches in a different way. The effect
by a third, a result that is highly statistically significant. The of ␤-blockers may have been greater than that of the other
result cannot reasonably be explained by either chance or drugs (Figure), which might reflect the recognized action of
bias. In particular, publication bias, whereby trials showing a ␤-blockers in reducing the somatic manifestations of anxiety,
reduction in the prevalence of headache are more likely to be but it is not recognized that any of the other classes of drug
published than other trials, is unlikely. Many of the trials in share this action. The 1 action that the drugs are recognized to
our original data set28 did not report on headache, but this was share, blood pressure reduction, should be the probable
because they reported only on symptoms recognized as being mechanism of effect.
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2304 Circulation October 11, 2005

Odds ratio (odds of participants reporting to not reporting headache in treated groups divided by that in placebo groups), with 95% CI
in 94 randomized trials of 4 classes of blood pressure–lowering drugs. For each class of drug, there is a separate data point for each
of the larger trials (⬎10 participants reporting headache); the smaller trials are combined into a single data point. Citation numbers refer
to the citations of the individual trials in the Data Supplement (http://circ.ahajournals.org/cgi/content/full/112/15/2301/DC1).

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Law et al Headaches and Blood Pressure–Lowering Drugs 2305

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Correction

In the article, “Headaches and the Treatment of Blood Pressure: Results From a Meta-Analysis of
94 Randomized Placebo-Controlled Trials With 24 000 Participants,” by Law et al, which
appeared in the October 11, 2005, issue (Circulation. 2005;112:2301–2306), the authors have
found an error in the figure. The summary odds ratio at the bottom of the figure for all trials, all
classes of drug, should be the same as that reported in the text, 0.67 (95% CI 0.61 to 0.74), not
0.66 (0.60 to 0.73), as was published. The authors regret this error.
DOI: 10.1161/CIRCULATIONAHA.106.172847

(Circulation. 2006;113:e49.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

e49
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