Original Article

Cephalalgia
2014, Vol. 34(7) 523–532
A comparative study of candesartan ! International Headache Society 2013
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versus propranolol for migraine sagepub.co.uk/journalsPermissions.nav

DOI: 10.1177/0333102413515348
cep.sagepub.com
prophylaxis: A randomised,
triple-blind, placebo-controlled,
double cross-over study

Lars J Stovner1, Mattias Linde1, Gøril B Gravdahl1,

Erling Tronvik1, Anne H Aamodt1,2, Trond Sand1 and
Knut Hagen1

Abstract
Objective: The objective of this article is to see whether the effect of candesartan for migraine prevention, shown in one
previous study, could be confirmed in a new study, and if so, whether the effect was comparable to that of propranolol
(non-inferiority analysis), and whether adverse events were different.
Methods: In a randomised, triple-blind, double cross-over study, 72 adult patients with episodic or chronic migraine went
through three 12-week treatment periods on either candesartan 16 mg, propranolol slow-release 160 mg, or placebo.
The main outcome measures were days with migraine headache per four weeks (primary outcome), days with headache,
hours with headache, proportion of responders (>50% reduction of migraine days from baseline), and adverse events.
Results: In the modified intention-to treat-analysis, candesartan and propranolol were both superior to placebo: 2.95
(95% confidence interval: 2.35–3.55%) and 2.91 (2.36–3.45%), versus 3.53 (2.98–4.08%) for migraine days per month
(p ¼ 0.02 for both comparisons, Wilcoxon’s paired signed rank test, blinded statistical analysis). Candesartan was non-
inferior to propranolol (and vice versa). The proportion of responders was significantly higher on candesartan (43%) and
propranolol (40%) than on placebo (23%) (p ¼ 0.025 and <0.050, respectively). There were more adverse events on
candesartan (n ¼ 133%) and propranolol (n ¼ 143%) than on placebo (n ¼ 90%), and the adverse event profiles of the
active substances differed somewhat.
Conclusion: It is confirmed that candesartan 16 mg is effective for migraine prevention, with an effect size similar to
propranolol 160 mg, and with somewhat different adverse events.

Trial registration: EUDRACT (2008-002312-7), ClinicalTrials.gov (NCT00884663).

Keywords
Candesartan, propranolol, migraine, prophylaxis, clinical trial
Date received: 11 September 2013; revised: 30 October 2013; 6 November 2013; accepted: 6 November 2013

Introduction
Migraine is the most common neurological disorder,
imposing a large burden on many of the sufferers
(1,2) and also on society (3). The majority of patients
have relatively rare attacks which can be treated with
acute medication. However, a sizeable proportion of
patients fulfils criteria for prophylactic treatment, but
use of such treatment is limited (4), possibly owing to
lack of effectiveness, contraindications, or side effects of
currently available drugs (5).
1
Norwegian National Headache Centre, Department of Neuroscience,
Norwegian University of Science and Technology (NTNU), and St. Olavs
Hospital, Norway
2
Department of Neurology, Oslo University Hospital – Rikshospitalet,
Norway
Corresponding author:
Lars J Stovner, Norwegian National Headache Centre, Department of
Neuroscience, Norwegian University of Science and Technology and
St. Olavs Hospital, N-7491 Trondheim, Norway.
Email: lars.stovner@ntnu.no
524 Cephalalgia 34(7)

Table 1. Proportion answering yes to a predetermined list of questions about AEs recorded during the consultation in week 10–11
of each treatment period (SD).

p value

PLA (n ¼ 61) CAN (n ¼ 59) PRO (n ¼ 61) PLA vs CAN PLA vs PRO CAN vs PRO

Reduced physical capacity 0.2 (0.4) 0.2 (0.5) 0.5 (0.7) 0.48 <0.01 <0.01
Tiredness 0.3 (0.5) 0.4 (0.7) 0.6 (0.7) 0.1 <0.01 0.13
Dizziness 0.2 (0.4) 0.5 (0.7) 0.3 (0.5) 0.01 0.3 0.07
Nausea 0.1 (0.4) 0.1 (0.4) 0.2 (0.5) 0.76 0.11 0.22
Constipation 0.0 (0.2) 0.1 (0.3) 0.2 (0.4) 0.7 <0.01 0.1
Sexual dysfunction 0.0 (0.0) 0.1 (0.2) 0.1 (0.3) 0.08 0.2 1.0
Sleep disturbance 0.1 (0.3) 0.3 (0.5) 0.4 (0.6) 0.07 0.02 0.24
Sum of side effects 0.9 (1.4) 1.6 (1.8) 2.2 (2.0) 0.01 <0.01 0.03
AEs: adverse events; SD: standard deviation; PLA: placebo; CAN: candesartan; PRO: propranolol.

Among the most commonly used preventive drugs
are beta-blockers, of which propranolol (PRO) has
been most studied and is the most used active compara-
tor for new migraine prophylactics. In 2003, our group
reported that the angiotensin II receptor1A blocker
candesartan (CAN) was effective for migraine in a
cross-over study (6). CAN is now used for migraine
in many countries (see e.g. Silberstein et al. (7), Evers
et al. (8) and Stark and Stark (9)), in spite of the limited
evidence for its efficacy.
The present study was undertaken to test whether it
was possible to confirm that CAN is superior to pla-
cebo (PLA) as a migraine prophylactic, and if so,
whether the effect was comparable to that of PRO,
evaluated by a non-inferiority analysis. Also, it was
an aim to compare the side effect profiles of the two
active substances.
Materials and methods
The study was designed as a placebo-controlled double-
blind, double cross-over trial, with a four-week open
baseline period, and three 12-week treatment periods
with a four-week wash-out period between each treat-
ment period. It was conducted at the neurological
outpatient clinic of St. Olavs University Hospital
between April 2009 and March 2012. Patients were
recruited either from patients referred to the clinic, or
among those who contacted the study nurse after
advertisements in newspapers or on the Internet, or
after information on a national TV channel.
The study followed the International Headache
Society (IHS) guidelines for trials on prophylactic
medication in migraine (10) and chronic migraine
(11). The primary efficacy variable was number
of days with moderate or severe headache, lasting
4 hours or being treated with the patient’s usual
medication (‘migraine days’) per four weeks, which
is according to the guidelines for chronic migraine
studies (11). Secondary measures were: days with
headache, hours with headache, headache intensity on
days with headache, doses of analgesics, doses of trip-
tans, days with sick leave, number of responders
(50% decrease in migraine days compared with base-
line). The main adverse events (AEs) measures were the
occurrence of AEs (Yes/No), the level of discomfort
due to AEs (scale 1–5), the number of AEs occurring
during treatment periods, and the occurrence of seven
pre-defined AE variables asked for during the visit at
the end of each treatment period (see Table 1).
Inclusion criteria
Inclusion criteria were: age 18–65 years; signed
informed consent; migraine with or without aura (10),
or chronic migraine (11); in retrospect, 2 migraine
attacks per month during the last three months before
inclusion, and 2 migraine attacks during the four-
week baseline period documented in the diary; debut
of migraine 1 year prior to inclusion, and before the
age of 50.
Exclusion criteria
Exclusion criteria were: interval headache not distin-
guishable from migraine; chronic tension-type or
other headache occurring on 15 days/month; preg-
nancy, nursing or not using contraceptives in fertile
women; heart conduction block or other significant
abnormality on electrocardiogram; heart rate <54 (sit-
ting, after three minutes’ rest); asthma or diabetes;
decreased hepatic or renal function; hypersensitivity
to active substances; history of angioneurotic oedema;
psychiatric illness; use of daily migraine prophylactics
Stovner et al.
less than four weeks prior to start of study; having tried
3 prophylactic drugs against migraine during the last
10 years; previous use of PRO or CAN in adequate
doses (16 mg or 160 mg) and duration (6 weeks);
previous discontinuation of CAN or any beta-blocker
because of AEs; current use of antihypertensive medi-
cation; use of rizatriptan 10 mg tablet; regular ergota-
mines or opioids use; consistent failure to respond to
any acute migraine medication; alcohol or illicit drug
dependence.
At the screening visit to the neurologist, a thorough
history was taken to ascertain compliance with inclu-
sion and exclusion criteria. All subjects had a neuro-
logical examination, blood pressure (BP) and pulse
measurement, and electrocardiogram. During the
whole study, patients were to keep a headache diary
recording relevant attack variables, as well as AEs or
other health-related condition.
The four-week baseline period without medication
before randomisation was used to ascertain whether
patients had 2 attacks per month. If <2, the baseline
period was extended by four more weeks, and if there
were 4 attacks during the whole eight-week period,
the patient could be included. After the baseline
period, there was a new visit to evaluate whether the
patient could be included, before randomisation and
dispensing study medicines for the first period.
Adherence was defined as using the medicines >2
months in accordance with the prescription, and it
was measured using self-reports and pill counts.
Seventy-two patients were randomised in blocks of 12
to one of six possible treatment sequences. The study
drug consisted of tablets with either CAN 8 mg or
PLA, or capsules of either PRO slow-release formula-
tion or PLA. In week 1 and 12, the patient took one
tablet and one capsule each day (CAN 8 mg or PRO
80 mg or placebo), and during weeks 2–11, two tablets
and two capsules (CAN 16 mg or PRO 160 mg or pla-
cebo). After two weeks in each treatment period, all
patients were contacted by telephone by the study
nurse who checked for AEs and compliance with the
protocol. If there were AEs after increasing the dose,
the dose could be reduced to one tablet and one capsule
per day for the rest of the period. If the drug was not
tolerated at all, it could be discontinued for the rest of
that period, and the patient could start on the next
period after 12 weeks and still be included in the mod-
ified intention-to-treat (mITT) analysis. In week 10 or
11, the patients visited the doctor for evaluation, and
they were subjected to heart rate variability and baro-
receptor sensitivity tests (to be reported in a separate
publication). Adherence was checked and study drug
for the next period was also handed out.
Approximately one month after the end of study
period 3, there was a final visit.
525
AEs were recorded in the headache diary (free text,
one line for each day), asked about at telephone calls
and visits and also registered after an open question
about side effects and other health-related complaints.
An AE reported several times during one treatment
period was counted only once.
The study was approved by the local ethics review
board (where the full trial protocol can be accessed on
request: rek-4@medisin.ntnu.no), the Norwegian Data
Inspectorate, and the Norwegian Medicines Agency.
Randomisation, blinding and
data handling
Participants fulfilling criteria for randomisation were
consecutively given a randomization number (1–72)
assigning them to one of the six treatment sequences
(Figure 1) according to a computer-generated list, pre-
made by the company producing the drugs, but
unknown to participants, clinicians and statistician.
Randomisation numbers were pre-printed on study
medication labels, and on three sealed envelopes con-
taining information about the medication in each
period for each participant. Hence, in case of serious
AEs (SAEs), it was possible to unblind a single period.
These envelopes were kept in a limited-access area.
PLA tablets and capsules were identical to those with
active medication and packaged in identical bottles.
According to the protocol, to be included in the per-
protocol (PP) analysis participants had to fill out head-
ache diaries for 8 of 12 weeks for all three treatment
periods, and to be included in the mITT analysis, 4
weeks for at least two periods. For patients who missed
one or (up to) four weeks, the denominator was
adjusted so that ‘migraine days per 4 weeks’ was cor-
rectly calculated. To be included in the analysis of free-
text AE variables (Table 2) it was required that the
patient had taken 1 dose of the medicine.
Data entry was performed by the study nurse. After
completion of the study, the data file, together with the
unopened envelopes containing randomisation codes,
were handed over to personnel at the Unit for
Applied Clinical Research at the Faculty of Medicine
who opened the codes and returned the file with each
treatment type having a code (A, B or C). A predeter-
mined statistical protocol had been written for the ana-
lysis of the primary and secondary efficacy variables,
and the statistician (TS) performed analysis of this file
without knowing the actual type of treatment. This was
revealed first after tables with efficacy data had been
created (triple-blind study). A few data entry errors
were detected during the blinded analysis, and these
were corrected before the final unblinding.
The study was monitored by an employee at the
Norwegian University of Science and Technology
526 Cephalalgia 34(7)

232 Assessed for

eligibility by nurse 140 Cause for exclusion or not
fulfilling inclusion criteria

92 Screened by doctor
7 Cause for exclusion or not
fulfilling inclusion criteria
2 Declined
83 Signed consent and
entered baseline period
3 Withdrew consent
3 Had too few attacks
1 Other disease
72 randomised to a treatment sequence
4 Unknown

Sequence 1 2 3 4 5 6
# (N ) I or (12) I (12) I (12) D I (12) D (12) D I (12a)
D
Period 1 PLA PLA CAN 3 1 CAN 2 PRO 3 PRO
Period 2 CAN 1 PRO PLA PRO PLA 1 3b CAN
Period 3 PRO 1 CAN 1 PRO 1 PLA CAN PLA

61 ITT 12 12 8 10 8 11
completers
54 PP 10 11 7 10 5 11
completers

I: interrupted; D: drop-out; PLA: placebo; CAN: candesartan; PRO: propranolol; ITT: intention to treat; PP: per protocol.
a
One patient was excluded because of too few attacks in baseline period. b Two patients left the study late in the PLA
period and therefore had enough data to be counted as completer of the period, but lost next period.

Figure 1. Flow of participants through the study (figures refer to number of patients).

(NTNU) Department of Neuroscience who had experi-
ence and formal training in monitoring clinical trials.
Statistical methods
The predetermined hypotheses were: H1: CAN is better
than PLA (superiority analysis). H2: CAN is not infer-
ior to PRO (non-inferiority analysis). H3: CAN has
fewer AEs than PRO (superiority analysis).
A power analysis before study start indicated that
60 evaluable patients would give >80% power to
detect a difference between CAN and PLA of 0.5
standard deviation (SD) (two-sided test) for the
main efficacy variable. Expecting a drop-out rate of
15%–20%, we decided that 72 patients would have
to be included.
All statistical tests were between treatment periods,
and did not include baseline data (except for analyses of
responder rate). In accordance with the predetermined
statistical protocol, H1 (CAN-PLA-difference) was
tested with Wilcoxon’s paired signed rank test, and like-
wise the secondary comparisons (CAN-PRO and PLA–
PRO). The differences in responder rate and AE pro-
portions were tested with a standardised normal deviate.
SYSTATv11 (Systat Software Inc, Chicago, IL, USA)
was used with two-sided level of significance 0.05,
and subjects fulfilling mITT-requirements were included
in the main analysis.
H2 was tested in accordance with CONSORT rec-
ommendations for non-inferiority analysis (12%),
including only PP completers (n ¼ 54). A mean differ-
ence of 1.2 days per four weeks was chosen as the cut-
off delta value. This was deemed to be a clinically rele-
vant improvement corresponding to an expected stan-
dardised difference of 0.35 SD, but clearly less than the
effect (0.5 SD) considered in the power calculation for
the main superiority hypothesis. In order to select an a
priori reasonable delta, we calculated the probability of
reaching an inconclusive result, i.e. we calculated power
for detecting true inferiority as a function of both delta
and the ‘true active comparator difference’. For a rea-
sonably small true active comparator difference ¼ 0.1
SD (or even 0 SD) and delta ¼ 0.35 SD, the power for
detecting true non-inferiority was deemed acceptable
¼ 58% (or 83% for 0 SD, i.e. true equality).The
expected treatment effect difference between the active
drugs was estimated from a previous migraine trial (13).
Results
Of the 72 patients randomised to treatment, 17 were
recruited from the outpatient clinic and 55 were
Stovner et al. 527

Table 2. Adverse events (AEs) (n of patients reporting the AE become pregnant a short time after randomisation.
1 time during the treatment period). Hence, two drop-outs in each treatment period were
not related to pregnancy. One pregnancy later ended
PLA CAN PRO
na ¼ 64 na ¼ 66 na ¼ 67 in spontaneous abortion after the CAN period while
the others were uncomplicated and the newborns were
Respiratory tract infections 27 24 26 healthy. One drop-out in the PRO period (Table 4) was
Bodily pain 11 13 23b related to a moderate depression, and in combination
Dizziness 6 24c 13d with disorientation, sleep problems and eating disorder,
Sleep problems 9 11 10 this caused a breaking of the randomisation code.
Tiredness 1 11c 11c There were seven partial completers (Table 4 and
Bowel infection/diarrhoea 8 9 6 Figure) interrupting the study on either PLA (n ¼ 3),
Reduced physical capacity 4 5 9
CAN (n ¼ 3) or PRO (n ¼ 1), all because of AEs.
Only one of them did not provide data for the PLA
Skin problem/itching 5 4 4
and the PRO period, whereas five did not for the
Nausea 3 5 3
CAN period.
Coughing 3 1 4 As to the primary efficacy variable (migraine days
Psychic problems 1 3 4 per four weeks, Table 5), CAN (2.95 (95% confidence
Sweating/feeling warm 1 3 4 interval (CI) 2.35–3.55)) and PRO (2.91 (2.36–3.45))
Fainting 2 3 1 were both significantly better than PLA (3.53 (2.98–
Paraesthesia 0 4b 2 4.0)), with a reduction of 0.58 and 0.62 days, respect-
Oedema 2 1 3 ively. For the secondary variables (Table 5), CAN and
Feeling cold, cold hands/feet 0 3 3 PRO were mostly significantly better, except for head-
Palpitations 1 2 2 ache days for PRO, number of analgesics doses for
Anaemia 1 2 1 CAN, and days with absence from work (both CAN
Low heart rate at exercise 0 0 4b,d
and PRO). The only significant difference between
CAN and PRO was with regard to number of doses
Visual symptoms 0 2 2
with analgesics, favouring PRO. Analysis of PP com-
Cognitive problems 0 1 2
pleters gave essentially the same results as mITT-ana-
Tooth problem 1 1 1 lysis (data not shown). Testing migraine days per four
Constipation 1 0 2 weeks for non-inferiority among PP completers con-
Reduced libido 0 1 1 firmed that the paired CAN-PRO difference was smal-
Urinary infection 0 0 2 ler (0.002 days, (90% CI –0.48 to 0.49 days), n ¼ 54)
Hair loss 1 0 0 than the pre-defined limit (1.2 days).
Throat swelling 1 0 0 The proportion of responders was significantly
Nose bleeding 1 0 0 higher on CAN (24/56, 43%) and PRO (24/60, 40%)
Sum 90 133c 143c than on PLA (14/60, 23%) (p ¼ 0.025 and <0.050,
a
respectively). Among the 55 who completed both
Number of patients who took at least one dose of the substance. CAN and PRO periods, 13 responded to both treat-
b
p< 0.05 compared to PLA.
c
p 0.001 compared to PLA.
ments, 10 only to CAN, eight only to PRO, and 24 to
d
p< 0.05 compared to CAN, difference in proportions (standardised neither of the two.
normal deviation). PLA: placebo; CAN: candesartan; PRO: propranolol. There were five SAEs (Table 4, footnote), three
pregnancies, and two requiring hospitalisation.
Patients reported more discomfort due to AEs on
among those who contacted the study nurse after media CAN and PRO than on PLA (Table 5). There
coverage. Flow of participants is shown in the Figure. were more AEs since last visit on PRO than on
The mITT and PP groups (61 and 54 patients, PLA, but no significant difference between CAN
respectively) were quite similar (Table 3). Of the 72 and PRO in this respect. Tiredness and the sum of
randomised patients, one woman was later excluded free-text AEs were also significantly higher on either
before unblinding because it was detected that she did CAN or PRO compared to PLA (Table 4). Some
not fulfil inclusion criteria (too few headache attacks in AEs seemed to be specific for either PRO (bodily
baseline period). In addition, 10 patients dropped out pain and low pulse at exercise) or CAN (dizziness
of the study (Figure, Table 4), five on CAN, three on and paraesthesia) (Table 2). As to the predefined
PRO, and two on PLA. Three women dropped out AEs (Table 1), the sum was higher on both CAN
because of pregnancy (two on CAN and one on and PRO than on PLA, but also significantly higher
PRO), and one (on CAN) because she wanted to on PRO than CAN.
528 Cephalalgia 34(7)

Table 3. Baseline variables of the whole (n ¼ 72), modified intention-to-treat (mITT) (n ¼ 61) and per-protocol (PP)
population (N ¼ 54).

Whole mITT PP

Females, n (%) 59 (82) 51 (84) 45 (83)

Mean age in years (SD) 37 (11) 38 (11) 37 (11)
Mean duration of headache history in years (SD) 19 (11) 20 (11) 19 (11)
Mean number of attacks per month (SD) 4.8 (3.6) 4.8 (3.3) 4.7 (3.0)
Mean number of migraine days per four weeks (SD) 4.9 (3.0) 4.8 (3.4) 4.5 (2.6)
Migraine without aura, n (%) 38 (53) 32 (52) 29 (54)
Migraine with aura, n (%) 6 (8) 4 (7) 4 (7)
Migraine with and without aura, n (%) 27 (38) 24 (39) 21 (39)
Chronic migraine, n (%) 1 (1) 1 (2) 0 (0)

Table 4. Patients who dropped out of the study (n ¼ 10), were partial completers (n ¼ 7), or who reduced dose in one period
(n ¼ 3).

Sex Period Medication

Drop-outs (n ¼ 10) Reason for dropping out

F 1 CAN Pregnancy, later spontaneous abortiona
F 1 PRO Pregnancya
F 1 CAN Wanting to become pregnant
F 1 CAN Pregnancya
M 2 PLA High blood pressure (after PRO)b
F 1 CAN Unknown, declined any contact
M 1 CAN Tiredness
F 1 PRO Weight increase, nightmares, sleep problems, neck pain
F 2 PLA Head trauma, got new type of headache, wanted to discontinue study
F 1 PRO Depression, disorientation, sleep problem, eating disorderb
Partial completers (n ¼ 7) Description of protocol deviation
M 2 PLA Left study late in period 2 (PLA) owing to side effect (tinnitus, sleep problems).
F 2 PLA Interrupted study owing to hospitalisation for suspected heart disease.
Resumed study in period 3
F 2 CAN Interrupted study early in period 2 (CAN) owing to tiredness and fatigue.
Resumed study in period 3
F 1 CAN Interrupted study owing to sleep problems and nightmares.
Resumed study in period 2
F 2 PLA Left the study at the end of period 2 owing to worsening of psoriasis
F 3 PRO Left study owing to sleep problems and constipation
F 3 CAN Left study owing to indeterminable side effects and influenza
Reduced daily dose to 8 mg (n ¼ 3) Reason for dose reduction
F 3 PRO Status migrainosus
F 2 PRO Nausea, dizziness, cold hands and feet
M 3 CAN Dizziness
CAN: candesartan; PLA: placebo; PRO: propranolol; F: female; M: male.
a
SAE: randomisation code not broken.
b
SAE: randomisation code broken.
Table 5. Efficacy and adverse event variables in different treatment periods, modified ITT-analysis. Wilcoxon’s signed rank test, or *test for differences in proportions.

p value
Stovner et al.

Baseline PLA CAN PRO PLA vs PLA vs CAN vs

(n ¼ 61) (n ¼ 60) (n ¼ 56) (n ¼ 60) CAN PRO PRO

Migraine days per four weeks 4.82 (4.16–5.47) 3.53 (2.98–4.08) 2.95 (2.35–3.55) 2.91 (2.36–3.45) 0.02 0.02 0.88
(primary efficacy variable),
mean (95% CI)
Headache days per four weeks, 8.21 (7.18–9.24) 5.97 (4.96–6.99) 5.30 (4.24–6.36) 5.75 (4.40–7.09) 0.01 0.16 0.96
mean (95% CI)
Headache hours per four weeks, 59.2 (47.7–70.7) 43.5 (33.7–53.2) 35.1 (26.7–43.5) 41.4 (27.2–55.6) 0.004 0.04 0.96
mean (95% CI)
Average headache intensity 1.9 (1.8–2.0) 1.8 (1.7–1.9) 1.8 (1.7–1.9) 1.8 (1.6–1.9) 0.05 0.02 0.85
(0–3)a, mean (95% CI)
Average function level during 1.4 (1.3–1.6) 1.4 (1.3–1.5) 1.3 (1.1–1.4) 1.2 (1.1–1.4) 0.01 0.01 0.84
attacks (0–3)b, mean (95% CI)
Triptan doses per four weeks, 4.5 (3.6–5.4) 3.5 (2.9–4.2) 2.4 (1.7–3.1) 2.9 (2.1–3.7) 0.001 0.04 0.41
mean (95% CI)
Analgesics doses per four weeks, 7.0 (4.5–9.6) 5.4 (3.3–7.5) 5.0 (3.2–6.8) 3.5 (2.2–4.9) 0.23 0.003 0.01
mean (95% CI)
Work absence (days per four 0.78 (0.50–1.06) 0.43 (0.27–0.59) 0.39 (0.24–0.53) 0.47 (0.26–0.67) 0.34 0.56 0.97
weeks), mean (95% CI)
Satisfaction with treatment n.a. 3.0 (3.0–5.0) 5.0 (3.0–6.0) 4.5 (4.0–5.0) 0.001 0.002 0.85
effectc, median (25%–75%
percentile)
Lack of discomfort due to AEsd, n.a. 5.0 (4.5–5.0) 4.0 (3.5–5.0) 4.0 (3.0–5.0) 0.001 0.003 0.26
median (25%–75% percentile)
AEs since last visit (yes/no, %)* n.a. 20/40, 33 28/28, 50 35/25, 58 0.07 0.006 0.37
Other illness since last visit (yes/ n.a. 31/29, 52 27/29, 48 26/34, 43 0.71 0.36 0.60
no, %)*
ITT: intention to treat; AEs: adverse events; CAN: candesartan; PLA: placebo; PRO: propranolol; CI: confidence interval; n.a.: not applicable.
a
None, mild, moderate, severe.
b
Normal, reduced, markedly reduced, in bed.
c
From 1: extremely dissatisfied, to 7: extremely satisfied.
d
From 1: very unpleasant, to 5: not unpleasant at all.
529
530
Discussion
This study confirms the previous finding that CAN
16 mg is superior to PLA for migraine prophylaxis,
and it shows that the effect is not inferior, in fact
almost identical for the primary efficacy variable, to
that of PRO. With regard to AEs, sleep problems
and/or nightmares, well-known AEs of PRO, were pre-
sent in two of three patients who dropped out on PRO
(Table 4).
As to the predefined AEs (Table 1), CAN was better
than PRO. However, in retrospect it must be admitted
that these AEs were biased towards typical AEs of
beta-blockers. Overall, CAN was different from PLA
and similar to PRO with regard to general questions
about AEs or other illnesses, level of discomfort due to
AEs (Table 5), and number of free-text AEs (Table 2).
Hence, we conclude that the previous contention that
CAN has an AE profile similar to PLA in migraine
patients (6) was not confirmed in the present study. It
does seem, however, that AE profiles differ between
CAN and PRO (Table 2). The practical consequence
of this observation, and the fact that some respond only
to CAN and some only to PRO, is that the other drug
could be tried even if one was not well tolerated or
effective in a given patient.
Strengths of this study are the rather strict accord-
ance with International Headache Society guidelines
for migraine prophylaxis studies (10,11), pre-deter-
mined hypotheses and statistical methods, and blinded
statistical evaluation. In addition, our study allowed
direct comparison of the two active substances, both
with regard to effect sizes and AE profiles.
Comparison of effects across different studies is dif-
ficult because of variations in methodology, effect vari-
ables and patient samples. The effect of CAN in this
study (14% compared to PLA period, 38% compared
to baseline period) is somewhat lower than that seen in
the previous CAN study with a similar design (29% and
47% respectively) (6). Similarly, the effect of PRO mea-
sured as responder rate in this study (40%) seems to be
lower than the 68% in a Cochrane review (14). The
lower effect size may be due to the very marked PLA
effect, known to be higher with cross-over design (15),
in which the patients knew they would receive active
medication in two of three periods. Compared to the
PLA period in the present study, the reduction on
active medication was only approximately 0.6 days
per four weeks (17%), whereas it was around 1.9 days
(40%) compared to baseline. The clinical usefulness of
CAN is perhaps better shown by the fact that there
were 20% more responders (i.e. 50% reduction in
migraine days) in the CAN than in the PLA period.
Cephalalgia 34(7)
The cross-over design is accepted in the IHS
Guidelines (10), although it has some inherent limita-
tions. Carry-over and period effects could not be esti-
mated with sufficient power in the present design (16),
and these effects have accordingly been minimised and
probably largely eliminated by using adequate wash-
out periods and balanced cross-overs. Both drugs are
quickly eliminated from the body (T1/2  11 hours) but
the possibility of long-term effects cannot be excluded
(17,18). Any carry-over effect would tend to make dif-
ferences between substances less than real and could
also make AE profiles more similar.
Another problem with cross-over studies may be
high drop-out rates and low adherence to protocol, par-
ticularly in studies like the present one which lasted
almost a year for each patient. In this study, the
drop-out rate was relatively low (15%) and the propor-
tion of PP completers high (75%), probably owing to
close follow-up by the study nurse.
The chosen non-inferiority margin (delta) may seem
large. Delta is often defined as the ‘smallest value that
would be a clinically significant effect’ (12), but there is
no definite guideline for choosing its value. Our choice
was based partly on our clinical impression that most
migraineurs would appreciate at least one additional
headache-free day per four weeks, and partly on
power analysis to ensure a reasonable probability for
avoiding ‘inconclusive’ results for definitely clinically
insignificant differences (see figure in Piaggio et al.
(12)). What would be the advantage of choosing a smal-
ler delta, of e.g. 0.25 SD? In the case of a larger, pos-
sibly clinically significant ‘true active comparator
difference’, e.g. 0.2 SD, the probability to falsely con-
clude with ‘non-inferiority’ will then decrease from
30% to 10%. The downside is that even small true dif-
ferences like 0 or 0.1 SD may be deemed ‘inconclusive’
with 100–58 ¼ 42% and 100–30 ¼ 70% probability,
respectively. Hence, delta has to be chosen as a reason-
able compromise between the up- and downsides. It
should be emphasised that our actual results for non-
inferiority still holds, even with a (post-hoc) delta ¼ 0.2
SD (0.7 migraine days per four weeks) because the esti-
mated 95% CI for the active comparator difference, i.e.
0.58 migraine days per four weeks, is still lower than 0.7
days. We admit, however, that we may have overesti-
mated the value of a non-inferiority analysis in a study
of the present size in general, because CIs will tend to
be large and interpretation could have been difficult if
results had been less clear.
It is interesting, although not surprising, to see the
large improvement in the placebo period compared to
baseline (Table 5). Also, it is of interest that although
the frequency was reduced the intensity of the
Stovner et al.
headaches that did occur in all three periods was not.
In addition, the two active drugs, though better
than PLA, were not rated all that highly by patients
(Table 5, satisfaction with treatment effect). This
shows the shortcomings of even the best prophylactic
drugs available today.
One may speculate that a higher dose could result
in more responders. The choice of dose of CAN
(16 mg per day) in this study was based on the pre-
vious migraine study that showed effect and excellent
tolerability (6), but a dose of 32 mg has been tried
with good tolerability in cluster headache (19).
A dose-finding study in adults with migraine seems
warranted.
For acceptance of the present study as valid corrob-
oration of the previous CAN study, it may be a prob-
lem that both studies come from the same research
group. It is not known why no other groups have
tested CAN for migraine, but problems with funding
trials with drugs where the patent is about to expire
may be a reason. However, another angiotensin recep-
tor blocker (telmisartan) has been tested for migraine in
a parallel group study. The results were in favour of
telmisartan over PLA, but not significantly with the
Clinical implications
. Candesartan is effective for migraine prevention.
. The effect is similar to that of propranolol.
. The adverse event profile is different from that of propranolol.
. Candesartan may become a drug of first choice for migraine prevention.
Author contributions
Lars Jacob Stovner and Trond Sand had full access to
all the data in the study and take responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Stovner, Hagen, Sand.
Acquisition of data: Stovner, Hagen, Linde,
Tronvik, Aamodt, Gravdahl.
Statistical analysis: Sand, Stovner.
Drafting of the manuscript: Stovner, Sand, Hagen,
Linde, Tronvik, Aamodt, Gravdahl
Funding
AstraZeneca provided the drugs and gave an unconditional
grant of NOK 500,000 to support the study. The company
has had no role in the design and conduct of the study, or in
collection, analysis and interpretation of the data.
Representatives of the company have reviewed and approved
the manuscript.
531
pre-determined statistical analysis, possibly because
it did not take differences in baseline headache
frequency into account, and was underpowered (20).
These problems are avoided with cross-over studies
in which all patients are exposed to all study drugs,
and a much higher statistical power is attained with
fewer patients (10). Two uncontrolled and open studies
on patients with migraine and hypertension or pre-
hypertension have also shown a marked decrease
in headache frequency with both CAN (21) and olme-
sartan (22).
An advantage with CAN is that is has fewer contra-
indications than beta-blockers and can be prescribed to
migraineurs with, for example, asthma, diabetes, or
heart conduction block. Hypotheses about the mechan-
ism for the anti-migraine effect of CAN have been pro-
posed previously (23), but on the whole it is poorly
understood.
In conclusion, this study confirms that CAN is a
good alternative to PRO for migraine prevention.
With a somewhat different AE profile and fewer contra-
indications, this easy-to-use drug may become useful in
the treatment of one of the most prevalent disorders
worldwide.
Conflicts of interest
Lars Jacob Stovner has received speaker fees from
GlaxoSmithKline (GSK), honorarium to participate in meet-
ings with Pfizer, and research grants and support from
Allergan and AstraZeneca.
Mattias Linde has received speaker fees from Allergan and
St. Jude Medical, honoraria from Allergan and GSK to par-
ticipate in scientific meetings, and research grants and support
from AstraZeneca.
Erling Tronvik has received fees for or is currently
involved as site clinical investigator in studies initiated by
GSK and Abbot.
Anne Hege Aamodt has received an honorarium to par-
ticipate in meetings with Boehringer Ingelheim and speaker
fees from Pfizer and Boehringer Ingelheim.
Knut Hagen is a member of an Allergan
international advisory board on chronic migraine and
has received a research grant and financial support from
Allergan.
Gøril Bruvik Gravdahl and Trond Sand have nothing to
declare.
532
Acknowledgement
We thank Professor Harald Schrader, the lead author of the
first controlled study on an angiotensin-converting enzyme
(ACE) inhibitor and the first to discover the potential of
the angiotensin-II-receptor blocker candesartan for
migraine-prophylaxis, for his initiative and help to start the
present study.
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