RESEARCH

Transdermal and oral hormone replacement therapy and the

risk of stroke: a nested case-control study
Christel Renoux, fellow,1 Sophie Dell’Aniello, statistician,1 Edeltraut Garbe, professor,2 Samy Suissa,
professor1

1
McGill Pharmacoepidemiology ABSTRACT used for the relief of climacteric symptoms in post-
Research Unit, Center for clinical Objectives To determine the risk of stroke associated with menopausal women. Although many observational
epidemiology, Jewish General
Hospital, and the Departments of oral and transdermal routes of administration of hormone studies have suggested a protective effect against
Epidemiology and Biostatistics and replacement therapy. cardiovascular disease, this has been challenged by
of Medicine, McGill University, Design Population based nested case-control study. the results of randomised controlled trials. In particu-
Montreal, Canada H3T 1E2
2 Setting About 400 general practices in the United lar, several clinical trials have shown an increased risk
Department of Clinical
Epidemiology, Bremen Institute Kingdom contributing to the General Practice Research of stroke associated with HRT in postmenopausal
for Prevention Research and Database. women. This was confirmed in recent meta-analyses
Social Medicine, University of
Bremen, 28359 Bremen, Participants Cohort of all women in the database aged showing a 30% increased risk of stroke, identical for
Germany 50-79 years between 1 January 1987 and 31 October oestrogens alone or in combination with
Correspondence to: S Suissa 2006 who were members of a practice that fulfilled progestogen.1-3 However, these clinical trials evaluated
[email protected] predefined quality criteria and without a diagnosis of oral HRT and did not explore other routes of adminis-
Cite this as: BMJ 2010;340:c2519 stroke before cohort entry. For each case of stroke tration. One observational study suggested a lower risk
doi:10.1136/bmj.c2519 occurring during follow-up, up to four controls were of transient ischaemic attack with transdermal oestro-
selected from among the cohort members in the risk sets gen use compared with oral oestrogen, but the risk of
defined by the case. Exposure to hormone replacement stroke could not be estimated because of the small
therapy (HRT) was categorised into oestrogens only, number of cases.4
oestrogens plus progestogen, progestogen only, and Transdermal oestrogen preparations are effective in
tibolone. Oestrogens were further subdivided according the treatment of postmenopausal symptoms5 in a man-
to the route of administration (oral v transdermal) and ner similar to oral oestrogens.6 Several studies suggest
dose (high v low). that the transdermal route exerts a different impact on
Main outcome measures Rate ratio of stroke associated biological cardiovascular risk markers by avoidance of
with current use of oral and transdermal HRT compared the first pass effect in the liver.7 Thus different routes of
with no use. Current use was considered as a prescription administration of HRT may be associated with a differ-
whose duration included the index date. ent risk of cerebrovascular events in postmenopausal
Results There were 15 710 cases of stroke matched to women.
59 958 controls. The rate of stroke in the cohort was 2.85 The objective of our study was to assess the risk of
per 1000 per year. The adjusted rate ratio of stroke stroke associated with oral and transdermal routes of
associated with current use of transdermal HRT was 0.95 administration of HRT in a cohort of postmenopausal
(95% CI 0.75 to 1.20) relative to no use. The risk of stroke women using a nested case-control analysis.
was not increased with use of low oestrogen dose patches
(rate ratio 0.81(0.62 to 1.05)) compared with no use, METHODS
whereas the risk was increased with high dose patches Source of data
(rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT We used the United Kingdom’s General Practice
had a higher rate of stroke than non-users (rate ratio 1.28 Research Database (GPRD), for which detailed char-
(1.15 to 1.42)) with both low dose and high dose. acteristics have been described elsewhere.8 9 In brief,
Conclusions The use of transdermal HRT containing low the GPRD is a large computerised database of anon-
doses of oestrogen does not seem to increase the risk of ymised longitudinal records containing medical infor-
stroke. The presence of residual confounding, however, mation on a population of more than six million
cannot be entirely excluded in the interpretation of this patients (about 8% of the UK population) who partici-
finding. pate in this database via about 400 contributing general
practices. The population in the database broadly
INTRODUCTION reflects the demographics of the general UK popula-
Hormone replacement therapy (HRT), especially oes- tion. Information collected includes demographic
trogen alone or in combination with progestogen, is characteristics, lifestyle factors, medical symptoms
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 RESEARCH

and diagnoses, laboratory tests and test results, pre- tibolone. Oestrogens were further subdivided accord-
scriptions with dose instructions, referrals to specia- ing to the route of administration (oral or transdermal)
lists, and hospital discharge reports. Quality control and to the dose. Hence, oral low dose products con-
of data entry and consistency with medicals files are tained ≤0.625 mg of equine oestrogen or ≤2 mg of
checked regularly, and several studies have shown estradiol and high dose products contained
the high quality of recorded data.10 11 >0.625 mg of equine oestrogen or >2 mg of estradiol;
transdermal low dose products contained ≤50 μg of
Study design oestrogen and high dose products contained >50 μg.
The cohort and case-control subjects used in this study The duration of each prescription was calculated from
have been reported previously.12 Briefly, we con- the number of tablets or patches prescribed, combined
ducted a case-control study within the cohort consist- with dosing instructions. When no dosage instructions
ing of all women in the GPRD aged 50-79 between 1 were provided with the prescription, we imputed the
January 1987 and 31 October 2006 who were mem- mean duration of use of the same HRT product.
bers of a practice that fulfilled predefined quality cri-
teria (“up to standard”). For all cohort members, cohort Data analysis
entry (time zero) was defined by the latest of the follow- Incidence rate ratios of stroke associated with current
ing: 1 January 1987, the patient’s 50th birthday, or the use of the various HRT products and the route of
date of joining the “up to standard” practice. In other administration were estimated from the odds ratios cal-
words, all women aged 50-79 on 1 January 1987 and culated by means of conditional logistic regression.
registered with a suitable practice entered the study at Current use was considered as a prescription whose
this date. Younger women or women not followed in duration included the index date. Current HRT users
an “up to standard” practice entered the study later, at were categorised into the following groups: oral oestro-
the time they fulfilled both entry criteria of age and gens, transdermal oestrogens, oral oestrogens plus pro-
registration with a practice up to standard. Women gestogen, transdermal oestrogen plus progestogen,
with a diagnosis of stroke before joining a suitable prac- tibolone, progestogen only, and more than one type
tice or their 50th birthday were excluded. All cohort of HRT. Past use was defined by a prescription of
subjects were followed until the date of stroke, death, HRT in the year before the index date that stopped
end of registration with the practice, or end of the study before the index date. Past users were grouped
period (31 October 2006), whichever occurred first. together irrespective of the type and route of HRT
used. Non-users were individuals with no prescription
Cases and controls of any HRT in the year before the index date and con-
Within the study cohort, we identified all cases of a first stituted the reference group. In addition, we estimated
recorded diagnosis of stroke (ischaemic, haemorrha-
gic, or not further specified) occurring during the
study period by means of OXMIS or Read diagnostic Women in GPRD practice fulfilling quality criteria
codes referring to these events. The same diagnostic (n = 3 327 211)
codes related to stroke were used in a previous study
Excluded:
of the association between cyclo-oxygenase-2 selective <50 years old at end of study period
non-steroidal anti-inflammatory drugs and stroke.13 (n = 2 210 941)
>80 years old at cohort entry (n= 188 780)
The index date was defined as the date of the first Transferred out of practice before “up to
recorded stroke. standard” date (n = 44 376)
Each risk set, at each case’s index date, included all Date inaccuracies (n = 46)

individuals who were still at risk of the event (controls).

Women aged 50-79 between 1 Jan 1987
For each case, up to four controls were randomly and 31 Oct 2006 (n = 883 068)
selected among the cohort members in the risk sets
Excluded:
defined by the case. Controls were matched to cases Stroke before age 50 or before
on age (within 1 year) at the date of the case’s diagnosis, entry into “up to standard”
practice (n = 12 782)
the general practice attended, and the year of start in
the practice. The index date for the controls was
Women included in study cohort (n = 870 286)
defined as the event date for their matched case.
Matching on calendar time allowed us to control for
Excluded:
trends over time in the use of HRT. Cases for whom no matched
controls were found (n = 392)
Exposure information
We identified all prescriptions for any HRT issued dur-
ing the year preceding the index date—that is, in the
year before the date of stroke for cases and in the year Stroke cases (n = 15 710) Matched controls (n = 59 958)
before the same index date for matched controls. HRT
products were categorised as oestrogens only, oestro-
gens plus progestogen, progestogen only, and Details of cohort and case-control definitions

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Table 1 | Characteristics of women aged ≥50 years who had had a stroke (cases) and their categorised as <30, ≥30, or missing value; smoking
matched controls* (values are percentages (numbers) unless stated otherwise) was classified as current, former, never, or missing
value.
Characteristic Cases (n=15 710) Controls (n=59 958)
To assess the robustness of our results, we performed
Mean (SD) age (years) 70.3 (7.3) 70.3 (7.4)
sensitivity analyses exploring the effect of potential
Mean (SD) follow-up from practice’s “up 6.68 (4.46) 6.68 (4.44)
to standard” date (years)†
misclassification of current exposure on the estimated
Body weight status:
rate ratios. The calculated duration of use was pro-
Obese 15.5 (2434) 13.5 (8113)
longed by 28 days for all cases and controls exposed.
Thus some subjects not classified as currently exposed
Not obese 54.4 (8546) 56.9 (34 143)
at the index date based on the calculated duration of
Unknown 30.1 (4730) 29.5 (17 702)
use in our main analysis became exposed. We also
Smoking status:
evaluated the impact of missing data for body mass
Current 20.8 (3264) 13.5 (8112)
index and smoking status on our results by repeating
Former 13.0 (2043) 11.7 (6995)
our analyses using the subgroup of patients with no
Never 42.7 (6704) 50.7 (30 408)
missing values for any of these variables. All computa-
Unknown 23.5 (3699) 24.1 (14 443)
tions were performed using the SAS software version
Alcohol misuse 0.9 (142) 0.3 (204)
9.1.3 (SAS Institute, Cary, NC, USA).
Hypertension 45.6 (7159) 31.4 (18 832)
Hyperlipidaemia 17.7 (2783) 11.5 (6909) RESULTS
Atrial fibrillation 10.2 (1598) 3.5 (2072) Background data
Cardiovascular disease 23.5 (3698) 13.7 (8188) We identified a cohort of 883 068 women in the Gen-
History of transient ischaemic attack 15.2 (2386) 2.7 (1644) eral Practice Research Database (GPRD) aged 50-79
Diabetes 10.5 (1645) 4.5 (2707) between 1 January 1987 and 31 October 2006 who
Hysterectomy 18.4 (2899) 18.1 (10 852) were members of a practice fulfilling quality criteria
Oophorectomy 4.0 (626) 3.8 (2253) (figure). Within this cohort, 12 782 women had a stroke
Aspirin use 27.5 (4317) 12.6 (7542) before the age of 50, before their registration into the
Other non-steroidal anti-inflammatory drug use 25.5 (4002) 23.0 (13 784) practice, or before the practice achieved “up to stan-
*Cases and controls were matched for age, the practice attended, and the year of joining the practice. For dard” status and were therefore excluded, leaving a
controls, means are weighted by the inverse of the number of controls matched to each case. final cohort of 870 286 women. A total of 16 102
†Length of time that women could be followed in a practice that had achieved “up to standard” quality.
women in this final cohort had a first diagnosis of stroke
during follow-up. Of these, 392 (2.4%) were excluded
the risk of stroke associated with current use of HRT because no suitable controls could be identified, leav-
but with oral use as the reference category in order to ing a study of 15 710 cases of stroke and 59 958 ran-
compare directly the transdermal and oral routes. Our domly selected matched controls.
classification of current, past, and non-use of HRT was Table 1 describes the characteristics of the cases of
based on our previous finding that the risk of stroke stroke and their matched controls (as reported
associated with HRT use is higher at the time of current previously 12). The mean age of cases and controls at
use and rapidly disappears in the months after the index date was 70 years. The mean duration of fol-
discontinuation.12 low-up in the “up to standard” practices was 6.7 years
In a separate analysis, we determined the risk of for cases and controls. As expected, all cardiovascular
stroke according to the duration of HRT use (≤1 year risk factors were more common in cases than in control
or >1 year) for women who had been exposed to one subjects.
HRT type only.
Although the nested case-control approach does not Use of hormone replacement therapy
allow a direct estimation of the absolute risk of stroke, A total of 1214 (7.7%) cases and 4124 (6.9%) controls
we estimated the number of additional strokes accord- had received at least one HRT prescription in the year
ing to the route of administration by using the rate of before the index date. Of these, 798 (5.1%) cases and
stroke in our study population as the baseline rate and 2748 (4.6%) controls were current users, with 2.2% of
applying the estimated rate ratios for each exposure cases and 1.9% of controls being current users of oes-
group. trogens alone, and 2.4% of cases and 2.2% of controls
In addition to the matching factors, all rate ratios current users of oestrogen-progestogen. In controls,
were adjusted for body mass index, smoking status, the oral route was more common than the transdermal
alcohol misuse, and for the presence of diabetes, route, accounting for 72% of current users of oestro-
hyperlipidaemia, hypertension, atrial fibrillation, gen-only therapy and 91% of oestrogen-progestogen
cardiovascular disease (including angina, coronary therapy. Among these control users, the commonest
heart disease, congestive heart failure, left ventricular oestrogen dose was 0.625 mg, taken by 46% of users
hypertrophy, and myocardial infarction), transient of oral products, and 50 μg taken by 68% of users of
ischaemic attack, hysterectomy or oophorectomy at transdermal products. Among the 2025 control users
any time before the index date, and aspirin or other of oral HRT containing oestrogens, 82.7% had been
non-steroidal anti-inflammatory drug use in the year exposed only to oral preparations at any time before
before the index date. Body mass index was the index date, and, among these, 87.5% had been
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Table 2 | Crude and adjusted rate ratios of stroke associated with current use of hormone replacement therapy (HRT) by drug
type and route of administration (values are percentages (numbers) unless stated otherwise)
Rate ratio (95% CI)
Type of HRT Cases* (n=15 710) Controls* (n=59 958) Crude Adjusted†
None 92.27 (14 496) 93.12 (55 834) 1.00‡ 1.00‡
Transdermal route: 0.66 (103) 0.74 (441) 0.92 (0.74 to 1.14) 0.95 (0.75 to 1.20)
Oestrogen only 0.52 (81) 0.53 (317) 1.00 (0.78 to 1.28) 1.02 (0.78 to 1.34)
Oestrogen-progestogen 0.14 (22) 0.21 (124) 0.70 (0.45 to 1.11) 0.76 (0.47 to 1.22)
Oral route: 3.93 (618) 3.38 (2025) 1.20 (1.09 to 1.33) 1.28 (1.15 to 1.42)
Oestrogen only 1.67 (262) 1.34 (802) 1.28 (1.11 to 1.48) 1.35 (1.16 to 1.58)
Oestrogen-progestogen 2.27 (356) 2.04 (1223) 1.15 (1.02 to 1.31) 1.24 (1.08 to 1.41)
*One case and 7 controls were exposed to tibolone in combination with oestrogen-progestogen, 4 cases and 9 controls were exposed to progestogen
only, and 72 cases and 266 controls were exposed to tibolone. These 3 HRT categories were included in the model. Former users of HRT (416 cases
and 1376 controls) were also included in the model.
†Adjusted for age, body mass index, smoking status, alcohol misuse, diabetes, hyperlipidaemia, hypertension, atrial fibrillation, cardiovascular
disease, transient ischaemic attack, aspirin or other NSAID use, and history of hysterectomy or oophorectomy
‡Reference category, defined as no prescription of HRT in the 12 months before index date.

exposed to oral HRT for more than one year. Among oral HRT: the rate ratio was 1.54 (1.18 to 2.00) for
the 441 current patch users in the control group, 60.3% women whose exposure stopped within one month
had been exposed only to patches, and most of these before the index date but was only 1.09 (0.83 to 1.42)
for more than one year before the index date (82.3%). for women whose exposure stopped more than four
Of note, all these figures do not represent the overall months before the index date.
exposure during the entire study period, but instead at There was a total of 16 102 cases of stroke during
the time of the index date for cases and controls. 5 659 035 person years of observation, resulting in a
Since the mean age at the time of stroke for cases (and rate of 2.85 strokes per 1000 person years. The 28%
at the corresponding index date for matched controls) increase in risk associated with the use of oral oestro-
was 70 years, the uptake of HRT was low. In the year gens (alone or in combination with a progestogen)
before the index date, 2649 transdermal HRT prescrip- leads to 0.8 additional strokes per 1000 person years.
tions were delivered to controls, of which 77% were Considering the risk of stroke associated with high or
oestrogen only, 15% were transdermal oestrogen-pro- low oestrogen doses of transdermal and oral formula-
gestogen, and 8% were oestrogen patch combined with tions, we found that the risk of stroke was not increased
oral progestogen. The duration of 3.3% of HRT pre- with current use of low dose patches (rate ratio 0.81
scriptions could not be calculated, and for these we (0.62 to 1.05)) compared with no use, whereas the
used the mean duration for the corresponding HRT. risk was increased with current use of high doses
patches (rate ratio 1.89 (1.15 to 3.11)) (table 3). The
Stroke risk associated with HRT increased risk of stroke associated with current oral
The adjusted rate ratio of stroke associated with current use was virtually the same with low dose (rate ratio
use of transdermal oestrogens (alone or with progesto- 1.25 (1.12 to 1.40)) and high dose (rate ratio 1.48
gen) was 0.95 (95% confidence interval 0.75 to 1.20) (1.16 to 1.90)) compared with no use.
relative to non-use of HRT (table 2). The rate of stroke In the group of women currently exposed to one
did not increase with the addition of a progestogen to HRT type only, we found that short term users did
the transdermal oestrogens. The rate ratio of stroke for not have a higher risk of stroke, whether exposed to
current users of transdermal oestrogens alone was 1.02 transdermal oestrogens (rate ratio 0.98 (0.50 to 1.91))
(0.78 to 1.34) compared with non-users and 0.76 (0.47 or to oral oestrogens (rate ratio 1.02 (0.75 to 1.38))
to 1.22) for current users of transdermal oestrogens (table 4). Long term users (>1 year) of transdermal
plus progestogen. Conversely, current users of oral oestrogens may have had a slightly increased risk
oestrogens alone or in combination had a higher rate (rate ratio 1.13 (0.83 to 1.54)) whereas long term users
of stroke compared with non-users of HRT (rate ratio of oral oestrogens had a 35% increased risk (rate ratio
1.28 (1.15 to 1.42)). Current use of oral oestrogens 1.35 (1.20 to 1.52)).
alone increased the risk by 35% (rate ratio 1.35 (1.16 Our sensitivity analyses, which involved the addi-
to 1.58)) and current use of oral oestrogens plus proges- tion of 28 days to the duration of exposure, did not
togen by 24% (rate ratio 1.24 (1.08 to 1.41)). change the sense of our results. The rate of stroke
Direct comparison of transdermal HRT with oral remained virtually the same for current users of trans-
therapy showed that the risk of stroke was lower dermal oestrogens alone or in combination (rate ratio
among transdermal users (rate ratio 0.74 (0.58 to 0.95 (0.77 to 1.18)) and for current users of oral oestro-
0.95)). Past use of transdermal HRT did not increase gens alone or in combination, who had an increased
the risk of stroke (rate ratio 0.99 (0.76 to 1.28)) com- rate of stroke (rate ratio 1.30 (1.18 to 1.44)). Restricting
pared with non-use, unlike past use of oral HRT (rate the analyses to patients without missing values for
ratio 1.36 (1.17 to 1.59)). However, this increased risk body mass index and smoking status yielded virtually
concerned mainly the first few months after stopping the same results with a rate ratio of 0.99 (0.77 to 1.29)
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Table 3 | Crude and adjusted rate ratios of stroke associated with current use of hormone replacement therapy (HRT) by drug
dose and route of administration (values are percentages (numbers) unless stated otherwise)
Rate ratio (95% CI)
Type of HRT Cases* (n=15 710) Controls* (n=59 958) Crude Adjusted†
None 92.27 (14 496) 93.12 (55 834) 1.00‡ 1.00‡
Transdermal route: 0.66 (103) 0.74 (441) 0.92 (0.74 to 1.14) 0.95 (0.75 to 1.20)
Low dose (≤50 μg) 0.48 (76) 0.64 (384) 0.78 (0.61 to 1.00) 0.81 (0.62 to 1.05)
High dose (>50 μg) 0.17 (27) 0.10 (57) 1.87 (1.17 to 2.98) 1.89 (1.15 to 3.11)
Oral route: 3.93 (618) 3.38 (2025) 1.20 (1.09 to 1.33) 1.28 (1.15 to 1.42)
Low dose § 3.28 (515) 2.92 (1753) 1.16 (1.04 to 1.29) 1.25 (1.12 to 1.40)
High dose § 0.66 (103) 0.45 (272) 1.51 (1.20 to 1.90) 1.48 (1.16 to 1.90)
*The model also included current users of tibolone, tibolone in combination with oestrogen-progestogen, and progestogen as well as former users of
HRT (see table 2 for details).
†Adjusted for age, body mass index, smoking status, alcohol misuse, diabetes, hyperlipidaemia, hypertension, atrial fibrillation, cardiovascular
disease, transient ischaemic attack, aspirin or other NSAID use, and history of hysterectomy or oophorectomy.
‡Reference category, defined as no prescription of HRT in the 12 months before index date.
§ Low dose of oral HRT defined by ≤0.625 mg of equine oestrogen or ≤2 mg of estradiol and high dose of oral HRT defined by >0.625 mg of equine
oestrogen or >2 mg of estradiol.

for current users of transdermal HRT and 1.26 (1.12 to considered only new users who had not been exposed
1.42) for current users of oral HRT. to other HRT types or formulations.
Although clinical studies are lacking, there is biolo-
DISCUSSION gical evidence to support the idea that risk of vascular
Our population based, observational study of the risk events differs according to the route of administration
of stroke associated with oral and transdermal hor- of HRT.21 The transdermal route avoids the first pass
mone replacement therapy in postmenopausal effect in the liver and therefore reduces the induction of
women showed that the risk differed according to the hepatic protein synthesis of clotting factors and various
route of administration of HRT and oestrogen dose. inflammation markers. In light of our results of an
Indeed, we found that use of low dose transdermal oes- increased risk of stroke with transdermal products con-
trogen replacement therapy with or without progesto- taining high doses of oestrogens, however, the biologi-
gen was not associated with an increased risk of stroke, cal impact of the route of administration may vary
although a slightly increased risk with long term use according to the oestrogen dose delivered. Many stu-
cannot be excluded. Conversely, high dose trans- dies found that transdermal HRT administration has
dermal HRT and oral HRT increased the risk of stroke no or minimal effect on several cardiovascular and
by 25%–88%. thromboembolic risk markers, unlike oral oestrogens.
However, the impact of different doses of oestrogen
Comparison with other studies was not considered, as the 50 μg dose was almost exclu-
To our knowledge, the influence of route of adminis- sively studied.7
tration of HRT on the risk of stroke has not been stu- Information on risk of ischaemic heart disease asso-
died to date. A recent cohort study using the General ciated with different routes of administration of oestro-
Practice Research Database (GPRD) reported a lower gens is scarce. The few observational studies found no
risk of transient ischaemic attack with transdermal oes- increased risk of myocardial infarction with transder-
trogens (odds ratio 0.86 (95% confidence interval 0.43 mal oestrogens, though the same studies did not find an
to 1.73) than with oral oestrogen (odds ratio 1.47 (1.09 increased risk with the oral form either.22 23 One rando-
to 1.97)).4 The number of transdermal oestrogen users mised, placebo controlled trial, the Papworth HRT
was small as reflected by the wide confidence interval Atherosclerosis Study (PHASE), examined the risk of
and the risk of stroke could not be estimated. acute coronary events (cardiac mortality, non-fatal
Our finding of an increased rate of stroke associated myocardial infarction, and hospitalisation with
with current use of oral oestrogens is in accordance unstable angina) associated with transdermal oestro-
with results of most randomised controlled trials and gens (dose 80 μg) in postmenopausal women with
recent meta-analyses.1-3 14-20 Our results suggest that angiographically proved ischaemic heart disease.24
this risk is higher in prolonged users of oral HRT, Among the 255 women recruited, 134 were randomly
although the large confidence intervals preclude any assigned to transdermal oestrogen (alone or combined
firm conclusion and an increased risk in recent users with a progestogen) and 121 to placebo. The HRT
cannot be excluded. In a recent study also using the group had a higher event rate compared with the pla-
GPRD, the risk of transient ischaemic attack and cebo group, but the difference was not statistically sig-
ischaemic stroke was more marked during the first nificant (rate ratio 1.29 (95% confidence interval 0.84
year of HRT therapy.4 However, no distinction was to 1.95)). However, the study had several limitations,
made between new users and individuals who had including a high withdrawal rate in the HRT group
switched from another HRT type, whereas we (40%).
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Table 4 | Crude and adjusted rate ratios of stroke associated with current use of oestrogen (alone or in combination) by
duration of use and route of administration in women not previously exposed to other hormone replacement therapy (HRT)*
(values are percentages (numbers) unless stated otherwise)
Rate ratio (95% CI)
Type of HRT Cases* (n=15 710) Controls* (n=59 958) Crude Adjusted†
None 92.27 (14 496) 93.12 (55 834) 1.00‡ 1.00‡
Exclusive transdermal route: 0.46 (72) 0.44 (266) 1.05 (0.80 to 1.36) 1.10 (0.83 to 1.46)
For ≤1 year 0.08 (12) 0.08 (47) 0.95 (0.50 to 1.80) 0.98 (0.50 to 1.91)
For >1 year 0.38 (60) 0.37 (219) 1.07 (0.80 to 1.43) 1.13 (0.83 to 1.54)
Exclusive oral route: 3.28 (516) 2.79 (1675) 1.21 (1.09 to 1.34) 1.30 (1.16 to 1.45)
For ≤1 year 0.38 (59) 0.38 (230) 0.92 (0.69 to 1.23) 1.02 (0.75 to 1.38)
For >1 year 2.91 (457) 2.41 (1445) 1.26 (1.13 to 1.41) 1.35 (1.20 to 1.52)
*The model also included current users of tibolone, tibolone in combination with oestrogen-progestogen, and progestogen; former users of HRT; as
well as current oestrogen users (alone or in combination) who switched from another formulation or HRT product.
†Adjusted for age, body mass index, smoking status, alcohol misuse, diabetes, hyperlipidaemia, hypertension, atrial fibrillation, cardiovascular
disease, transient ischaemic attack, aspirin or other NSAID use, and history of hysterectomy or oophorectomy.
‡Reference category, defined as no prescription of HRT in the 12 months before index date.

More information is available on the impact of the no cardiovascular benefit, it is unlikely that one route of
route of oestrogen administration on the risk of venous administration would be favoured over the other. Also,
thromboembolism. Although there are no randomised we could not adjust for our cohort subjects’ socioeco-
controlled trials, recent observational studies and one nomic status or educational attainment, but our match-
meta-analysis suggest that transdermal oestrogen does ing of cases and controls on the general practice attended
not increase the risk of venous thrombosis in postme- represents an indirect attempt to adjust for such potential
nopausal women,25-27 and that it confers no additional confounders. We cannot, however, exclude the possibi-
risk of venous thromboembolism in obese women28 or lity that users of transdermal and oral HRT differed for
in those with prothrombotic mutations, in contrast to such characteristics, resulting in some residual con-
oral oestrogens.29 The risk of venous thrombosis asso- founding. Finally, the changes in trends of HRT expo-
ciated with different doses of transdermal oestrogens sure over time, which were likely to have occurred, were
was not investigated. Two other studies found no dif- taken into account in our analyses by the matching of
ference between transdermal and oral use, but their cases and controls for calendar time.
results were based on only five and seven cases using Some potential limitations inherent to the database
transdermal oestrogens, respectively.30 31 must be considered. We did not have access to
patients’ charts to validate the diagnosis of stroke.
Strengths and limitations of the study However, the use of GPRD diagnosis codes for stroke
The use of a computerised longitudinal database pro- has been shown to be accurate in a recent study where
vides several advantages in terms of selection of sub- 78 of the 88 (89%) recorded stroke diagnosis codes
jects and measurement of exposure. Selection bias is were in agreement with the written medical records.32
unlikely since we analysed a well defined cohort of all We were unable to differentiate between ischaemic
women aged 50–79 registered in the GPRD during the and haemorrhagic stroke accurately, as most diagnos-
study period using a nested case-control design. Clas- tic codes for stroke do not include this information. We
sification of exposure to HRT was made according to therefore could not explore the effect of the route of
the prescriptions issued by the women’s physicians, administration on stroke subtypes. Some delay may
which are electronically recorded at the time of pre- also exist between the date of occurrence of stroke
scription, precluding any information (recall) bias due and its recording in the GPRD, although this should
to the retrospective assessment of exposure. Some have minor impact on our results as we did not study
degree of misclassification could have occurred since the acute effect of HRT. Finally the exposure to HRT at
exposure status was not based on prescriptions actually the time of stroke was low, around 7% in both cases and
filled or taken by the patients, and information on com- controls. This is not surprising, however, considering
pliance was not available. However, examining poten- that this percentage reflects the current exposure of
tial misclassification of exposure in sensitivity analyses patients at the time of stroke, and not the overall per-
did not change our findings. centage of patients exposed at any time during follow-
We were able to adjust for many potential confounder up. Also, because of the small number of exposed
variables, including some lifestyle risk factors. One cases, we did not estimate the impact of the type of
unmeasured potential confounder was age at meno- combined progestogen.
pause. Although we cannot exclude the presence of
some residual confounding, this confounding is likely Conclusions
to be non-differential between the two routes of HRT The increased risk of stroke associated with HRT use
administration. In other words, if patients with a higher has been a constant finding among most observational
cardiovascular risk profile were more likely to be pre- studies and randomised controlled trials to date. Our
scribed HRT before the results of clinical trials showing study suggests that the use of transdermal oestrogen
page 6 of 7 BMJ | ONLINE FIRST | bmj.com
 RESEARCH

9 Garcia Rodriguez LA, Perez GS. Use of the UK General Practice

WHAT IS ALREADY KNOWN ON THIS TOPIC Research Database for pharmacoepidemiology. Br J Clin Pharmacol
1998;45:419-25.
Oestrogen replacement therapy with or without progestogen is associated with an increased 10 Jick H, Jick SS, Derby LE. Validation of information recorded on
risk of stroke in postmenopausal women general practitioner based computerised data resource in the United
Kingdom. BMJ 1991;302:766-8.
11 Jick SS, Kaye JA, Vasilakis-Scaramozza C, Garcia Rodriguez LA,
WHAT THIS STUDY ADDS Ruigomez A, Meier CR, et al. Validity of the general practice research
database. Pharmacotherapy 2003;23:686-9.
The use of transdermal hormone replacement therapy containing low doses of oestrogen was 12 Renoux C, Dell’Aniello S, Garbe E, Suissa S. Hormone replacement
not associated with an increased risk of stroke, in contrast to the oral route of oestrogen therapy use and the risk of stroke. Maturitas 2008;61:305-9.
13 Andersohn F, Schade R, Suissa S, Garbe E. Cyclooxygenase-2
alone or combined with a progestogen selective nonsteroidal anti-inflammatory drugs and the risk of
ischemic stroke: a nested case-control study. Stroke
Transdermal administration of hormone replacement therapy may be a safer alternative to 2006;37:1725-30.
the oral route of administration 14 Simon JA, Hsia J, Cauley JA, Richards C, Harris F, Fong J, et al.
Postmenopausal hormone therapy and risk of stroke: The Heart and
Estrogen-progestin Replacement Study (HERS). Circulation
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replacement therapy containing low doses of oestro- 15 Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A
clinical trial of estrogen-replacement therapy after ischemic stroke. N
gen could be associated with a lower risk of stroke Engl J Med 2001;345:1243-9.
than the oral route of administration since we found 16 Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H,
et al. Oestrogen therapy for prevention of reinfarction in
no significant difference in stroke rates for low dose postmenopausal women: a randomised placebo controlled trial.
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these results alone do not represent definitive evidence Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on
to promote the use of the transdermal route over oral stroke in postmenopausal women: the Women’s Health Initiative: a
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administration of oestrogen replacement therapy, this 18 Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA,
study should encourage further research on the impor- Black H, et al. Effects of conjugated equine estrogen in
postmenopausal women with hysterectomy: the Women’s Health
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Kooperberg C, Rossouw JE, et al. Effects of conjugated equine
the treatment of menopausal symptoms. estrogen on stroke in the Women’s Health Initiative. Circulation
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Contributors: All authors contributed to the study design, SD’A performed 20 Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM,
the statistical analysis, CR wrote the initial draft, and all authors critically et al. Postmenopausal hormone therapy and risk of cardiovascular
revised the manuscript. All authors had full access to all of the data disease by age and years since menopause. JAMA
(including statistical reports and tables) in the study and can take 2007;297:1465-77.
21 Modena MG, Sismondi P, Mueck AO, Kuttenn F, Lignieres B,
responsibility for the integrity of the data and the accuracy of the data Verhaeghe J, et al. New evidence regarding hormone replacement
analysis. SS is the guarantor for the paper. therapies is urgently required: transdermal postmenopausal
Funding: This research was funded by grants from the Canadian Institutes hormone therapy differs from oral hormone therapy in risks and
of Health Research (CIHR), the Canadian Foundation for Innovation, and benefits. Maturitas 2005;52:1-10.
Organon. SS is the recipient of a distinguished investigator award from 22 Varas-Lorenzo C, Garcia-Rodriguez LA, Perez-Gutthann S,
Duque-Oliart A. Hormone replacement therapy and incidence of
the CIHR. CR is the recipient of a postdoctoral fellowship from the acute myocardial infarction. A population-based nested case-control
Multiple Sclerosis Society of Canada study. Circulation 2000;101:2572-8.
The study sponsor had no role in study design; in the collection, analysis, 23 de Vries CS, Bromley SE, Farmer RD. Myocardial infarction risk and
and interpretation of data; in the writing of the report; or in the decision to hormone replacement: differences between products. Maturitas
submit the article for publication. All authors declare they are 2006;53:343-50.
24 Clarke SC, Kelleher J, Lloyd-Jones H, Slack M, Schofiel PM. A study of
independent from all source of funding. hormone replacement therapy in postmenopausal women with
Competing interests: SS received research funding from Organon, ischaemic heart disease: the Papworth HRT atherosclerosis study.
Schering, and Wyeth, makers of hormone replacement therapy. EG BJOG 2002;109:1056-62.
received research funding and acted as a consultant to Schering AG. 25 Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral
Ethical approval: The study was approved by the Scientific and Ethical and transdermal oestrogen-replacement therapy with venous
thromboembolism risk. Lancet 2003;362:428-32.
Advisory Board of the GPRD. 26 Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H,
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Lancet 1997;350:1097-9. Accepted: 8 November 2009

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