Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study.
ABSTRACT Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT.
We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT.
One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07).
The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.
- Journal of Thrombosis and Haemostasis 03/2010; · 5.55 Impact Factor
- Chemistry and Physics of Lipids 08/2011; 164:S29. · 2.59 Impact Factor
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ABSTRACT: Hormone replacement therapy (HRT) for post-menopausal women is known to promote venous thromboembolism (VTE), ie, deep venous thrombosis and pulmonary embolism, though the absolute risk for a given patient is very small. The risk of VTE appears to be greatest soon after after the initiation of HRT and returns to the baseline level of risk of non-HRT users after discontinuation. There is inconsistent data about whether estrogen-only or combined estrogen-progestin HRT are associated with similar VTE risk. Retrospective analyses suggest that transdermal HRT is not as prothrombotic as oral HRT, though this has not been evaluated in randomized clinical trials. Increasing age and weight further promote HRT's VTE risk. Some studies have investigated whether prothrombotic combinations may increase HRT's VTE risk and there is evidence that Factor V Leiden may do this. However, no benefit to screening prospective HRT users has been described, yet. Advanced proteomic and genomic studies may hold promise in the future for better elucidating which HRT users are at highest risk for VTE. Presently, physicians and prospective HRT users should discuss the potential risks and benefits for the individual patient, acknowledging there is no way to fully mitigate the risk of VTE.The Journal of steroid biochemistry and molecular biology 09/2013; · 3.98 Impact Factor
Does the type of hormone replacement therapy influence the
risk of deep vein thrombosis? A prospective case–control study
J. D. DOUKETIS, J. A. JULIAN,*? C. KEARON, D. R. ANDERSON,?? M. A. CROWTHER, S. M. BATES,
M. BARONE,? F. PIOVELLA,? A. G. TURPIE, S. MIDDELDORP,– P. VAN NGUYEN,**
P. PRANDONI,§ P. S. WELLS,?? M. J. KOVACS,§§ M. R. MACGILLAVRY,–– L. COSTANTINI?
and J. S. GINSBERG
Departments of Medicine, *Clinical Epidemiology and Biostatistics, and the ?Hamilton Civic Hospitals Research Center, McMaster University,
Hamilton, Canada; ?Servizio Malattie Tromboemboliche, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy; §Department of Medicine and Surgical
Sciences, University of Padua, Padua, Italy; –Academic Medical Center, Amsterdam, the Netherlands; **Hotel Dieu Hospital, Montreal,
Canada; ??Queen Elizabeth II Health Sciences Center, Halifax, Canada; ??Ottawa Civic Hospital, Ottawa, Canada; §§London Health Sciences
Center, London, Canada; and the ––Slotervaart Hospital, Amsterdam, the Netherlands
To cite this article: Douketis JD, Julian JA, Kearon C, Anderson DR, Crowther MA, Bates SM, Barone M, Piovella F, Turpie AG, Middeldorp S, van
Nguyen P, Prandoni P, Wells PS, Kovacs MJ, MacGillavry MR, Costantini L, Ginsberg JS. Does the type of hormone replacement therapy influence
the risk of deep vein thrombosis? A prospective case–control study. J Thromb Haemost 2005; 3: 943–8.
therapy (HRT) is associated with an increased risk of deep
combined estrogen-progestin HRT and estrogen-only HRT.
Methods:We prospectively studied postmenopausal women
with suspected DVT in whom HRT use status was ascertained
and who subsequently had objective diagnostic testing to
confirm or exclude DVT. Cases were patients with idiopathic
DVT, in whom there were no DVT risk factors, and controls
were patients without DVT, in whom there were also no DVT
risk factors. The risk of DVT was determined in users of
and controls without DVT (reference group). Multivariable
regression analysis was done to adjust for factors that might
confound an association between HRT use and the risk of
DVT. Results:One thousand one hundred and sixty-eight
postmenopausal women with suspected DVT were assessed,
from whom 95 cases of idiopathic DVT and 610 controls
without DVT and no DVT risk factors were identified.
Estrogen-only HRT was associated with an increased risk for
DVT that was not statistically significant [odds ratio (OR) ¼
1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-
progestin HRT was associated with a greater than 2-fold
increased risk for DVT (OR ¼2.70; 95% CI 1.44, 5.07).
Conclusion: The risk of developing DVT may be higher in
users of combined estrogen-progestin HRT than in users of
Keywords: deep vein thrombosis, estrogen, hormone replace-
ment therapy, progestin.
An association between oral hormone replacement therapy
use confers a 2–3-fold increased risk of developing DVT [1–8].
One issue that requires further consideration is the effect of the
type of HRT on the risk of DVT, specifically whether the risk
of DVT differs in users of combined estrogen-progestin HRT
and unopposed estrogen-only HRT. Previous observational
studies provided conflicting results: the risk of DVT was higher
with estrogen-progestin HRT in two studies [1,4]; the risk of
DVT was higher with estrogen-only HRT in one study ; the
risk of DVT was essentially the same with estrogen-progestin
and estrogen-only HRT in one study . Furthermore, the
validity of these findings might be questioned because ascer-
tainment of the type of HRT used was based on a retrospective
review of patient records, with the potential to misclassify the
type of HRTusedand, therefore, misrepresenttherisk of DVT
with estrogen-progestin and estrogen-only HRT [1–4]. Rand-
omized controlled trials have not been able to address this
issue, as these studies assessed the risk of DVT only with
estrogen-progestin HRT [6–8].
Investigating the risk of DVT with different types of HRT is
proportion of postmenopausal women who have had a
Correspondence: J. D. Douketis, St Joseph’s Hospital, Room F-541,
50 Charlton Ave. East, Hamilton, Ontario, Canada, L8N 4A6.
Tel.: +1 905 521 6178;fax: +1 905 521 6068;
Received 7 May 2004, accepted 6 January 2005
Journal of Thrombosis and Haemostasis, 3: 943–948
? 2005 International Society on Thrombosis and Haemostasis
it is important to provide reliable estimates of the risk of DVT
for such patients. Second, prior knowledge of whether the
progestin component of HRT influences the risk of DVT is
relevant when considering the safety of progestin-only hormo-
nal therapy in women with previous DVT in whom estrogen-
containing hormonal therapy is avoided . Although
progestin-only hormonal therapy is considered safe in women
with previous DVT [11–13], the absence of a prothrombotic
effect of progestins, which would support this practice, is not
study to investigate the risk of DVT in users of estrogen-
progestin HRT and estrogen-only HRT.
Patients and methods
We prospectively assembled a group of postmenopausal
women with suspected DVT. Patients were recruited from
outpatient, emergency room, or in-hospital settings from
12 clinical centres (eight in Canada, two in Italy, two in the
Netherlands). Patients were enrolled between 1998 and 2001,
. After a clinical assessment, during which information was
obtained about HRT use and DVT risk factors, objective
diagnostic testing for DVT was performed to confirm or
exclude DVT reliably. Cases were defined as patients with
idiopathic DVT who had no known DVT risk factors, and
controls were defined as patients without DVT who, similarly,
had no known DVT risk factors. This study design has two
advantages over previous case–control studies that investigated
HRT use and DVT risk. First, cases and controls were
phenotypically similar, as they were derived from the same
group of postmenopausal women with suspected DVT .
Second, the exposure of interest (HRT use) was ascertained
prior to and independent of the outcome of interest (DVT).
Consecutive postmenopausal women with suspected lower
limb DVT were eligible for this study. Postmenopausal status
was defined by one of the following criteria [15,16]: sponta-
neous menopause, with no menses for at least 6 months;
surgical menopause due to bilateral oopherectomy; or the
presence of menopausal symptoms, such as vasomotor flush-
ing, for at least 6 months. Patients were excluded if they had
one or more of the following characteristics: suspected
pulmonary embolism; amenorrhea due to primary or secon-
dary ovarian failure; cognitive impairment or language barrier.
Patients with suspected pulmonary embolism were excluded
because the accuracy of diagnostic testing is suboptimal, as up
to 20% of patients will not have pulmonary embolism reliably
diagnosed or excluded .
Eligible and consenting patients had a clinical assessment
that included documentation of presenting clinical features,
risk factors for DVT, and factors that might influence HRT
use. HRT use status was ascertained by direct patient
questioning, and was aided by showing patients photographs
of current HRT preparations. The clinical likelihood of DVT
was subjectively classified as low, moderate or high, based on
an assessment of patients’ presenting clinical features. After the
clinical assessment, patients underwent objective diagnostic
testing for DVT, with test interpretation by observers who had
no prior knowledge of patients’ HRT use status.
Determination of HRT use status
HRT was defined as an oral or transdermal formulation
consisting of an estrogen with or without a progestin. Patients
who were current users of selective estrogen receptor modula-
tors, estrogen antagonists, or phytoestrogens were excluded
were classified as HRT current users or HRT non-users, with
the latter group consisting of previous and never users. Current
userswereHRT userswhohadbeenreceiving HRT foratleast
1 month prior to the study assessment. Previous users were
patients who had received HRT prior to 1 month of the study
assessment but not within the month before the assessment.
Never users were patients who had never received HRT. In
current users, the HRT type was classified as estrogen-
progestin or estrogen-only, and as oral or transdermal.
Determination of DVT status
Diagnostic testing for DVT was based on center-specific
diagnostic algorithms. However, all patients required objective
confirmation or exclusion of DVT based on validated criteria
to be included in the study. DVT was confirmed by a non-
compressible vein segment on venous ultrasound , or a
constant intraluminal filling defect on two or more views on
venography . DVT was excluded by one or more of the
following: normal venography ; normal compression
ultrasound and a normal SimpliREDTMD-dimer test (Agen
Inc., Brisbane, Australia) [20,21]; normal compression ultra-
sound and a low clinical likelihood for DVT [21–23]; normal
serial compression ultrasound testing on day 1 and day 7 ± 3
after presentation ; or normal impedance plethysmography
and a normal SimpliREDTMD-dimer test .
Identification and definition of cases and controls
From the assembled study population, cases and controls were
identified centrally, by the Study Coordinating and Methods
Center, based on prespecified criteria. Cases were identified
from patients in whom DVT was confirmed and controls were
identified from patients in whom DVT was excluded. Cases
were defined as patients with idiopathic DVT, in whom DVT
occurred in the absence of the following DVT risk factors:
recent (within 1 month) surgery, immobility or trauma;
thrombophilia; previous venous thromboembolism; active
cancer (treated within 6 months or palliative) . Controls
944 J. D. Douketis et al
? 2005 International Society on Thrombosis and Haemostasis
were defined as patients in whom DVT was excluded, and who
did not have any of the aforementioned DVT risk factors.
To assess the effect of HRT type on the risk of DVT, we
compared the proportion of cases with idiopathic DVT who
were current users of estrogen-progestin or estrogen-only HRT
with the proportion of controls without DVT risk factors who
were current users of estrogen-progestin or estrogen-only
HRT. In this way, an effect of HRT on the risk of DVT
would not be confounded by additional DVT risk factors such
as recent surgery or active cancer. Reported risk estimates were
based on the multivariable modeling and expressed as odds
ratios (ORs), with corresponding 95% confidence intervals
(CIs). All P-values were two-sided.
Multivariable logistic regression analysis (SAS version 8.1,
Cary, NC, USA) was done to adjust for factors (unrelated to
DVT risk) that might confound an association between HRT
use and DVT risk. The potential confounders considered were:
clinical center; patient age (deciles); education level (primary,
secondary, postsecondary); body mass index (£ 19.9, 20–29.9,
or ‡30 kg m)2); smoking status (yes/no); previous hysterec-
tomy (yes/no); bilateral oopherectomy (yes/no); vertebral or
long bone fracture (yes/no); osteoporosis (yes/no); breast
cancer (yes/no); and clinical likelihood for DVT (low, moder-
ate, high). Variables in the final multivariable models were
selected based on their achieved level of statistical significance,
defined as P < 0.10 in the simple single-factor univariate
clinical centers, interaction terms between the HRT variable
and center were added to the model and assessed using the
likelihood ratio test.
There were 1178 postmenopausal women with suspected DVT
who were assessed for this study. After a post hoc review of
patient data, we excluded 10 patients with thrombophilia
because this small sample would preclude meaningful analyses
of such patients. From the remaining group of 1168 patients,
we identified 95 cases with idiopathic DVT and no antecedent
DVT risk factors (other than possible HRT use), and
610 controls without DVT and no DVT risk factors. The
1168 patients are presented in Table 1.
Effect of HRT type and risk of DVT
As shown in Table 2, use of any type of HRT was associated
with about a 2-fold increased risk of DVT compared with no
HRT use (OR ¼1.93; 95% CI 1.16, 3.22). Users of estrogen-
compared with non-users (OR ¼2.70; 95% CI 1.44, 5.07).
compared with non-users that was not statistically significant
(OR ¼1.22; 95% CI 0.57, 2.61). Despite the discrepant point
estimates of DVT risk with estrogen-progestin and estrogen-
onlyHRT(2.70 vs.1.22),adirect comparison of risks basedon
not attain statistical significance (P ¼ 0.096). The exclusion of
26 cases and controls who were current users of transdermal
HRT did not change these findings.
In terms of results across clinical centers, there was no
statistically significant difference in center-specific point esti-
tests (P ¼ 0.24), thereby indicating no significant across-center
heterogeneity of results and supporting the calculation of
summary effect measures across centers.
Potential confounders included in the final multivariable
models were previous hysterectomy and clinical center. A pre-
vious hysterectomy is likely to be a confounder with regard to
the HRT type used because patients with an intact uterus
typically receive estrogen-progestin HRT, whereas those with a
hysterectomy receive estrogen-only HRT . Clinical center
HRT use rates and confirmed DVT rates across centers, which
probably reflect country-specific HRT use patterns and center-
specific patient referral patterns, respectively. Other potential
confounders that were considered and rejected (P > 0.10) for
the final multivariable models were: age, education level, body
mass index, smoking status, bilateral oopherectomy, vertebral
or long bone fracture, osteoporosis, breast cancer, and the
clinical likelihood of DVT.
DVT appeared stronger in users of estrogen-progestin HRT
(OR ¼2.70) than in users of estrogen-only HRT (OR ¼1.22).
This finding is unexpected because progestins have not been
considered to have prothrombotic properties [11–13,27].
However, there is emerging evidence that progestin-only
hormonal therapy may be associated with an increased risk
for DVT. High-dose medroxyprogesterone, when used for the
treatment of menstrual disorders, is associated with a 5-fold
increased risk of DVT [28,29]. Furthermore, the progestin
component of the oral contraceptive appears to influence the
risk of DVT [30–32]. Finally, observational studies involving
women who were receiving progestin-only oral contraceptives
suggest that preparations such as intramuscular medroxypro-
gesteronemayconfer anincreased riskof DVT[28,29]. Despite
such data that support a progestin-associated prothrombotic
effect, the biological mechanism to account for these findings is
The type of hormone replacement therapy and deep vein thrombosis 945
? 2005 International Society on Thrombosis and Haemostasis
not known. Although it has been postulated that progestins
might augment a prothrombotic effect of estrogen, due to
conversion of progestins into estrogenic compounds [33,34],
this process appears to be marginal and unlikely to be of
clinical importance . Furthermore, studies investigating the
effect of HRT on coagulation parameters have not found
differences in coagulation activation between estrogen-proges-
tin and estrogen-only HRT preparations [35,36].
The validity of our findings is contingent on demonstrating
that the potential for bias, which can occur in any
Table 1 Patient characteristics: cases, controls, and all patients
Characteristic95 cases (%)610 controls (%)
Age (years): < 503 (3)
Body mass index* < 20 kg m)2
20–29 kg m)2
> 29 kg m)2
Highest level of education attained?
primary (grades 1–6)
secondary (grades 7–12)
(college or university)
Previous bilateral oopherectomy (with or without hysterectomy)
Previous hysterectomy only (without bilateral oopherectomy)
Previous vertebral or long bone fracture
Previous breast cancer
Hormone replacement therapy use current users
Current hormone replacement therapy users (duration) <1 year
Current hormone replacement therapy users (type)
Clinical likelihood for DVT low
Risk factors for deep vein thrombosis:
Previous venous thromboembolism
Active cancer (palliative or treated within 6 months)
Recent (within 4 weeks) confinement to bed for ‡3 days
Recent (within 4 weeks) lower limb trauma
Recent (within 4 weeks) surgery requiring an anesthetic
Lower limb paralysis
Currently receiving tamoxifen therapy
*Body mass index unavailable for 23 patients.?Education level unavailable for 17 patients.
Table 2 Risk of deep vein thrombosis (DVT) related to hormone replacement therapy (HRT) use
HRT use statusCasesControls
Risk of DVT
HRT non-users (reference group)
Current HRT users (any type)?
1.42 (0.91, 2.23)
1.93 (1.16, 3.22)0.011
0.68 (0.36, 1.31)
3.10 (1.79, 5.38)
1.22 (0.57, 2.61)
2.70 (1.44, 5.07)
OR, Odds ratio. *Comparison with HRT non-users in adjusted analysis.?Adjusted for hysterectomy and clinical center in final multivariate logistic
946 J. D. Douketis et al
? 2005 International Society on Thrombosis and Haemostasis
observational study, would not have influenced the study
results. In this study, the main source of bias is diagnostic
suspicion bias—that HRT users with DVT were preferen-
tially referred for diagnostic assessment over HRT users
without DVT, which would artificially strengthen an associ-
ation between HRT use and DVT. We believe this potential
source of bias was minimized and did not influence the
validity of our findings based on the following considera-
tions. First, cases with DVT and controls without DVT were
derived from a single population of postmenopausal women
with clinically suspected DVT, thereby ensuring that all
patients were subjected to the same referral process. This
would minimize preferential referral of HRT users with DVT
over HRT users without DVT. Second, DVT was diagnosed
by objective criteria, and diagnostic testing was performed
without prior knowledge of HRT use, thereby minimizing
the likelihood of preferential diagnosis of DVT in HRT users
over non-users. Third, ascertainment of HRT exposure
occurred prior to and independent of diagnostic testing for
DVT, thereby minimizing the potential that HRT use would
be preferentially ascribed to patients with DVT than without
DVT. Furthermore, it is likely that the ascertainment of
HRT exposure was reliable because this information was
obtained prospectively during a face-to-face patient interview,
and with the use of pictorial aids to assist in patients’ recall
of the HRT preparations they might have been receiving.
Fourth, when we performed a sensitivity analysis of results
by adjusting for patients with a low clinical probability for
DVT who, in the presence of minimal symptoms, might have
been preferentially referred for diagnostic DVT testing
because of HRT use, our findings remained unchanged.
Finally, diagnostic suspicion bias would not have influenced
the risk of DVT in users of estrogen-progestin HRT and
estrogen-only HRT, because it is unlikely that there was
preferential referral of patients based on the type of HRT
they were receiving.
Our study has potential limitations that warrant discussion.
First, we could not assess the risk of DVT in users of
transdermal HRT as only 26 patients were users of this type of
HRT. This issue is important, because of evidence suggesting
that transdermal HRT does not confer an increased risk of
DVT . Second, we acknowledge that when we compared
the risk of DVT in users of estrogen-progestin and estrogen-
only HRT, the difference in the risk ratio point estimates (2.70
vs. 1.22) was not statistically significant (P ¼ 0.096). However,
our findings appear consistent with data from the recently
published Women’s Health Initiative randomized placebo-
controlledtrial investigating estrogen-onlyHRT.Whereas,
estrogen-progestin HRT was associated with a greater than 2-
fold increased risk for venous thromboembolism (risk ratio ¼
with a non-significant increased risk of venous thromboembo-
lism (risk ratio ¼1.33; 95% CI 0.99, 1.79) .
The principal clinical implication of our study is that the
recommended use of progestin-only hormonal therapy in
women with previous DVT and women with other DVT risk
factors, based on its purported lack of a prothrombotic effect,
should be reconsidered [11–13]. Although our study showed
that a higher risk of DVT occurred when a progestin was
coadministered with estrogen, the possibility that progestin-
only therapy confers an increased of DVT should be consid-
effects of progestin-only therapy and to determine if such
treatment can be safely administered in women with previous
DVT or other risk factors for DVT.
In summary, our study suggests that the risk of developing
DVT may be higher in users of combined estrogen-progestin
HRT than in users of estrogen-only HRT.
This study was supported by funding from the Physician’s
Hamilton Civic Hospitals Research Center. The authors thank
the following colleagues for their valued assistance in comple-
P. Stevens, J. Johnson and S. Smail.
Contribution of authors
Study conception and design: J.D.D., J.A.J., J.S.G., C.K.,
S.M.B. Acquisition of data: J.D.D., J.A.J., M.A.C., C.K.,
S.M.B., M.B., F.P., A.G.T., S.M., P.v.N., P.P., D.R.A.,
P.S.W., M.J.K., M.R.M-G., L.C., J.S.G. Analysis and inter-
pretation of data: J.D.D., J.A.J., C.K., D.R.A., J.S.G. Drafting
of the manuscript: J.D.D., J.A.J., C.K., D.R.A., J.S.G. Critical
revision of the manuscript for important intellectual content:
J.D.D., J.A.J., M.A.C., C.K., S.M.B., M.B., F.P., A.G.T.,
S.M., P.v.N., P.P., D.R.A., P.S.W., M.J.K., M.R.M-G., L.C.,
J.S.G. Statistical expertise: J.A.J. Obtained funding: J.D.D.,
J.A.J., J.S.G. Administrative, technical, or material support:
J.D.D., J.A.J., M.A.C., L.C., J.S.G., M.A.C., C.K., S.M.B.,
M.B., F.P., A.G.T., S.M., P.v.N., P.P., D.R.A., P.S.W.,
M.J.K., M.R.M-G. Study supervision: J.D.D., L.C., J.S.G.
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