Bias from depletion of susceptibles: the example of hormone replacement therapy and the risk of venous thromboembolism.
OBJECTIVE
The data on the association between hormone replacement therapy and the increased risk of venous thromboembolism (VTE) in postmenopausal women are conflicting. The observed differences between oral estrogen and oral estrogen-progestogen combination formulations may be the result of bias from depletion of susceptibles.


METHODS
We used United Kingdom's Clinical Practice Research Datalink to identify the cohort of all women aged 50 to 79 during 1987-2008, with all incident cases of VTE occurring during the study period identified. Using a nested case-control approach, the rate ratios (RRs) of VTE with current use of oral estrogen and oral estrogen-progestogen combinations were estimated as a function of duration of use using conditional logistic regression with cubic splines.


RESULTS
The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched to 231 562 controls. The risk of VTE was increased with current use of oral estrogen (RR 1.49; 95% confidence interval: 1.37 to 1.63) and oral estrogen-progestogen (RR 1.54; 95% confidence interval: 1.44 to 1.65), relative to non-use. When assessed by duration of use, the risks with oral formulations were particularly elevated during the first year of use and were reduced subsequently.


CONCLUSIONS
The phenomenon of depletion of susceptibles should be considered in cohort studies evaluating acute side effects of medications. This can be achieved by estimating the risk as a function not only of current use but also of duration of use. Copyright © 2017 John Wiley & Sons, Ltd.
Centre for Clinical Epidemiology, Lady Davis Research Institute Jewish General Hospital, Montreal, Canada.|Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
Christel
C
Renoux
Centre for Clinical Epidemiology, Lady Davis Research Institute Jewish General Hospital, Montreal, Canada.
Sophie
S
Dell'Aniello
Rambam Hospital and Technion University, Haifa, Israel.
Benjamin
B
Brenner
Centre for Clinical Epidemiology, Lady Davis Research Institute Jewish General Hospital, Montreal, Canada.|Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.
Samy
http://orcid.org/0000-0002-1281-5296
S
Suissa
D000284:Administration, Oral; D000368:Aged; D015982:Bias; D016022:Case-Control Studies; D016208:Databases, Factual; D015914:Estrogen Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D017698:Postmenopause; D011372:Progestins / Q000008:administration & dosage / Q000009:adverse effects; D012306:Risk; D013997:Time Factors; D006113:United Kingdom; D054556:Venous Thromboembolism / Q000453:epidemiology* / Q000209:etiology
D004967:Estrogens; D011372:Progestins
bias; cohort studies; depletion of susceptibles; hormone replacement therapy; pulmonary embolism; venous thrombosis