Estrogen/Progestagen combinations increase the risk of venous thromboembolism, as a class. As illustrated by the WHI study on HRT these products increase venous thromboembolism maximally during the first year of use, after which the risk declines (starter effect). Women who are susceptible to VTE probably experience a thrombosis soon after they start HRT intake and then stop treatment. Therefore, a population of long-term users who do not switch between different preparations includes only a few high-risk patients and therefore has a low VTE rate. The starter effect repeats itself at a lower level after a period of discontinuation (re-starter effect).[7,8] Furthermore, women at high risk tend selectively to switch to the most recently marketed product (switcher effect). For the sake of the validity of the study results and the comparability of the cohorts it is essential to record precise information on duration of use, discontinuation periods and risk factors. Long-term users of a HRT preparation should not be included in the study.
The diagnosis of venous and arterial thromboembolism is not always confirmed by methods with a high sensitivity and specificity (e.g., phlebography). Therefore, the classification of reported thromboembolic events has to be done by a predefined algorithm. Definite and probable events will be considered as confirmed. All other cases will be classified as "not confirmed".
One of the most crucial factors to ensure the validity of the study is a low "lost to follow-up" rate. In order to minimize loss to follow-up a multi-faceted, four level follow-up process was established. The level1 activities include the mailing of the follow-up questionnaire and - in case a woman does not respond - two reminder letters. If level1 activities do not lead to a response multiple attempts are made to contact her, her husband, friends, relatives and the gynecologist/primary care physician per phone. In parallel to these level2 activities searches in national and international telephone and address directories are started (level3 activities). If this is not successful, an official address search via the respective governmental administration is conducted (in some countries centralized, in others decentralized at community level). This level4 activity can provide information on a new address (or information that the respondent has moved abroad or has died). If necessary, a search in the national death registers could be started at the end of the study to clarify the vital status of patients who are lost to follow-up after level4 activities. Overall, the investigators estimate that the loss to follow-up of the combined cohort could be kept at less than 5% of the recruited population.
The authors would like to thank the members of the Advisory Council for carefully reviewing the manuscript as well as Anita Assmann for establishing the logistic infrastructure for the field work of this study.Funding information
The study is funded by Schering AG, Berlin Germany.
Address: Center for Epidemiology & Health Research Berlin, Invalidenstrasse 115, 10115 Berlin, Germany
BMC Womens Health. 2006;6 © 2006 Dinger and Heinemann; licensee BioMed Central Ltd.
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Cite this: European active surveillance study of women taking HRT (EURAS-HRT): study protocol [NCT00214903] - Medscape - Jan 01, 2006.