The study protocol was published after ethical approval of the study documents
. In brief, a large
cohort of women starting OC treatment (first-ever users or switchers to
a new product) was actively monitored for the occurrence of rare or unexpected
adverse outcomes possibly related to exposure to OCs.
The primary focus of the active study monitoring was to assess the occurrence
of new cardiovascular events. These events were monitored continuously
for the duration of the study.
In addition, all other serious adverse events (i.e., adverse events that
result in death, a life-threatening experience, inpatient hospitalization,
persistent or significant disability/incapacity, or require medical/surgical
intervention to prevent one of said outcomes) were fully documented and
reviewed by both the investigator and the Advisory Council at least twice
2.1 Study objectives
2.2 Study population
Recruitment of the cohort members was conducted via a network of physicians
who prescribe OCs.
Plans called for the combined cohort to include at least 50,000 women
recruited in seven European countries: Austria, Belgium, Denmark, France,
Germany, the Netherlands, and the United Kingdom.
At the participating centers, all women who received a prescription for
a new OC were asked by their physicians whether they were willing to participate.
These women could be either OC starters (first-ever users) or OC switchers.
More specific inclusion or exclusion criteria were not applied because
of the non-interference approach of the study design.
The objective was to avoid influencing preference for specific OCs, while
at the same time to undertake significant efforts to ensure standardized,
comprehensive, and reliable documentation of all baseline characteristics
and adverse events during the follow-up period.
2.3 Baseline survey and follow-up
Baseline data were recorded on a questionnaire that addressed the participants'
state of health and potential risk factors. Participants provided their
medical history, including medication history and history of OC use.
They also provided their addresses and phone numbers, those of relatives
or friends who could serve as back-up contacts, and those of their primary
Follow-up assessments for each woman were scheduled every 6 months. The
self-administered follow-up questionnaires addressed the occurrence of
adverse events. Reasons for discontinuing OC use or switching to another
OC were requested if applicable.
The questionnaires were reviewed for completeness and plausibility/consistency
of the responses. Missing or inconsistent information was clarified directly
with the women by phone.
A low “loss to follow-up rate” was essential for the validity
of the study. In order to minimize loss to follow-up, a four-level follow-up
process was established. Level1 activities included mailing the follow-up
questionnaire and --- in case of no response --- two reminder letters.
If level1 activities did not lead to a response, multiple attempts were
made to contact the woman, her friends, relatives, and gynecologist/primary
care physician by phone. In parallel to these level2 activities, searches
in national and international telephone and address directories were started
If this was not successful, an official address search via the respective
governmental administration was conducted (in some countries centralized,
in others decentralized at community level). This level4 activity usually
yielded information about a new address (or information that the respondent
had moved abroad or died).
A self-administered questionnaire used by patients at six-month intervals
is a very sensitive tool that captures almost all serious clinical outcomes.
From a methodological point of view, it captures a much higher proportion
of these outcomes than methods that rely solely on the prescribing gynecologist
who often is not directly involved in the diagnosis and treatment of these
outcomes (e.g., cardiovascular events).
However, it must be considered that there is a significant difference
between the rates of reported and validated events, because laypersons
often misclassify adverse events (e.g., pain in the legs after standing
for a long period of time as “thrombosis”, or migraine attacks
as “stroke”, even if modern imaging procedures do not provide
any indication of the perceived event). Therefore, validation of the self-reported
events was of great importance.
Follow-up questionnaires that contained information about such events
were immediately passed on to the medical reviewer group. In case of unclear
or missing information, the women were contacted by phone, e-mail or other
means. For many events it was necessary to contact the diagnosing and/or
treating physician for clarification and validation of the information
received from the patient. This procedure was mandatory for all serious
adverse events (including all main outcomes of interest).
Under routine medical conditions, diagnosis of a serious adverse event
is not always confirmed by a diagnostic method with high specificity.
Therefore, investigators classified all serious adverse events as “confirmed”
or “not confirmed”. Events that were confirmed by diagnostic
measures with high specificity (e.g., phlebography for DVT or cerebral
MRT for cerebrovascular accidents) or a clinical diagnosis supported by
a diagnostic test with low specificity (such as D-dimer for VTE) were
Events were considered not confirmed if the diagnosis reported by the
patient was excluded by diagnostic measures, if a different medical condition
was diagnosed by the attending physician, or if the reporting woman did
not contact a health professional to clarify her symptoms and no diagnostic
measures were performed that could have clarified the diagnosis.
2.5 Blinded adjudication
For the purpose of continuously monitoring safety data during the study,
classification of reported serious adverse events was performed by the
investigators. For the final analysis, classification of the primary outcome
of interest --- VTE --- was verified by a process of independent blinded
In order to minimize classification bias, the decisions made by the investigators
were reassessed by three independent medical experts specializing in radiology/nuclear
medicine, cardiology, and internal medicine/phlebology. These specialists
reviewed all available information on the reported VTE.
Brand names, dose, regimen, and composition of the OC(s) used by the reporting
woman were rendered anonymous for this process. These adjudicators performed
their reviews independently of each other and without knowing the judgment
of the other adjudicators or the investigators.
Using a conservative approach for the final analysis, a reported VTE was
classified as confirmed if at least one adjudicator had considered the
event as confirmed.
The EURAS study was powered to demonstrate the non-inferiority of DRSP-containing
OCs regarding VTE risk in comparison to LNG-containing OCs and ‘Other
OCs’. Cox regression analyses of the main clinical outcomes were
carried out in accordance with the final analysis plan, which was approved
by the Advisory Council before the first interim analysis.
The following pre-defined confounder variables were included in the Cox
regression model: age, BMI, duration of use, and VTE history for VTE;
and age, BMI, smoking, and hypertension for arterial thromboembolism (mainly,
acute myocardial infarction and ischemic stroke).
Based on the rather small number of outcomes, the Advisory Council limited
the number of confounder variables to these well-established risk factors
for the outcomes.
The analyses focused on comparisons among the three OC cohorts (DRSP-containing
OCs, LNG-containing OCs, ‘Other OCs’).
Over the years of follow-up, however, many women: