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ObjectiveTo evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen.Study designWe pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors.ResultsAnalyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI

ObjectivesTo evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials.Study designThe two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings.ResultsOf 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment.ConclusionsE4/DRSP is associated with a favorable tolerability and safety profile.Implications statementPooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

ObjectiveTo evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen.Study designWe pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes.ResultsWe included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event.ConclusionE4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns.Implications statementMost estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

ObjectiveTo assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.Study designWomen aged 16 to 50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle.ResultsWe enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73-3.88), method-failure PI of 1.43 (95% CI 0.7-2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred.ConclusionE4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates.Implications statementA new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.

Among young persons, ease of use, high efficacy, and high acceptability makes the etonogestrel contraceptive implant an important choice for this age group. Adolescent-friendly, patient-centered counseling considers the patient's cognitive development, the influence of friends and family, as well as their own preferences and values. Age-appropriate language, graphics, and models are useful to explain contraceptive options and relevant side effects. Effectiveness, reversibility, safety, noncontraceptive benefits, and side effects are important attributes and should be discussed when teens are choosing a contraceptive method. In this review we describe suggested best practices for counseling adolescents about the etonogestrel implant so they can make informed, prudent decisions about using this contraceptive method.

ObjectivesTo evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use.Study designWe reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as "favorable" (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or "unfavorable' (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively.ResultsWe evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75-85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%-50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001).ConclusionImplant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant.

BackgroundWhether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown.ObjectiveTo examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups.DesignSubgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611).Setting40 U.S. clinical centers.Participants9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status.InterventionConjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years.MeasurementsIncidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a "global index" (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up.ResultsThe effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age.LimitationsThe timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing.ConclusionThe effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term.Primary funding sourceThe WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.

Lifestyle-related factors influence risk of endometrial and ovarian cancers, but few studies have examined their joint associations with risk of these cancers. Using multivariable Cox regression models, we assessed the association of a healthy lifestyle index (HLI-a composite score (range, 0-20) involving diet, alcohol consumption, physical activity, body mass index, and smoking; higher scores represent healthier behavior) with risk of endometrial and ovarian cancers among 108,136 postmenopausal women who were recruited in the US Women's Health Initiative study between 1993 and 1998. After a median follow-up of 17.9 years, 1,435 endometrial cancer cases and 904 ovarian cancer cases had been ascertained. Women in the highest quintile of the HLI score had a lower risk of overall, type I, well-differentiated, moderately differentiated, poorly differentiated, and localized endometrial cancer than those in the lowest quintile (for quintile 5 vs. quintile 1, hazard ratio (HR) = 0.61 (95% CI: 0.51, 0.72), HR = 0.60 (95% CI: 0.49, 0.72), HR = 0.66 (95% CI: 0.46, 0.96), HR = 0.69 (95% CI: 0.52, 0.90), HR = 0.49 (95% CI: 0.34, 0.72), and HR = 0.61 (95% CI: 0.50, 0.74), respectively). The HLI score had a weak positive association with risk of serous ovarian cancer. Our findings underscore the potential importance of a healthy lifestyle in lowering endometrial cancer risk among postmenopausal women.

ObjectiveVasomotor symptoms (VMS) may be a marker of cardiovascular risk. We aimed to evaluate the cross-sectional association of VMS presence and severity with hemostatic parameter levels measured at baseline among Women's Health Initiative (WHI) Hormone Therapy trial postmenopausal participants.MethodsThis cross-sectional analysis included 2,148 postmenopausal women with measures of VMS presence and severity reported in the 4 weeks before WHI baseline, who were not using warfarin or hormone therapy and for whom the following baseline hemostatic parameters were measured within the WHI Cardiovascular Disease Biomarker Case-Control Study: antithrombin, plasminogen activator inhibitor-1, protein C antigen, total and free protein S antigen, total and free tissue factor pathway inhibitor, D-dimer, normalized activated protein C sensitivity ratio, and thrombin generation. Using multiple linear regression, we estimated the adjusted average difference in each hemostatic parameter associated with VMS presence and severity. A multiple comparisons-corrected P value was computed using the P-min procedure to determine statistical significance of our smallest observed P value.ResultsWomen were 67 years of age on average and 33% reported VMS presence at baseline. There was some suggestion that VMS presence may be associated with a -0.34 adjusted difference in normalized activated protein C sensitivity ratio compared with no VMS (95% CI, -0.60 to -0.087; P = 0.009), but this association was not significant after correction for multiple comparisons (P = 0.073). VMS presence or severity was not significantly associated with the other hemostatic parameters.ConclusionsWe found no convincing evidence that VMS presence or severity was associated with levels of hemostatic parameters among postmenopausal women.

ObjectiveThe objective was to monitor the effectiveness of the etonogestrel implant clinical training program through a voluntary active monitoring program (AMP).Study designUS health care providers underwent mandatory training by the manufacturer on etonogestrel implant insertion, localization and removal. After training, health care providers could enroll in a voluntary AMP to provide outcome data to meet a postmarketing commitment of the manufacturer with the US Food and Drug Administration (FDA). Those who volunteered completed and faxed forms to the manufacturer after implant insertion and removal detailing the procedure and device-related outcomes, including insertion-, localization- or removal-associated events. Experts reviewed outcome data quarterly, which the Sponsor then reported to the FDA.ResultsAmong 42,337 health care providers completing the training program, 4294 (10.1%) volunteered to participate in the AMP. The 26,198 forms submitted over 6.4 years included more insertion (n=20,497) forms than removal forms (n=5701). The volunteers reported 646 events on 566 (2.2%) forms related to insertion (n=197), localization (n=34), removal (n=357) and "other" (n=58). Clinically important events included noninsertion (n=4), serum etonogestrel positive but implant not found (n=1), and possible nerve (n=66) or vascular (n=5) injury. The reports did not include any insertion-, localization- or removal-associated hospitalizations. Eight (0.14%) removal reports described referral for surgical implant removal.ConclusionEvents related to insertion, localization or removal of the etonogestrel implant are uncommon among US providers who received mandatory training in the use of the implant.ImplicationsThis report presents results from the first mandatory US contraceptive training program. Health care providers volunteered to report information about etonogestrel implant insertion, localization and removal. Although the data do not demonstrate whether a mandatory program improves outcomes, they elucidate the utility and real-life experience that clinical training programs can provide.