Oral Contraceptive Reduced Heavy Bleeding

Major Finding: Among 135 evaluable women, complete resolution of abnormal menstrual symptoms was achieved in 44% of those receiving an oral contraceptive containing estradiol valerate/dienogest (E2V/DNG) vs. 4% of those given placebo.

Data Source: The mean change in menstrual blood loss volume was quantified using the alkaline hematin method.

Disclosures: The study was funded by Bayer Schering Pharma AG, which is developing E2V/DNG. Dr. Jensen has received research support from Bayer and Warner-Chilcott, and served as consultant for Bayer and Schering Plough. His coauthors disclosed employment with Bayer Schering and consultant roles with Bayer.

ATLANTA — An oral contraceptive known in Europe as Qlaira significantly reduced menstrual blood loss in women suffering from idiopathic heavy and/or prolonged menstrual bleeding, in a multinational, double-blind phase III trial.

Among 135 evaluable women, complete resolution of abnormal menstrual symptoms was achieved in 44% of those receiving the oral contraceptive containing estradiol valerate/dienogest (E2V/DNG) vs. 4% of those given placebo.

The mean change in menstrual blood loss volume, as quantified using the alkaline hematin method, was −353 mL in the E2V/DNG arm vs. 130 mL in the placebo arm (P less than .0001).

The dramatic reduction in blood loss was apparent in 3 months, and was accompanied by improvements in iron metabolism parameters, said lead researcher Dr. Jeffrey T. Jensen, professor of obstetrics and gynecology at the Oregon Health and Science University in Portland.

Significant improvements were observed at 196 days with E2V/DNG vs. placebo in the mean change from baseline in the hematocrit (1.4% vs. −0.05%), ferritin (2.9 ng/mL vs. −0.4 ng/mL), and hemoglobin (0.6 g/dL vs. 0.1 g/dL) levels.

E2V/DNG was approved for contraception in Europe under the trade name Qlaira in 2009, and may become available in 2010 in the United States where duel indications for contraception and heavy menstrual bleeding are being discussed, Dr. Jensen said at the annual meeting of the American Society for Reproductive Medicine. While dienogest is a new progestin in the United States, it is available in Europe as a single-agent pill to treat endometriosis, and in combination with ethinyl estradiol for contraception.

During a discussion of the study, audience members questioned the lack of an active comparator in the study and the high number of patients excluded from analysis. Dr. Jensen said that it was a weakness not to have an active comparator, but that the study design was required by the Food and Drug Administration. An identically designed trial conducted in Europe and Australia produced similar results.

Furthermore, unpublished data from a third trial showed a similar reduction in bleeding at 3 months with E2V/DNG and the approved levonorgestrel-releasing intrauterine system (LNG-IUS) and a better response at 6 months with LNG-IUS.

“Having placebo-controlled data is very useful as far as getting a benchmark, and there's lots of women out there that aren't currently using any other products,” he said. “Now whether this is a better treatment than other oral contraceptives, we don't know. The data [don't] support that,” he said.

A recently published comparative trial conducted by one of Dr. Jensen's coinvestigators in 798 healthy women seeking contraception, reported significantly fewer bleeding/spotting days among women given E2V/DNG than those given ethinyl estradiol 20 mcg/levonorgestrel 100 mcg (EE/LNG): 17.3 vs. 21.5 days (P less than .0001). No unintended pregnancies occurred with E2V/DNG and only one occurred with EE/LNG, while adverse drug reactions occurred in 10% vs. 8.5% of women (Contraception 2009;80:436–4).

Estradiol-containing oral contraceptives have demonstrated effective contraception, but have been problematic in terms of cycle control, notably with bleeding irregularities leading to premature discontinuation. E2V/DNG is administered using a dynamic estrogen step-down and progestin step-up dosing regimen designed to overcome unacceptable cycle control.

In the current study, a total of 190 women from the United States and Canada with heavy and/or prolonged menstrual bleeding without recognizable pelvic pathology were randomized in a 2:1 ratio to E2V 3 mg on days 1–2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25–26, and placebo on days 27–28 or placebo on days 1–28. Their mean age was 37 years.

A total of 54 withdrew from the study, 44 discontinued treatment, 5 never took the study medication, and 6 were lost to follow-up. In all, 84 women in the E2V/DNG arm and 51 in the placebo arm were available for analysis.

Dr. Jensen noted that a composite of up to eight individual criteria were used for achieving a complete response. Based on a subjective assessment, 81% of the women given E2V/DNG reported improvement vs. 38% of those given placebo.