Critical commentary on ‘Oestrogen-free oral contraception with a 4 mg drospirenone-only pill: new data and a review of the literature’

The study by Palacios et al. [1] did not clearly establish the purposes or endpoints. The authors have included the most relevant articles on the 4mg DRSPOP. However, they are not devoid of limitations. The weaknesses of the multicenter phase III clinical trial by Archer et al. [3], conducted on 713 subjects (7638 cycles) that stated a similar contraceptive efficacy between DRSPOP and combined oral contraceptives (COCs), include the noncomparative design and the fact that cycle-control and drug adherence assessments were based on participants’ diaries [4]. Palacios et al. [5] performed the first report on DRSPOP providing clinical efficacy similar to COCs, with a good safety profile, and favourable cycle control in a significant number of participants with cardiovascular risk factors. The main weaknesses are the noncomparative design and the high discontinuation rate given that 3333 women-years cases would have been needed to assess the statistical number of events without any hormonal influence and the total observational period of the studies enrolled 1102 women-years, as the primary endpoint was the definition of Pearl index. They found differences in the Pearl index between European trials and USA trial. The USA trial by Kimble et al. [6] included, as inclusion criteria, participants with regular menstrual cycles. The safety of DRSPOP was evaluated in 1006 women. Reasons for participants-drop out of the study were reported. No cases of thromboembolic disease were reported, although the sample size may have been too low to observe rare events. This effect could be explained by the fact that a greater number of subjects is needed to demonstrate an effect of this type (>10,000 users). This was a single-arm, noncomparative study; therefore, no direct comparisons can be made with other types of contraception. The study product, trial procedures (such as multiple site visits) or socioeconomic factors may have contributed to a high dropout rate. Overall, there was a high level of participant satisfaction. Although 86 % agreed or strongly agreed that they were satisfied with DRSPOP, some of the 269 women lost to follow-up may have disliked the study drug due to bleeding, a tolerability issue or even pregnancy. Other phase III clinical trial by Palacios et al. [7] specified the primary and secondary endpoints and used statistical methods in order to calculate the number needed to treat, employing non-inferiority tests, sample size calculations, and confidence intervals for results. The limitation of the study remains in the rate of patients with data available for the bleeding and spotting analyses during the 9 cycles of treatment. Another limitation is that they compared two different dosing regimens (continuous vs. 24/4) and this makes the analyses of some parameters like scheduled bleedings more challenging. In the case of the study by Regidor et al. [8], the main limitation is that the baseline mean values of clotting factor VII and protein C activity was statistically lower for the DRSPOP group. Lastly, the main weakness of the study by Palacios et al. [9] remains at the difference of sample sizes and recorded cycles between both groups (858 women with 6691 DRSPOP and 332 women with 2487 desogestrel-only pill). The main limitations of this review are the scarcity of studies with a comparative design, a high discontinuation rate and the use of participants diaries to assess menstrual cycle control. There is a need for quality studies on the comparison between DRSPOP and oral combined contraceptives and DRSPOP and desogestrel-only pill.