CME Author: Zeena Nackerdien
Study Authors: Stephanie B. Teal, David K. Turok, et al.
Target Audience and Goal Statement
Gynecologists, obstetricians, and internists
To learn more new data from a phase III clinical trial of levonorgestrel-releasing uterine system (LILETTA®; 52 mg; LNG-IUS; Allergan) which confirmed efficacy, safety, and tolerability through five years.
Approximately 43 million (70%) reproductive-aged women in the U.S., are at risk for unplanned pregnancies. Needless to say, for the nearly half of all U.S. pregnancies that are unplanned there are elevated risks of morbidity and mortality, and socioeconomic costs. Several available methods of birth control have pros and cons, including lack of convenience; success rates not high enough to gain peace of mind about the risks of pregnancy; and potentially needing a waiting period when a woman decides she wants to become pregnant.
Long-acting reversible contraception (LARC) methods represent viable birth control alternatives, as they do not require daily adherence and effectively improve women’s health by enabling child spacing. Generally, a return to fertility is rapid after LARC removal. Prior studies have shown that lowering barriers to LARC access has resulted in greater LARC uptake and a drop in unwanted pregnancy and abortion rates. LARC usage increased from 6% in 2008 to 14% in 2014, according to a separate survey of women taking birth control.
According to The American College of Obstetricians and Gynecologists (ACOG), five intrauterine devices are currently marketed in the U.S.: the copper-containing intrauterine devices (IUD) and four levonorgestrel-releasing IUDs. Nearly two-thirds of women obtaining a LARC method choose a hormonal intrauterine system (IUS). Based on the prescribing information, the mechanism of the LGS-IUS used in this study is not known, but may involve prevention of fertilization due to the thickening of the cervical mucus, which inhibits sperm passage through the cervix, inhibition of sperm mobility and function (capacitation), and alteration of the endometrium.
The LNG 52-mg IUS under investigation was granted four-year approval by the U.S. Food and Drug Administration (FDA) in 2017 based on an ongoing phase III study (NCT00995150). Because evidence of acceptability and success is lacking among women who opt for short-acting methods, the investigators designed this ongoing study to address health and socioeconomic concerns. Some of these concerns include safety issues and non-eligibility of nulliparous women at the user and provider levels, over-estimation of the efficiency of other contraceptive methods, the ability of users to optimally use them, and a perception of higher costs.
Study Synopsis and Perspective
The randomized, open-label, ongoing ACCESS-IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) study of the LGS-IUS at 29 centers in the U.S. was conducted in 1751 women (ages 16-45), of whom 58% were nulliparous and 42% were parous. Body mass index (BMI) ranged from 15.8 to 61.6 kg/m2 among study participants. Other patient demographics were: Caucasian 78.4%, Black or African American 13.3%, Asian 3.9%, American Indian or Alaska Native 1.2%, Native Hawaiian or Other Pacific Islander 0.3%; 2.9% identified multiple races, and 14.7% indicated Hispanic ethnicity.
According to the prescribing information, the LGS-IUS contains 52 mg of levonorgestrel, a progestin, and is intended to provide an initial release rate of 19.5 mcg/day of levonorgestrel. Unless contraindicated, the LGS-IUS is approved to prevent pregnancy for up to 5 years. Participants received this novel LGS-IUS and after year 1, study visits occurred every 6 months, with a phone call (starting at month 9) at the 3-month point between visits, the authors said. Successful intrauterine system placement occurred in 1,714 women (97.9%), including 1,568 women ages 16-35, and 146 ages 36-45. A total of 1,538 eligible participants were included in the efficacy evaluation portion of the trial. The primary outcome of pregnancy rate (Pearl Index; [number of pregnancies × 12] × 100) / (number of women in the study × duration of study in months) in females ages 16–35 was assessed at enrollment through 60 months
Pearl Indices for year 1 and 5 were 0.15 (95% CI 0.02-0.55) and 0.20 (95% CI 0.01-1.13) pregnancies per 100 women-years, respectively, reported Stephanie B. Teal, MD, of the University of Colorado in Aurora, and colleagues. Cumulative life-table pregnancy rate was 0.92% (95% CI 0.46-1.82%) through 5 years, the authors wrote in their article.
For patients ages 16-35 (1011 nulliparous and 438 parous women), 9 pregnancies occurred, including 4 in nulliparous women and 1 in an obese woman. One pregnancy occurred after perforation and one after expulsion in this age group. Six (67%) of the pregnancies were ectopic. The investigators also noted that no pregnancies occurred in LNG 52-mg IUS users ages 36-45 at enrollment.
Examining safety, the analysis included patients who used the system for up to, or beyond 7 years. Participants ages 16-35 were significantly more likely to have new or worsening acne, dyspareunia, pelvic pain, and dysmenorrhea, while older participants were likely to report new or worsening weight increases, Teal and co-authors said.
Of the 18.8% of participants who discontinued treatment due to an adverse event, partial or complete expulsion was the most common for those with successful insertion (3.8%), although the researchers noted that the rates of expulsion did not differ between participants ages 16-35 and 36-45.
Bleeding symptoms were among the most common non-expulsion adverse events that led to at least 0.5% of participants requesting discontinuation during more than 7 years of intrauterine system use, the researchers added.
They noted one death that occurred during the first year of use, but it was the result of a preexisting illness and was not related to the intrauterine system.
Obstetrics & Gynecology, Dec. 04, 2018; DOI: 10.1097/AOG.0000000000003034
Study Highlights: Explanation of Findings
The LILETTA trial is the largest ongoing phase III, IUS clinical trial in the U.S. The main conclusion is that LNG-IUS is more than 99% effective in preventing pregnancy for up to five years in many women irrespective of age, race, body mass index (BMI), or parity — whether a women gave birth to at least one child. By the first year post-insertion, about 20% of LNG-IUS users experienced amenorrhea during at least one 90-day interval (i.e., the composite estimated showed that most study participants did not experience amenorrhea during the first year). While almost half of the women (42%) of the study participants had amenorrhea at the end of five years, only 2.2% of women discontinued use due to bleeding complaints.
Outcomes from this study will enable healthcare providers to counsel women to make a more informed contraceptive selection.
Teal and colleagues added that this is an ongoing trial, and the plan is to evaluate the levonorgestrel 52-mg intrauterine system for up to 10 years of continuous use. “Use of the same product for a longer period of time would allow for fewer procedures, which will both decrease healthcare costs and result in less discomfort and risk for females to endure,” the team concluded.
Molly Walker wrote the original story for MedPage Today
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner