By Jeffrey T. Jensen, MD, MPH
Synopsis:The drospirenone venous thrombosis controversy remains a topic of interest in Europe and is influencing prescribing practices. Many clinicians and professional groups are recommending the use of levonorgestrel pills as first-line products, and some products have been removed from the market. In the United States, the issue has received less attention from clinicians, but is a hot topic for trial lawyers. This special feature will review the current information on pill safety with an emphasis on practice in the United States.
I recently spent several days at the first global conference on Contraception, Reproductive and Sexual Health in Copenhagen. During the 3-day meeting, the topic of venous thrombosis (VTE) and hormonal contraception received plenty of attention, with presentations during a special symposium, a plenary session panel discussion, a plenary session debate, and in four other free communication and congress forums. I had the opportunity to participate in several of these sessions, and attend the others. I particularly enjoyed meeting and hearing first-hand descriptions of results from the Danish database studies presented by Professor Ojvind Lidegaard. Since I have presented my perspective on these studies in several OB/GYN Clinical Alert commentaries, I thought I should review the arguments shaping practice decisions in some European nations.
I admire Lidegaard for his determination and scientific diligence. He is an imposing figure and a relentless advocate. As a practicing clinician, he understands the problems we face each day in patient care, and he has deep concern for the welfare of women. His position is straightforward; the overwhelming majority of studies support a doubling of risk of VTE with drospirenone, third-generation, and cyproterone acetate combined hormonal methods when compared to levonorgestrel (LNG) pills. Since the only studies that do not support the increase in risk are post-marketing studies funded by the pharmaceutical companies, he argues that these findings are unreliable, even though many experts believe the opposite.1,2 Although the increase in the attributable risk of VTE with use of the newer progestogens is low (about 2-3 cases per 10,000 women years of exposure), Lidegaard reminded conference attendees that real women are affected and some will die or suffer permanent disability. Since safer alternatives (e.g., LNG pills) are available, he maintains that women need to be counseled about this increase in risk with newer products, and that practice guidelines and government reimbursement policies should take these recommendations into account. Lidegaard believes that we have sufficient evidence to end the debate about whether these products increase risk, and that we should move directly toward implementation of policy. A "pill scare" can be avoided, he believes, by quietly implementing these policies without alarming the public or undermining confidence in hormonal methods. He claims that this approach has become policy in Denmark, and the shift in prescription habits toward safer pills is having a measurable impact on the population-based incidence of VTE risk (unpublished data presented at the meeting).
Let’s evaluate these claims and determine if a course of action in our own clinical contraception practice is necessary. First, emotion runs high, and the science is often trumped by highly publicized media reports of unfortunate but rare serious adverse events in young women using combined hormonal contraceptives. A policy labeling some pills as safe and others as high-risk is not likely to be successful, as the public concludes that all pills and hormones in general are unsafe.
This is exactly what has occurred in France in response to reports of stroke and death in users of the 35 mcg EE cyproterone acetate (CPA) pill (Diane®). It is important to understand that Diane® received marketing approval in France in 1987, not as an oral contraceptive, but as a treatment for acne. Four deaths have been associated with thrombosis events in Diane® users over the almost 30 years of approved use. Ironically, since Diane® did not carry a labeling indication as a contraceptive, some providers would prescribe concurrent use of another oral contraceptive along with Diane® (in most of the other 135 countries where Diane® or Dianette®, same pill, different name was marketed, it had a duel indication for contraception). Also, since acne is associated with polycystic ovary syndrome and obesity, and obesity is an independent risk factor for VTE, Diane® users may have been at a higher baseline risk of VTE. Unfortunately bad press trumps good science, and the French regulatory authorities hastily called together expert groups. Diane® was pulled from the market, and the safety of other combined hormonal contraceptives questioned. In fact, an official statement from prominent French reproductive endocrinologists called for limitations on the prescription of other progestogens, and even suggested that prescription of combined pills should be restricted to gynecologists!
Since Diane® was never approved in the United States, this story has not received much media attention here. However, since the data linking CPA to an increase in VTE risk comes from many of the same database and case-control studies that support an increased risk with third-generation and drospirenone pills, you can bet that U.S. trial attorneys have been following this closely.
Although in Europe each nation independently controls and approves the sale of drugs within its borders, the European Medicines Agency (EMA, a central regulatory agency similar to our FDA) also exists. French regulatory authorities requested that the EMA review Diane® approval. On May 17, 2013, the Pharmacovigilance Risk Assessment Committee (PRAC) released a supported continued approval for CPA/EE pills stating that the benefits outweigh its risks in certain patients, as long as measures are taken to minimize the risk of thromboembolism. The recommendations (adopted with a 31:1 majority) state that Diane® and its generics can be used in the treatment of moderate-to-severe acne related to androgen sensitivity or hirsutism in women of reproductive age when alternative treatments, such as topical therapy and oral antibiotic treatment, have failed. Despite the near unanimous recommendation of the PRAC, the French National Agency for the Safety of Medicine and Health Products suspended the marketing authorizations for CPA in France. The result of all of this publicity has been a decrease in oral contraceptive use; many abortion providers at the Copenhagen meeting presented anecdotal evidence that abortion rates are rising.
With this action, a new European war has erupted. On one side, the group led by Lidegaard believes that the consistency of the scientific studies have settled the debate on safety, and that professional and regulatory groups should restrict or withdraw the use of certain products in favor of second-generation pills.3-5 The other position, championed by Samuel Shapiro and other experts, suggests that the evidence of an increase in risk is not only insufficient but flawed, and that no practice changes are warranted.6Both sides claim to have the interest of women as their primary motivation, and accuse the other side of manipulating or ignoring data in a way that compromises the health of our patients. The net result of this disagreement has been a continuing decline in the public confidence regarding the safety of all combined methods.
In response to this new pill crisis, Johannes Bitzer in his role as President of the European Society of Contraception and Reproductive Health published a consensus paper signed by prominent gynecologists from several EU countries and the United States.7The statement (key points below) urges calm and a return to our shared objective of improving women’s health by focusing on a clinical risk/benefit discussion that should serve as a basis for the prescription of various combined hormonal contraceptives:
So how should we change practice in the United States? Although we don’t have a crisis with CPA pills, we still need to counsel our patients effectively. About 18% of reproductive age women use combined hormonal products, and many do so to achieve important noncontraceptive benefits. We know that discontinuation and incorrect use of combined oral contraceptives often result in unintended pregnancy, a condition with a substantially higher absolute risk of VTE. We also know that tolerability increases compliance and continuation with use. Although we don’t have Diane® in the United States, we do have combined pills with regulatory approval for the treatment of acne, premenstrual dysphoric disorder, and heavy menstrual bleeding. Although additional well-designed randomized comparator studies are needed to determine if these indications are unique, most clinicians recognize that tolerability of products is highly individual and that a range of different formulations provides the best option in female health care.
At the same time, the least expensive pills on the market are generic LNG, norethindrone, and norgestimate pills. These are widely available at discount pharmacies for $10 or less per cycle. Most women will tolerate these pills well. From a cost standpoint, it makes sense to recommend generic second-generation pills for all new starts unless other clinical considerations exist. One drawback to the generic pills is convincing data that suggest 24/4 dosing regimens are associated with a lower failure than 21/7 products.8 In the United States, the only approved 24/4 regimens are an expensive, brand-name norethindrone product, and one branded and one slightly less expensive drospirenone pill. Although any pill can be adapted to 24/4 or continuous dosing, the instructions require more time and counseling. Many other women have specific indications to consider use of low-androgen pills as a first-line therapy. Be cautious when prescribing any oral contraceptive to obese women, as they are at increased baseline risk for VTE. For cost, low-androgenicity, and effectiveness, I recommend the 24/4 drospirenone pills to many new starts.
The recent surge in the use of long-acting reversible contraceptive methods has led to a decrease in the prescription of pills by many Ob/Gyn residents. The general safety of combined oral contraceptives has also led to a lack of vigilance by some providers when assessing a woman for suitability for a pill (patch or ring) prescription. Excellent guidance is available through both the World Health Organization and Centers for Disease Control and Prevention medical eligibility criteria (MEC) for contraception. Notably, neither group calls special attention to progestogen type in practice recommendation. Although the MEC provides guidance for a number of medical comorbidities, it is important not to forget the basics when prescribing a combined method. The most commonly overlooked condition is a personal or family history of VTE. Asking about this in a variety of ways (e.g., "have you or anyone in the family ever had a blood clot?" "did your mother or sisters have any complications in their pregnancies?" etc.) should be routine prior to pill prescription, particularly for new starts. Obtaining a blood pressure is also mandatory. Both must be documented.
Moving back to the consensus statement, I think it is important to describe the current situation in plain terms to our patients. I generally approach the topic of pill prescription in terms of efficacy and safety. The pill is about 99% effective when used perfectly, but the real-world effectiveness is only 90% due to the difficulty in taking a pill each day. For this reason, taking the pill in a 24/4 or continuous regimen may make sense. Other factors that can influence success with taking the pill include cost and side effects. Most women will do very well on low-cost generic pills, and these generally should be recommended first. Some women may have baseline concerns about androgen-related side effects such as acne, and this should be taken into account during counseling. Although there are insufficient data to compare various preparations head-to-head, low androgen pills may be preferable under these circumstances. Other medical problems (cyclic mood disorders, heavy bleeding) also should be considered. All combined products carry an increase in risk of VTE that is 2-3 times higher than baseline, but about half as high as the risk seen in pregnancy. However, the absolute baseline risk of a clot in women with no personal or family history is low, so the additional risk due to pill use is only about 2-3 additional cases per 10,000 women. The risk of permanent injury due to a VTE puts the absolute number of affected individuals in the 2-3 per 100,000 to 1 million range, similar in magnitude to the impact of buying a second or third ticket on the chance of winning a lottery. There are some scientific data that suggest the risk of VTE may be slightly higher (1-2 additional nonfatal cases per 10,000 women) in pills containing drospirenone and desogestrel compared to pills containing LNG and norgestimate. The FDA has provided some of this information in the package inserts of drospirenone pills. During the clinical encounter, you and your patient need to decide on her priorities and goals for prescription of a combined hormonal method, and you should carefully document both the pertinent positive and negative findings on your history and exam, and the clinical decision-making used to choose a product. I believe this practice provides protection to you and choice to your patient.