July 2014

Quite a stir was created in December, 2013, when Vanity Fair magazine published an article in their January, 2014, issue entitled “Danger in the Ring: Why Is Potentially Lethal Contraceptive NuvaRing Still on the Market?” The article, by Vanity Fair writer-at-large Marie Brenner, contains interviews with the parents of a 24-year-old woman who experienced a fatal pulmonary embolism while using NuvaRing. In addition, it profiles Hunter Shkolnik, an attorney who has represented a number of plaintiffs in product liability lawsuits against Merck and Co, the manufacturer of NuvaRing. The article details Shkolnik’s claim that Organon (the pharma company that had developed the NuvaRing) covered up information regarding NuvaRing hormone release rate data, in particular, an allegation that NuvaRing releases “spurts” of estrogen which could account for a higher likelihood of deep vein thrombosis (DVT) and pulmonary embolism (PE). Importantly, the article cites a single study that compared DVT risk in NuvaRing users to users of other combined hormonal contraceptives (Lidegaard, O et. Al, BMJ 2012;344:e2290), while ignoring other much stronger epidemiologic studies. Furthermore, not a single national family planning expert was interviewed or quoted in the article; instead, they described an undercover visit with two clinicians at Planned Parenthood in New York City clinic, who endorsed the use of the NuvaRing in healthy women.

The fact that women who use combined hormonal contraceptives (CHC), including combined oral contraceptives (COC), OrthoEvra patch, and NuvaRing, have an increased risk of venous thromboembolic events (VTE) compared to non-users is well established. The Food and Drug Administration (FDA) mandated patient package insert for every CHC product on the market in the US contains the figure below which compares the absolute risk of VTE in different groups of women. Note that the rate of VTE is computed as the number of women with blood clots per 10,000 women per year.

Lidegaard’s 2012 retrospective study included 9.4 million woman years of observation and reported the rate of confirmed VTE events per 10 000 woman years as follows

• Non-users of hormonal contraception:  2.1
• Transdermal patches:                                       9.7
• Vaginal ring:                                                            7.8

Note that these VTE rates are within the range listed in the FDA Figure (3-12 VTE per 10,000 woman years), so this large study confirmed what was considered to be “conventional wisdom” regarding the VTE risk of CHC products.

However, the Vanity Fair article failed to cite two other well done epidemiologic studies assessed the risk of VTE associated with the use of NuvaRing compared to combined OC users. In these studies, one of which was sponsored by the FDA, NuvaRing users had a VTE similar risk to COC users.

The first, a large prospective, European observational study, (The Transatlantic Active Surveillance on Cardiovascular Safety of NuvaRing [TASC]), investigated the risk of VTE for 33,000 new users of NuvaRing and women starting, switching to, or restarting OCs. (Dinger J, Obstet Gynecol, 2013;122(4):800-808). The women were followed for 24 to 48 months and showed a similar incidence of VTE events per 10,000 woman years

• NuvaRing users                                    (n=16,864)                   8.3
• Using COCs                                              (n=16,431)                   9.2
• Using COCs, except desogestrel  (n=13,811)                   8.9

The second study was a retrospective cohort study using data from 4 health plans in the US, primarily Kaiser Northern California and state Medicaid data from Tennessee and Washington. (Sidney S, et.al, Contraception 2013;87:93-100). They computed the incidence of VTE events per 10,000 woman years as follows

• New users of NuvaRing                                                          11.3
• New users of a levonorgestrel COC                                   9.2
• Users of other available COCs                                              8.2

These two large studies were considered to be the “benchmark studies” used by the FDA when it approved a modification of NuvaRing product labelling in October, 2013. In essence, the FDA’s advice is that the risk of DVT in users of the NuvaRing is about the same as comparator OCs, but is higher than in non-hormone users and less than women who are pregnant or postpartum. As a consequence, the FDA chose not to place any new restrictions on the use of NuvaRing, but instead took the prudent course, through package labeling, of advising both clinicians and consumers of the findings of the best available current research.

What does this mean for clinicians?

• Some studies show that DVT risk is slightly higher with the NuvaRing, compared to a variety of COCs; others do not. The best prospective study concludes that the NuvaRing has no greater risk of DVT than other combined OC.
• The absolute risk of a DVT is low. When discussing this risk with a client, place this in the context of the risk of a DVT in pregnancy and postpartum.
• The increased risk of DVT with all combined hormonal contraceptives is confined to the first year of use.
• If a current NuvaRing user is doing well with her method, there is no need to advise her discontinue it.
• While there has been a voluntary label change of the NuvaRing to include the new studies, there are NO new FDA restrictions on its prescription or advice for use.

As a reminder, there are a variety of medical conditions that increase a woman’s risk of venous thrombotic events. Her risk can be mitigated by considering the client’s risk factors for DVT when you help her choose a hormonal method of contraception. They include

• Personal history of DVT or pulmonary embolism
• Age 35 years or older (45-49 years of age has a 6-fold risk of DVT compared to 15-19 years of age)
• Smoking (about twice the risk of non-smokers)
• Morbid obesity (obesity (body mass index above 35 kg/m² results in a 4-fold risk compared to a woman with a BMI of 20 to 25 kg/m²),
• Hereditary thrombophilia (Factor V Leiden mutation, Factor S and C deficiency, antiphospholipid syndrome
• Less than 21 days postpartum or 21-42 days postpartum with other risk factors
• Major surgery with prolonged immobilization
• Inflammatory bowel disease with active or extensive disease
• Systemic lupus with positive or unknown antiphospholipid antibody status
• Active cancer (metastatic, on therapy, or less than 6 months after clinical remission)

The Vanity Fair article does not change the playing field regarding the safety of the NuvaRing; it was unbalanced, incomplete, and biased. Most importantly, it did not include the perspective of the value of the NuvaRing as a family planning method for women, nor did it make any attempt to point out that the risk of DVT in pregnancy or in the post-partum period is far more than in users of combined hormonal contraceptive methods. Merck’s offer to settle pending NuvaRing product liability suits is a business decision, not a clinical statement about their confidence of the method.

There is risk involved in the use all medications, and the risks of using hormonal contraceptive methods are better understood than most. But, as Robert Reid, MD, noted in a recent editorial in on Oral Hormonal Contraception and Venous Thromboembolism (Contraception 2014;89:235-236):  “While important as potential markers for risk, such isolated post marketing case reports should carry no more weight in clinical decision making or health policy than would individual testimonials about how great a product might be. Medical care and public policy should be based on solid science”.

The FDA has not changed the status of the NuvaRing…and at this time, neither should we.

—Michael S. Policar, MD, MPH, Clinical Professor of Obstetrics, Gynecology and Reproductive Sciences, University of Californiat—San Francisco School of Medicine