Bulletin: New information emerges on risks associated with Ortho Evra

New information from two case control studies of the transdermal contraceptive (Ortho Evra, Ortho-McNeil Pharmaceutical, Raritan, NJ) indicates no increased risk of heart attack or stroke for women who choose the patch, but data conflict on the occurrence of venous thromboembolism (VTE).

Results from the first study, which have been published, suggest that risk of nonfatal VTE for the patch is similar to the risk for pills containing similar hormonal components.1 According to the second study, whose interim results were released by the patch’s manufacturer, findings indicate an approximate twofold increase in the risk of VTE in patch users compared with those using a comparable oral contraceptive.2

Julie Keenan, a spokeswoman for Ortho-McNeil, says data from the second study are going to be published later. She says the company decided to release the interim results now "so that physicians would have additional information to consider in making personal decisions with their patients," she says.

The first study used a nested case-control design based on information from PharMetrics, a Watertown, MA-based company that collects and organizes information on claims paid by managed care plans.1 The second study, conducted by i3 Drug Safety, a Basking Ridge, NJ, contract research organization, used information from a large medical insurance claims database for its report.2

Review the history

Clinicians have been fielding patients’ questions following media reports of the April 2004 death of an 18-year-old woman who had been using the transdermal contraceptive and a resulting July 2005 Associated Press analysis of adverse event reports filed with the Food and Drug Administration (FDA).

The FDA revised the transdermal contraceptive’s labeling last November when it added a bolded warning that the patch exposes women to higher total amounts of estrogen than a typical birth control pill containing 35 mcg estrogen.

The dust has not yet settled when it comes to comparing VTE risk between the patch and the Pill, says Andrew Kaunitz, MD, professor and assistant chair in the obstetrics and gynecology department at the University of Florida Health Science Center/ Jacksonville. In keeping with current package labeling, women at high risk for VTE continue not to be appropriate candidates for any combination hormonal contraceptive — whether it be an oral contraceptive, the patch, or the contraceptive vaginal ring (NuvaRing, Organon, West Orange, NJ). These women should consider using progestin-only or intrauterine methods, he advises.

Check published results

Susan Jick, DSc, co-director of the Boston Collaborative Drug Surveillance Program and an associate professor of epidemiology and biostatistics at Boston University School of Public Health, says her research team was contacted by Ortho-McNeil’s parent company, Johnson & Johnson of New Brunswick, NJ, to examine the patch following concerns raised by the FDA. The investigators have conducted similar studies on VTE risk in oral contraceptives.2,3

The study was nested among all women ages 15 to 44 who started the contraceptive patch or norgestimate-containing oral contraceptives with 35 mcg ethinyl estradiol after April 1, 2002. (The patch’s progestin component is norelgestromin, the active metabolite of norgestimate.) Cases involved women with current use of one of these two study drugs and a documented diagnosis of VTE in the absence of identifiable clinical risk factors; up to four controls were matched to each case by age and calendar time.1

Investigators identified 68 newly diagnosed, idiopathic cases of VTE in the study population. In the case-control analysis, the odds ratio comparing the contraceptive patch to norgestimate-35 pill was 0.9 (95% confidence intervals [CI] 0.5-1.6). The overall incidence rate for VTE was 52.8 per 100,000 women-years (95% CI 35.8-74.9) among users of the contraceptive patch and 41.8 per 100,000 women-years among users of norgestimate-35 (95% CI 29.4-57.6).1 The age-adjusted VTE incidence rate ratio for current use of the contraceptive patch vs. norgestimate-35 was 1.1 (95% CI 0.7-1.8).1

What are the strengths of the study? Jick cites four points: it was a formal epidemiological study; it was carefully conducted; it was conducted in a large population; and researchers used well-established methodology.

The current study differs from previous case-control comparisons in that earlier studies3,4 looked at drugs that had been marketed for several years. Because the patch is relatively new to the market, the investigators controlled for the difference by only including women who began use of the norgestimate/ethinyl estradiol pill after April 1, 2002, when the patch was released on the U.S. market, Jick explains.

Use data in counseling

No changes in Evra prescribing practices are warranted based on the current information, according to Vanessa Cullins, MD, vice president for medical affairs at the New York-based Planned Parenthood Federation of America. While the twofold increase in VTE recorded in the second study’s interim report may appear alarming, when one looks at the absolute numbers, the attributable risk is small, she says.

If the results of the second study hold true, the twofold increase in VTE among patch users in absolute numbers would translate into three to four more venous thromboembolism events per 10,000 women-years, explains Cullins. This number represents a very small increase and the benefits of using a contraceptive outweigh this risk for many healthy reproductive-age women who want to initiate or continue Evra, Cullins concludes. Additional research is needed to determine whether Evra users have higher rates of VTE, she notes.

Miriam Zieman, MD, adjunct associate professor of obstetrics and gynecology at Emory University in Atlanta, says until more data are released, clinicians should use more detailed counseling when it comes to the contraceptive patch.

"Until we have more research, we have to consider the possibility of an increased risk," she notes. "This possibility should be discussed during counseling, and women and their providers must weigh the possibility of an increased risk against the benefits that using the patch have for that individual."

References

  1. Jick SS, Kaye JA, Russmann S, et al. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 µg of ethinyl estradiol. Contraception 2006; 73:223-228.
  2. Ortho Women’s Health & Urology. Results of Two Epidemiological Studies Provide Important New Clinical Information about the Safety of ORTHO EVRA®. Press release. Issued Feb. 16, 2006.
  3. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestogen components. Lancet 1995; 346:1,589-1,593.
  4. Jick H, Kaye JA, Vasilakis-Scaramozza C, et al. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: Cohort and case-control analysis. Br Med J 2000; 321:1,190-1,195.