EVRA and Venous Thrombosis

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Two case-control studies produce conflicting results regarding the risk of venous thrombosis with the contraceptive patch.

Source: Jick SS, et al. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception. 2006;73:223-228.

Jick and colleagues, epidemiologists at Boston University School of Medicine, performed a case-control study of nonfatal venous thrombosis using information derived from a very large database that records prescriptions and diagnoses longitudinally in managed health care plans. The study over a 3-year time period compared new users of the contraceptive patch with new users of an oral contraceptive containing 35 µg ethinyl estradiol and norgestimate. Sixty eight cases of venous thrombosis and 266 controls were identified and matched for year of birth and for the date of the thrombotic episode (thus providing comparable dates for exposure). A comparison of the patch to the oral contraceptive indicated no difference in the risk of venous thrombosis:

A strength of the current report is that only new users were studied, eliminating the problem known as attrition of susceptibles (comparing new users to old users would be comparing 2 different groups of subjects). Adjusting for age, duration of exposure, hospitalization or non-hospitalization, and frequency of health care visits did not change the result. The risk for nonfatal venous thrombosis was similar in new users of the contraceptive patch compared with new users of oral contraceptives. An analysis for myocardial infarction and stroke risks in the database will be reported in the future.

Commentary

The US Food and Drug Administration issued a press release on November 10, 2005 calling attention to the fact that women using the oral contraceptive patch are exposed over time to a greater amount of estrogen. Subsequently, the patch labeling was updated to include a warning about this higher exposure.

Here are the facts:

  1. The contraceptive patch delivers daily 20 µg ethinyl estradiol and 150 mg norelgestromin (the primary active metabolite of orally administered norgestimate).
  2. The serum ethinyl estradiol concentration averages 50 pg/mL, with a range of 25 to 75 pg/mL.1,2
  3. The peak estrogen blood levels with the contraceptive patch are about 25% to 35% lower compared with oral products containing 30 µg or 35 µg ethinyl estradiol.3,package label
  4. Over time, patch users are exposed to about 60% more estrogen compared with an oral product containing 35 µg ethinyl estradiol.

Which is more important, a higher peak level or greater exposure over time? Or maybe it doesn’t make a difference. The first concern that there might be an increased risk of venous thrombosis with the patch was a consequence of reports in the media based on anecdotal reports provided to the FDA (a numerator without a denominator). Johnson & Johnson, the parent company for the EVRA patch, provided research funds for 2 epidemiologic studies. One is the case-control study reported above, the other is a case-control study that has not yet been published, but results were publicized by the FDA. The unpublished study using information from a different medical insurance database apparently had a different conclusion compared with the published report, a 2-fold increase in risk for non-fatal venous thrombosis compared with a 35 µg ethinyl estradiol oral contraceptive. The unpublished study is also assessing the risks of myocardial infarction and stroke, and thus far, has found no increase in either.

Comparison to OCs

It is difficult to make a valid comparison prior to the publication of the second study; however, the FDA has stated that the confidence intervals overlap and both studies may indicate no increased risk compared to oral contraceptives. (www.medpagetoday.com/Neurology/Strokes/tb/2697).

So where does that leave clinicians and patients? These are the first epidemiologic data on this important issue. One study is reassuring, one is disturbing. But note that the confidence interval in the second study is relatively wide, indicating imprecision of the conclusion. Overall, the results do not support a unique, adverse impact of the contraceptive patch on the risk of venous thrombosis.

I believe the strategy of the FDA in issuing press releases and making conclusions public before the publications are available for assessment by clinicians is harmful. Meaningful decision-making by patients and clinicians requires careful appraisal of published reports. Clinical decisions should not be based on FDA sound bites! At this point in time, there is little evidence that the contraceptive patch has a greater risk of venous thrombosis.

References

  1. Abrams LS, et al. Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception. 2001;64:287-294.
  2. Abrams LS, et al. Pharmacokinetics of a contraceptive patch (Evra/Ortho Evra) containing norelgestromin and ethinyloestradiol at four application sites. Br J Clin Pharmacol. 2002;53:141-146.
  3. van den Heuvel MW, et al. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72:168-174.