By Suhair Shawar, PharmD, PGY2 EM Pharmacy Resident // Edited by Liz Rozycki, PharmD, Specialty Practice Pharmacist, EM
A 32 year-old female patient presented to the emergency department (ED) with shortness of breath and chest pain. Patient’s work up included ruling out pulmonary embolism (PE). Otherwise healthy, the patient is currently on etonogestrel implant (Nexplanon®) for contraception. The clinical pharmacist in the ED was asked to help with literature search regarding thromboembolic risk associated with etonogestrel implant and other non-oral, hormonal contraceptive therapies.
Hormone contraceptive therapy is known to carry an increased risk for venous thromboembolism (VTE), although the exact risk depends on the specific hormonal components. Studies have demonstrated that the risk of VTE is increased among combined oral contraceptive (COC) users (3–9 cases/10,000 woman-years) compared with non-users who are not pregnant and not taking hormones (1–5 cases/10,000 woman-years) 1. Although estrogen was originally thought to be the only contributor to COC-induced thrombosis, certain progestins also seem to have important effects2. In addition to the dose of estrogen, patient age, and family history, the type of progestin has been identified as a risk factor for contraceptive related VTE. For example, drospirenone poses higher risk for VTE compared to other oral progestin formulations3.
The risk of VTE with patients using non-oral and non-estrogen contraceptives is a topic that clinicians must assess when evaluating patients in the ED. For example, Pulmonary Embolism Rule-out Criteria (PERC) is a clinical decision tool which allows physicians to forego diagnostic testing for PE in a very low-risk population4. Only the use of exogenous estrogen, including NuvaRing, is listed as risk factor in the PERC. Thus, for non-estrogen contraceptive users, a PERC score may not be a reflection of their true PE risk.
The package inserts for some of the most commonly used non-oral contraceptives, including Nexplanon®, Mirena®, Ortho Evra® and NuvaRing® all list a history of or current thromboembolic disorder as a contraindication (Table 1)5,6,7,8. Furthermore, they recommend careful assessment of women with known VTE risk factors before starting therapy.
Table 1. Commonly Prescribed Non-Oral Contraceptive Therapy
|Brand Name||Generic||Hormone type||Delivery system|
|Mirena ®||Levonorgestrel||Progestin||Intrauterine system|
|Ortho Evra ®||Norelgestromin / ethinyl estradiol||Progestin / Estrogen||Transdermal|
|NuvaRing ®||Etonogestrel / ethinyl estradiol||Progestin / Estrogen||Vaginal ring|
Primary Literature Review
In a retrospective cohort of 1,626,158 Danish women aged 15-49 years without a history of VTE, it was noted that women using a subcutaneous etonogestrel implant had a greater risk of VTE than women who do not use hormonal contraception9. During 29,497 woman years in users of the implant, there were 15 VTEs (adjusted relative risk (RR) 2.08, p=0.005). Of these, there were only five confirmed VTEs (adjusted RR1.4, p=0.45) (see Table 2). In addition, the analysis showed that when compared to non-hormone users, women using the transdermal patch and vaginal ring had a six to eight-fold increased risk for VTE. Meanwhile, the use of hormone releasing intrauterine system (IUS) had a protective effect compared with non-hormonal users. Furthermore, in an analysis with women taking COC as the reference group, women using the transdermal patch had increased VTE risk (adjusted RR 1.85, p=0.109), although not statistically significant, and vaginal ring users had increased VTE risk (adjusted RR 1.81, p=0.001). Meanwhile, the risk of VTE was lower for implant users (adjusted RR 0.88, p=0.62), although not statistically significant, and for levonorgestrel IUS users (adjusted RR 0.34, p=0.001).
Table 2: Risk of VTE with Hormonal Contraceptive Therapy9
|All Venous Thrombosis Events||Confirmed Thrombosis Events|
|Incidence per 10,000 exposure years||Adjusted Relative Risk
|P-value||Incidence per 10,000 exposure years||Adjusted Relative Risk
|COC w/norgestimate||6.63||2.63 (2.27 to 3.05)||<0.001||4.52||3.57 (2.98 to 4.27)||<0.001|
|Patch||11.3||4.40 (2.09 to 9.24)||<0.001||9.71||7.9 (3.54 to 17.65)||<0.001|
|Vaginal Ring||10.93||4.29 (3.27 to 5.62)||<0.001||7.75||6.48 (4.69 to 8.94)||<0.001|
|Implant||5.09||2.08 (1.25 to 3.46)||0.005||1.70||1.4
(0.58 to 3.38)
|Levonorgestrel IUS||3.67||0.80 (0.65 to 0.99)||0.040||1.38||0.57 (0.41 to 0.81)||0.002|
|Abbreviations: COC (combined oral contraceptive therapy), IUS (intrauterine system)|
Interestingly, regarding the higher VTE risk with vaginal ring compared to COC, the findings of this epidemiology study conflict with other studies which will be reviewed below. In theory and based on pharmacokinetic data, the vaginal ring is associated with lower systemic exposure to estrogen compared to both transdermal patch and COC, and thus would be expected to have a lower risk of VTE10. While the peak serum levels of estrogen with the patch are only approximately two-thirds as high as that observed with a 35-mcg comparator pill, because the hormone release from the patch is constant, the 24 hour estrogen exposure is about 60% higher than that of the pill.
In a retrospective cohort analysis conducted by the FDA that included 898,251 women aged 10 to 50 years, both the vaginal ring and transdermal patch were associated with a significantly higher risk of VTE compared to COC users with estimated relative risk of 1.5 for both11. However, when the analysis was restricted to new users of hormonal contraceptive therapy, only COC users had significantly higher risk of thromboembolic and arterial thrombotic events. Additionally, when compared to new users, the study found prolonged use (>12 months) of transdermal patch was associated with more than 3-fold increased risk of VTE. In a retrospective cohort of 340,377 women aged 15 to 44 years based on prescription insurance claims, Cole and colleagues found that women who had at least one dispensing of norelgestromin/ethinyl estradiol transdermal patch had more than two-fold increased risk for VTE compared to norgestimate-containing oral contraceptive users12. On the other hand, in a case-control study, Jick and colleagues found that transdermal patch users had similar VTE risk compared to COC (Odd Ratio= 0.9, 95% CI 0.5– 1.6)(13).
In summary, the use of combination hormonal contraceptives increases the risk of VTE. There is conflicting data regarding the exact VTE risk associated with non-oral hormonal contraceptives. There is a growing body of evidence suggesting that the risk of VTE associated with the vaginal ring and transdermal patch is similar or higher than that of COC. However, the use of non-estrogen, non-oral contraceptives is associated with a less clear risk of thromboembolic events. Furthermore, with scoring tools, such as PERC, not accounting for the use of non-estrogen contraceptives as a risk factor for VTE, it is important to note that these patients may actually have a slightly increased risk compared to non-users of hormonal contraceptive therapy.
- Food and Drug Administration. FDA drug safety communication: updated information about the risk of blood clots in women taking birth control pills containing drospirenone. Silver Spring (MD): FDA; 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm299305. Retrieved December 2, 2016.
- van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339:b2921.
- Lidegaard O, Lokkegaard E, Svendsen AL, et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339:b2890.
- Carpenter CR, Keim SM, Seupaul RA, et al. Differentiating low-risk and no-risk PE patients: the PERC score. J Emerg Med 2009; 36:317-322.
- NEXPLANON ® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc; 2001. Revised August 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021529s011lbl.pdf. Retrieved October 31, 2016.
- NUVARING ® [package insert]. Whitehouse Station, NJ; Merck & Co., Inc; 2001. Revised September 2016. Available at: https://www.merck.com/product/usa/pi_circulars/n/nuvaring/nuvaring_pi.pdf. Retrieved December 1, 2016.
- ORTHO EVRA® [package insert]. Raritan, NJ; Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2001. Revised July 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021180s029lbl.pdf. Retrieved December 1, 2016.
- MIRENA® [package insert]. Whippany, NJ; Bayer HealthCare Pharmaceutics, Inc.; 2000. Revised Octover 2015. Available at: http://labeling.bayerhealthcare.com/html/products/pi/Mirena_PI.pdf. Retrieved December 1, 2016.
- Lidegaard O, Nielson L, Skovlund CW, et al. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10. BMJ 2012; 344:e2990.
- van den Heuvel MW, van Bragt AJ, Alnabawy AK, 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.
- Food and Drug Administration. Combined Hormonal Contraceptives (CHCs) and the Risk of Cardiovascular Disease Endpoints. Available at: http://www.fda.gov/downloads/drugs/drugsafety/ucm277384.pdf. Retrieved November 20, 2016.
- Cole JA, Norman H, Doherty M, et al. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007; 109:339-346.
- Jick S, Kaye JA, Li L, et al. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 μg of ethinyl estradiol. Contraception 2007; 76