When prescribing combined oral contraceptives, choose one containing levonorgestrel and low-dose estrogen (20 mcg) to minimize the risks of pulmonary embolism, ischemic stroke, and myocardial infarction

Coe, Catherine

Lam, Yee

Mounsey, Anne

Prasad, Shailendra

University of Missouri: MOspace

454 THE JOURNAL OF FAMILY PRACTICE  |   JULY 2017  |   VOL 66, NO 7Priority Updates from the Research Literature from the Family Physicians Inquiries NetworkPURLs®Yee Lam, MD, PhD; Catherine Coe, MD; Anne Mounsey, MDUniversity of North Caro-lina School of Medicine, Department of Family Medicine, Chapel HillD E P U T Y  E D I T O RShailendra Prasad, MBBS, MPHUniversity of Minnesota, Department of Family Medicine and Community Health, St. Cloud Which combined OC to prescribe with CV safety in mind? With various formulations available, which combined OC should you recommend to minimize not only the risk of PE, but also the risk of stroke and MI?PRACTICE CHANGERWhen prescribing combined oral contracep-tives, choose one containing levonorgestrel and low-dose estrogen (20 mcg) to minimize the risks of pulmonary embolism, ischemic stroke, and myocardial infarction.STRENGTH OF RECOMMENDATION B: Based on a good quality, patient-oriented cohort study.Weill A, Dalichampt M, Raguideau F, et al. Low dose oestrogen com-bined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ. 2016;353:i2002.1ILLUSTRATIVE CASE A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend? When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” fa-vorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events. In general, when compared with nonus-ers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial in-farction (MI) and stroke.2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.2-6In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.7 The US Food and Drug Administra-tion (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits be-fore prescribing contraceptives containing drospirenone.8 The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informa-tional gap by providing risk estimates for the various COC options.STUDY SUMMARYOne combined oral contraceptive comes out ahead The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmo-nary embolism (PE), ischemic stroke, and MI.1 Data were collected from the French national health insurance database and the French national hospital discharge database.9,10 The study included just under 5 million women 455JFPONLINE.COM VOL 66, NO 7  |  JULY 2017  |  THE JOURNAL OF FAMILY PRACTICECONTINUED15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012. The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, ges-todene). The relative risk (RR) was adjusted for confounding factors, including age, com-plimentary universal health insurance, socio-economic status, hypertension, diabetes, and consultation with a gynecologist in the previ-ous year. ❚ The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose es-trogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143. Compared with levonorgestrel, desoges-trel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest over-all risks of PE and arterial thromboembolism.WHAT’S NEW?Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditionsPrior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is as-sociated with the lowest risks of PE, MI, and ischemic stroke.CAVEATSA cohort study, no contraceptive start date, and incomplete tobacco use dataThis is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large popula-tion, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is high-est in the first 3 months to one year of COC use.12 Data on tobacco use, a significant inde-pendent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.3,13CHALLENGES TO IMPLEMENTATIONLow-dose estrogen is associated with increased vaginal spottingOne potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estro-gen are associated with spotting in approxi-mately two-thirds of menstrual cycles over the course of a year.14 That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estro-gen pill.                     JFPACKNOWLEDGEMENTThe PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsi-bility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved. References 1.  Weill A, Dalichampt M, Raguideau F, et al. Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ. 2016;353:i2002. 2.  Lidegaard Ø, Løkkegaard E, Svendsen AL, et al. Hormonal contra-ception and risk of venous thromboembolism: national follow-up study. BMJ. 2009;339:b2890.Oral  contraceptives containing  levonorgestrel and low-dose  estrogen  resulted in the lowest overall risks of PE and arterial throm-boembolism.456 THE JOURNAL OF FAMILY PRACTICE  |   JULY 2017  |   VOL 66, NO 7PURLs® 3.  Lidegaard Ø, Løkkegaard E, Jensen A, et al. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366:2257-2266. 4.  Stegeman BH, de Bastos M, Rosendaal FR, et al. Different com-bined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347: f5298.  5.   US Food and Drug Administration. Combined Hormonal Con-traceptives (CHCs) and the Risk of Cardiovascular Disease End-points. Available at: https://www.fda.gov/downloads/drugs/drugsafety/ucm277384. Accessed February 23, 2017.   6.  Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism in women taking ethinyl estradiol/drospirenone and other oral contraceptives. Obstet Gynecol. 2007;110:587-593. 7.  European Medicines Agency. PhVWP Monthly report on safety concerns, guidelines and general matters. 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Re-port/2012/01/WC500121387.pdf. Accessed February 23, 2017. 8.  US Food and Drug Administration. FDA Drug Safety Communi-cation: Updated information about the risk of blood clots in wom-en taking birth control pills containing drospirenone. 2012. Avail-able at: https://www.fda.gov/Drugs/DrugSafety/ucm299305.htm. Accessed February 23, 2017.  9.  Tuppin P, de Roquefeuil L, Weill A, et al. French national health insurance information system and the permanent beneficiaries sample. Rev Epidemiol Sante Publique. 2010;58:286-290. 10.  Moulis G, Lapeyre-Mestre M, Palmaro A, et al. French health in-surance databases: what interest for medical research? Rev Med Interne. 2015;36:411-417. 11.  Farmer RD, Lawrenson RA, Thompson CR, et al. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997;349:83-88. 12.  Lidegaard Ø, Nielsen LH, Skovlund CW, et al. Risk of venous thromboembolism from use of oral contraceptives contain-ing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011;343:d6423. 13.  Zhang G, Xu X, Su W, et al. Smoking and risk of venous thrombo-embolism: a systematic review. Southeast Asian J Trop Med Public Health. 2014;45:736-745. 14.  Akerlund M, Røde A, Westergaard J. Comparative profiles of re-liability, cycle control and side effects of two oral contraceptive formulations containing 150 micrograms desogestrel and either 30 micrograms or 20 micrograms ethinyl oestradiol. Br J Obstet Gynaecol. 1993;100:832-838.A SPECIAL SUPPLEMENT TO Hot Topics in Primary CareDiscussion of primary care topics includes expert insight into: •  Biologics, Biosimilars, and Generics•  Community-Acquired Bacterial Pneumonia•   Cardiovascular Safety of Medications for Type 2 Diabetes Mellitus•  Dual therapy for Type 2 Diabetes Mellitus•  GLP-1R Agonists •  Medication Adherence in Type 2 Diabetes Mellitus•  NSAIDs•  Sublingual ImmunotherapyThis supplement is sponsored by Primary Care Education Consortium. -Irritable Bowel Syndrome -Liver Disease FREE 2.0 CME CREDITThis supplement can be found in the Education Center on the JFP website or directly at www.mdedge.com/jfponline/hottopics2017FAMILYPRACTICETHE JOURNAL OFHotTopics half page ad.indd   1 6/20/17   10:08 AM

Which combined oral contraceptives to prescribe with cardiovascular safety in mind?

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