Etiology
Review: Contemporary oral contraceptives are associated with venous thromboembolism and stroke
Peragallo Urrutia R, Coeytaux RR, McBroom AJ, et al. Risk of acute thromboembolic events with oral contraceptive use: a systematic review and meta-analysis. Obstet Gynecol. 2013;122:380-9.
Clinical impact ratings: F ★★★★★✩✩ H ★★★★★✩✩ Question Are contemporary oral contraceptive pills (OCPs) associated with acute thromboembolic events?
Review scope Included studies compared use of OCPs for contraception or primary prevention of ovarian cancer with other OCP formulations, use of contraception other than OCPs, or no contraceptive use, and reported on venous thromboembolism (VTE) (deep VTE or pulmonary embolism), stroke, or myocardial infarction. Studies that only reported outcomes related to use of OCPs for postcoital contraception or in specialized populations, or that did not report length of OCP use or OCP formulation, were excluded.
but not third- (OR 1.34, CI 0.91 to 1.98), generation progestins were associated with myocardial infarction.
Conclusion Current use of contemporary oral contraceptive pills is associated with venous thromboembolism and ischemic stroke. Sources of funding: Agency for Healthcare Research and Quality and Centers for Disease Control and Prevention, US Department of Health and Human Services. For correspondence: Dr. R. Peragallo Urrutia, University of North Carolina School of Medicine, Chapel Hill, NC, USA. E-mail [email protected]. ■
Commentary
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and reference lists of key review articles (1995 to Jun 2012) were searched for peer-reviewed, published controlled studies and pooled individual patient data meta-analyses published on or after 1 Jan 1995. Nonrandomized studies of < 100 patients were excluded. 83 articles reporting 50 studies met the selection criteria. OCPs were used for contraception in all studies. 4 studies included patients from the USA. The comparison group of noncurrent OCP users comprised former and never users. Study quality, assessed using Agency for Healthcare Research and Quality criteria, varied from poor to good.
Main results Current use of OCPs (overall and low- and high-estrogen doses) was associated with increased risk for VTE and ischemic stroke; current use was not associated with hemorrhagic stroke or myocardial infarction (Table). First- (odds ratio [OR] 4.06, 95% CI 2.66 to 6.19), second- (OR 3.28, CI 2.49 to 4.31), third- (OR 4.06, CI 3.09 to 5.32), and fourth- (OR 5.36, CI 2.78 to 10.32) generation progestins were associated with VTE. First- (OR 3.37, CI 2.04 to 5.54) and second- (OR 1.79, CI 1.16 to 2.75),
Estrogen-containing OCPs are the most commonly prescribed drugs in young women, with the greatest risk being thrombosis. In their review of 50 studies of OCPs over the past 17 years, Peragallo Urrutia and colleagues found that OCPs are associated with increased venous thrombosis and stroke but not myocardial infarction. Thromboembolic risk did not differ by estrogen dose or type of progestin. Although the increased risk seems ominous, it should be put in the context of the very low baseline thrombosis rate in young women (1 to 5/10 000). The review estimates a number needed to harm of 300 for venous thrombosis over 5 years of OCP use. In addition, the thrombosis rate of 1 to 2/1000 in pregnancy needs to be considered when weighing risks; although OCPs double the risk for stroke, the risk is 3 to 8 times greater during pregnancy.
Women with thrombosis risk factors may have been excluded from the studies included in this review. Patients with a history of venous thrombosis may have up to a 5 times greater risk for recurrence with OCPs (1). The baseline risk for thrombosis increases with age, so a 40-year-old woman with a baseline risk of approximately 10/10 000 may have up to a 1/500 increased risk for thrombosis with OCPs. Such traditional arterial risk factors as diabetes, smoking, and lipids increase risk for arterial Association between current use of oral contraceptive pills and acute events with OCPs. Obesity, a risk factor for thrombosis, thromboembolic events* also increases risk for thrombosis with OCPs (2). Contraceptive rings and patches carry similar risks Outcomes Estrogen Number Women-y in Odds ratio (95% CI) dose of studies exposed/unexposed for thrombosis as OCPs. The levonorgestrel-releasing groups intrauterine device does not increase thrombosis and Venous All 14 3 888 193/6 018 697 2.97 (2.46 to 3.59) should be considered for women who desire contrathromboembolism ception but have thrombosis risk factors (3, 4). Low (20 to 40 µg)
3
NA
3.39 (2.32 to 4.96)
High (50 µg)
3
NA
3.06 (1.32 to 7.10)
Ischemic stroke
All
7
186 848/123 716
1.90 (1.24 to 2.91)
Ischemic or undifferentiated stroke
All
9
186 848/123 716
2.15 (1.49 vs 3.11)
Low
3
NA
1.73 (1.29 to 2.32)
High
3
NA
4.10 (1.91 to 8.80)
Hemorrhagic stroke
All
4
NA
1.03 (0.71 to 1.49)
Myocardial infarction
All
8
186 910/123 716
1.34 (0.87 to 2.08)
*NA = not available; CI defined in Glossary. Comparator was noncurrent use of oral contraceptive pills (never users and former users).
17 December 2013 | ACP Journal Club | Volume 159 • Number 12
Thomas DeLoughery, MD, FACP, FAWM Oregon Health Science University Portland, Oregon, USA References 1. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. JAMA. 2005;293:2352-61. 2. Pomp ER, le Cessie S, Rosendaal FR, Doggen CJ. Br J Haematol. 2007;139:289-96. 3. van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. Arterioscler Thromb Vasc Biol. 2010;30:2297-300. 4. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. BMJ. 2009;339:b2890. © 2013 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929454/ by a University of California San Diego User on 01/24/2017
JC11
Review: Contemporary oral contraceptives are associated with venous thromboembolism and stroke
Peragallo Urrutia R, Coeytaux RR, McBroom AJ, et al. Risk of acute thromboembolic events with oral contraceptive use: a systematic review and meta-analysis. Obstet Gynecol. 2013;122:380-9.
Clinical impact ratings: F ★★★★★✩✩ H ★★★★★✩✩ Question Are contemporary oral contraceptive pills (OCPs) associated with acute thromboembolic events?
Review scope Included studies compared use of OCPs for contraception or primary prevention of ovarian cancer with other OCP formulations, use of contraception other than OCPs, or no contraceptive use, and reported on venous thromboembolism (VTE) (deep VTE or pulmonary embolism), stroke, or myocardial infarction. Studies that only reported outcomes related to use of OCPs for postcoital contraception or in specialized populations, or that did not report length of OCP use or OCP formulation, were excluded.
but not third- (OR 1.34, CI 0.91 to 1.98), generation progestins were associated with myocardial infarction.
Conclusion Current use of contemporary oral contraceptive pills is associated with venous thromboembolism and ischemic stroke. Sources of funding: Agency for Healthcare Research and Quality and Centers for Disease Control and Prevention, US Department of Health and Human Services. For correspondence: Dr. R. Peragallo Urrutia, University of North Carolina School of Medicine, Chapel Hill, NC, USA. E-mail [email protected]. ■
Commentary
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and reference lists of key review articles (1995 to Jun 2012) were searched for peer-reviewed, published controlled studies and pooled individual patient data meta-analyses published on or after 1 Jan 1995. Nonrandomized studies of < 100 patients were excluded. 83 articles reporting 50 studies met the selection criteria. OCPs were used for contraception in all studies. 4 studies included patients from the USA. The comparison group of noncurrent OCP users comprised former and never users. Study quality, assessed using Agency for Healthcare Research and Quality criteria, varied from poor to good.
Main results Current use of OCPs (overall and low- and high-estrogen doses) was associated with increased risk for VTE and ischemic stroke; current use was not associated with hemorrhagic stroke or myocardial infarction (Table). First- (odds ratio [OR] 4.06, 95% CI 2.66 to 6.19), second- (OR 3.28, CI 2.49 to 4.31), third- (OR 4.06, CI 3.09 to 5.32), and fourth- (OR 5.36, CI 2.78 to 10.32) generation progestins were associated with VTE. First- (OR 3.37, CI 2.04 to 5.54) and second- (OR 1.79, CI 1.16 to 2.75),
Estrogen-containing OCPs are the most commonly prescribed drugs in young women, with the greatest risk being thrombosis. In their review of 50 studies of OCPs over the past 17 years, Peragallo Urrutia and colleagues found that OCPs are associated with increased venous thrombosis and stroke but not myocardial infarction. Thromboembolic risk did not differ by estrogen dose or type of progestin. Although the increased risk seems ominous, it should be put in the context of the very low baseline thrombosis rate in young women (1 to 5/10 000). The review estimates a number needed to harm of 300 for venous thrombosis over 5 years of OCP use. In addition, the thrombosis rate of 1 to 2/1000 in pregnancy needs to be considered when weighing risks; although OCPs double the risk for stroke, the risk is 3 to 8 times greater during pregnancy.
Women with thrombosis risk factors may have been excluded from the studies included in this review. Patients with a history of venous thrombosis may have up to a 5 times greater risk for recurrence with OCPs (1). The baseline risk for thrombosis increases with age, so a 40-year-old woman with a baseline risk of approximately 10/10 000 may have up to a 1/500 increased risk for thrombosis with OCPs. Such traditional arterial risk factors as diabetes, smoking, and lipids increase risk for arterial Association between current use of oral contraceptive pills and acute events with OCPs. Obesity, a risk factor for thrombosis, thromboembolic events* also increases risk for thrombosis with OCPs (2). Contraceptive rings and patches carry similar risks Outcomes Estrogen Number Women-y in Odds ratio (95% CI) dose of studies exposed/unexposed for thrombosis as OCPs. The levonorgestrel-releasing groups intrauterine device does not increase thrombosis and Venous All 14 3 888 193/6 018 697 2.97 (2.46 to 3.59) should be considered for women who desire contrathromboembolism ception but have thrombosis risk factors (3, 4). Low (20 to 40 µg)
3
NA
3.39 (2.32 to 4.96)
High (50 µg)
3
NA
3.06 (1.32 to 7.10)
Ischemic stroke
All
7
186 848/123 716
1.90 (1.24 to 2.91)
Ischemic or undifferentiated stroke
All
9
186 848/123 716
2.15 (1.49 vs 3.11)
Low
3
NA
1.73 (1.29 to 2.32)
High
3
NA
4.10 (1.91 to 8.80)
Hemorrhagic stroke
All
4
NA
1.03 (0.71 to 1.49)
Myocardial infarction
All
8
186 910/123 716
1.34 (0.87 to 2.08)
*NA = not available; CI defined in Glossary. Comparator was noncurrent use of oral contraceptive pills (never users and former users).
17 December 2013 | ACP Journal Club | Volume 159 • Number 12
Thomas DeLoughery, MD, FACP, FAWM Oregon Health Science University Portland, Oregon, USA References 1. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. JAMA. 2005;293:2352-61. 2. Pomp ER, le Cessie S, Rosendaal FR, Doggen CJ. Br J Haematol. 2007;139:289-96. 3. van Hylckama Vlieg A, Helmerhorst FM, Rosendaal FR. Arterioscler Thromb Vasc Biol. 2010;30:2297-300. 4. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. BMJ. 2009;339:b2890. © 2013 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929454/ by a University of California San Diego User on 01/24/2017
JC11
