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Newer oral contraceptive combinations associated with higher VTE risk
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Newer preparations of oral contraceptives increased the risk for venous thromboembolism compared with second-generation drugs, according to study results.
Although oral contraceptives are known to increase the risk for VTE, the risk of individual third-generation drugs had not been quantified, according to study background. Previous analyses have also been inconclusive on the risk for VTE with combinations of these drugs.
Yana Vinogradova, a research fellow and statistician at the University of Nottingham, United Kingdom, and colleagues sought to quantify the associations between the use of combined oral contraceptives and VTE risk, adjusting for comorbidities and other factors.
Yana Vinogradova
“VTE risks associated with different progestogens used in combined oral contraceptives fall into two distinct groups,” Vinogradova told HemOnc Today. “Newer formulations, containing drospirenone, desogestrel, gestodene or cyproterone are associated with risks from 1.5 to 1.8 times higher than older ones using levonorgestrel, norethisterone or the relatively newer norgestimate. All, however, remain relatively safe in terms of their VTE risk — in particular much safer than pregnancy terminations or pregnancy itself.”
The researchers evaluated data from two nested case-controlled studies that tracked U.K. women aged 15 to 49 years who had a first diagnosis of VTE from 2001 to 2013 using the Clinical Practice Research Datalink (n = 5,062) and QResearch primary care database (n = 5,500). Researchers matched the women from the Clinical Practice Research Datalink to 19,638 controls and the women from the QResearch primary care database to 22,396 controls based on age, practice and calendar year.
Researchers defined current exposure to oral contraceptives as use within the last 28 days.
Overall, current exposure to any combination of oral contraceptives increased the risk for VTE when compared with no exposure in the previous 12 months in analyses adjusted for smoking status, alcohol consumption, ethnic group, BMI, comorbidities and other contraceptive drugs (OR = 2.97; 95% CI, 2.78-3.17).
Current exposure to desogestrel (OR = 4.28; 95% CI, 3.66-5.01), gestodene (OR = 3.64; 95% CI, 3.00-4.43), drospirenone (OR = 4.12; 95% CI, 3.43-4.96) and cyproterone (OR = 4.27; 3.57-5.11) significantly increased the risk for VTE compared with the second-generation drugs levonorgestrel (OR = 2.38; 95% CI, 2.18-2.59), norethisterone (OR = 2.56; 95% CI, 2.15-3.06) and norgestimate (OR = 2.53; 95% CI, 2.17-2.96).
The number of extra cases of VTE annually per 10,000 treated women was highest for desogestrel and cyproterone (14; 95% CI, 11-17 for both) and lowest for levonorgestrel (6; 95% CI, 5-7) and norgestimate (6; 95% CI, 5-8).
“In absolute terms, on average only one in 766 women taking the newest progestogen —drospirenone — is likely to be diagnosed with a VTE, whereas, for the older levonorgestrel, this would be one in 1,739 women,” Vinogradova said.
The researchers noted these data are limited by the potential for misclassifications of exposure to combined contraceptives because data do not indicate when women started taking the drug, or if they took it at all. The researchers also wrote some uncertainty exists for women who may have delayed the start of their use of the oral contraceptives, which could have increased the number of cases analyzed or women who stopped using the contraceptives before the current use period.
“Older contraceptives also have other side effects such as depression, headache, weight gain and inter-menstrual bleeding, so the overall health issues of each prospective user need consideration when selecting the most appropriate such drug,” Vinogradova said.
Still, Vinogradova believes these data provide sufficient adjustment to confounding factors to be considered an important study to clarify VTE risk.
“Our study provides the most reliable information to date for doctors, patients and health authorities developing prescribing guidelines,” Vinogradova said. “In particular, along with the Danish study (Lidegaard O, et al. BMJ. 2011;doi:10.1136/bmj.d6423) and a U.S. study (Jick SS, et al. Contraception. 2006;73:566-70), our results confirm the similarity of risks for levonorgestrel and norgestimate in a U.K. context.” – by Anthony SanFilippo
For more information:
Yana Vinogradova can be reached at the University of Nottingham, Nottingham NG7 2RD, United Kingdom; email: yana.vinogradova@nottingham.ac.uk.
Disclosure: Vinogradova reports no relevant financial disclosures. One researcher reports an employment relationship with ClinRisk.
Perspective
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Harry S. Jacob, MD, FRCPath(Hon)
A flurry of lawsuits — particularly involving drospirenone as the progestin combined with ethinyl estradiol (eg, Yasmin [Bayer], Yaz [Bayer], etc) or less prevalent with estradiol (Angeliq, Bayer) — emphasize the increased thrombotic risk of these new combination contraceptives. The work of Vinogradova and colleagues provides important information that perhaps will reduce this risk. Combination estrogens with levonorgestrel (eg, Altavera [Sandoz]) would seem to be a very good substitute with roughly half the thrombotic propensity. However, much more important, catastrophic thromboses are more than 10 times more likely to occur in patients with co-factors such as smoking, obesity, past history of thromboses or migraine headaches, diabetes etc. Many of the malpractice suits involving Yaz use, in fact, have involved patients with one or more of these cofactors rather than in factor-naive patients.
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