According to the EMA's Pharmacovigilance Risk Assessment 3 the overall adjusted odds ratio for 3rd and 4th versus 2nd generation oral contraceptives (COCs) was 1.5 to 2.0 fold. The risk is lowest with the COCs containing the progestogens levonorgestrel, norgestimate and norethisterone: it is estimated that each year there will be 5 to 7 cases of VTE per 10 000 women who use these COCs. The risk is estimated to be higher with the progestogens etonogestrel and norelgestromin, with 6 to 12 cases yearly per 10 000 women. The risk is also estimated to be higher with the progestogens gestodene, desogestrel, drospirenone, with 9 to 12 cases yearly per 10 000 women. For COCs containing chlormadinone, dienogest and nomegestrol, the available data are insufficient. For comparison, in women who are not using COCs and who are not pregnant, there will be around 2 cases of VTE each year per 10000 women.
The incidence of VTE in women not using COCs and aged 15-44 years is 2 cases per 10 000 women-years. In pregnancy 2, the incidence is estimated as 10-20 cases per 10 000 pregnancies. It is expected that 20% of the women affected by a VTE will develop a disabling post-thrombotic syndrome. The most serious complication of VTE is pulmonary embolism which occurs in about 10% of the cases.
The excess risk for users of third generation oral contraceptives over second generation preparations was estimated to be 1.5 per 10 000 woman years. Among new users the incidence would be 6.6 per 10 000 woman years.
Another meta-analysis2 from similar study material confirms these conclusions. The summary relative risk (95% CI) was 1.7 (1.3-2.1). The incremental risk of VTE was estimated to be about 1.1 per 10 000 women per year. An association was present when accounting for duration of use and when restricted to the first year of use in new users.
Another Cochrane review [Abstract] 4 included 25 observational studies (13 case-control, 9 cohort, and 3 nested case-control designs) with a total over 10 000 000 women years. The relative risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol (EE) and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.
A meta-analysis 5 included 22 articles. The use of COCs containing cyproterone acetate, desogestrel, drospirenone, or gestodene was associated with a significantly increased risk of VTE compared with the use of levonorgestrel-containing COCs (pooled risk ratios 1.5-2.0). The analysis restricted to monophasic COC formulations with 30 μg of ethinyl estradiol yielded similar findings. After adjustment for study characteristics, the risk estimates were slightly attenuated.
A database cohort study 6 included 4 945 088 women aged 15-49 years. 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years) were observed. After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% CI 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel.
A systematic review and meta-analysis 9 including 17 studies (11 case-control and 6 cohort studies) assessed VTE risk considering both progestogen type and estrogen dose. The pooled RR of VTE was associated with various COC, with the association depending on their respective estrogen dose and progestogen type. Compared to the reference, levonorgestrel with 30-40 μg EE, the overall risk of VTE was higher for all other COC. Preparations with desogestrel with 30-40 μg EE showed the highest relative risk (RR 1.46; 95% CI 1.33 to 1.59), while RRs for drospirenone (30-40 μg EE) and desogestrel (30-40/20 μg EE) were lower. COC containing gestodene and cyproterone with 30-40 μg EE showed the lowest risk (RR 1.27; 95% CI 1.15 to 1.41 and RR 1.29; 95% CI 1.12 to 1.49, respectively).
A case-control analysis 7 using German claims data included a total of 1166 cases of VTE matched to 11 660 controls nested in a cohort of 677 331 girls and young women after a 1-year period without any COCsin a cohort of new users of COCs. Compared with levonorgestrel with low EE (<50 μg), the risk of VTE was increased 2-fold for COCs containing dienogest (aOR 2.23, 95% CI 1.77 to 2.80), cyproterone (aOR 2.15, 95% CI 1.43 to 3.25), chlormadinone (aOR 2.06, 95% CI 1.58 to 2.68), desogestrel (aOR 1.93, 95% CI 1.44 to 2.61) and drospirenone (aOR 1.89, 95% CI 1.41 to 2.55), and increased 5-fold for gestodene (aOR 5.05, 95% CI 1.23 to 20.74). For norgestimate and nomegestrol, the point estimates suggest a 2-fold increased risk (aOR 1.90, 95% CI 0.62 to 5.81) and 40% increased risk (aOR 1.41, 95% CI 0.52 to 3.81), respectively.
Another nested matched case-control study 8 included 1405 women with incident acute VTE (case group), were matched to 107 025 women without prior VTE (control group). Current use of higher-dose progestogens was significantly associated with increased odds of VTE compared with nonuse (oral norethindrone acetate: adjusted odds ratio [aOR] 3.00, 99% CI 1.96 to 4.59; DMPA: aOR 2.37, 99% CI 1.95 to 2.88; and oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41 to 2.80). Current use of other progestogens was not significantly different from nonuse (LNG-IUD, etonogestrel implant, and oral progesterone) or had reduced odds of VTE (oral norethindrone).
In a nationwide cohort study (Danish national registries) 10 2 million women were followed for 21 million person years, 8710 VTEs occurred. Contraceptives were defined for risk groups. High risk: combined oestrogen and progestin patch, vaginal ring, and tablets containing 50 µg ethinyl oestradiol, or the progestins desogestrel, gestodene, drospirenone, or cyproterone. Medium risk: all other COCs and the medroxyprogesterone injection. Low/no risk progestin-only tablets, implants, and LNG-IUD. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of VTE of 7.2 (95% CI 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception.
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