In users of 2nd generation combined oral contraceptives (COCs), the incidence of venous thromboembolism (VTE) is estimated to be about 5 to 7 cases per 10 000 women-years of use. This translates into a mortality rate of 5 to 12 deaths per million women-years of use. In users of 3rd generation COCs the incidence of VTE is estimated to be about 6 to 12 cases per 10 000 women-years of use depending on the type of the progestogen used. 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.
A study 2 assessed the associations between systemic hormonal contraceptives and the risk of VTE in Finland.All fertile-aged women (15-49 years) using hormonal contraception (HC) in 2017 and their 1:1 age- and residence-matched controls not using HC (altogether 587 559 women) were selected from the Prescription Centre. All incident VTE cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design.Altogether, 1334 VTE cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% CI 1.08 to 1.20), with an incidence rate ratio of HC vs no HC use of 1.42 (95% CI 1.27 to 1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (EE) (adjusted odds ratio [aOR] 2.85; 95% CI 1.62 to 5.03), drospirenone and EE (aOR 1.55; 95% CI 0.98 to 2.44), desogestrel and EE (aOR 1.97; 95% CI 0.99 to 3.92), and transdermal patch releasing norelgestromin and EE (aOR 5.10; 95% CI 1.12 to 23.16), as well as continuing the use of gestodene and EE (aOR 2.60; 95% CI 1.61 to 4.21), drospirenone and EE (aOR 1.55; 95% CI 1.02 to 2.37), cyproterone-acetate and estrogen/EE (aOR 1.66; 95% CI 1.06 to 2.61), and vaginal ring releasing etonogestrel and EE (aOR 3.27; 95% CI 1.95 to 5.48) were associated with VTE risk. The highest risk was associated with current use (vs non use in the previous 180 days) of EE-containing preparations (aOR 2.20; 95% CI 1.82 to 2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04 to 1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with VTE risk after exclusion of cyproterone-acetate and estrogen/EE (aOR 1.05; 95% CI 0.66 to 1.66).
In a nationwide cohort study (Danish national registries) 5 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 EE, 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 HC, 11.0 (9.6 to 12.6) in women using high risk HC, 7.9 (5.9 to 10.6) in those using medium risk HC, and 4.5 (2.6 to 8.1) in users of low/no risk HC. The corresponding numbers of extra VTEs 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 HC, 23 (19 to 27) in women using high risk HC, 11 (7 to 15) in those using medium risk HC, and 3 (0 to 5) in users of low/no risk HC.
A systematic review and meta-analysis 6 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 COCs, 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.
A Cochrane review [Abstract] 3 included 25 observational studies (13 case-control, 9 cohort, and 3 nested case-control designs) with a total over 10 000 000 women years. Incidence of VTE in non-users from 2 included cohorts was 0.19 and 0.37 per 1 000 person years. Use of COCs increased the risk of VTE compared with non-use (relative risk 3.5, 95% CI 2.9 to 4.3). A dose related effect of EE was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.
A meta-analysis 4 assessed the thrombosis risk in thrombophilic COC-users. 12 case-control and 3 cohort studies were included. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). In COC-users, mild thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95%CI 4.21 to 8.23) and severe 7-fold (RR, 7.15; 95% CI, 2.93 to 17.45). The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). The investigators conclude that the additive VTE risk of mild thrombophilia is modest.
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