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      The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study

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          Abstract

          Objective To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands.

          Design Population based case-control study.

          Setting Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht).

          Participants Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls.

          Main outcome measures First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf’s method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model.

          Results Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives.

          Conclusions Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.

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          Most cited references35

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          Incidence and mortality of venous thrombosis: a population-based study.

          Estimates of the incidence of venous thrombosis (VT) vary, and data on mortality are limited. We estimated the incidence and mortality of a first VT event in a general population. From the residents of Nord-Trøndelag county in Norway aged 20 years and older (n = 94 194), we identified all cases with an objectively verified diagnosis of VT that occurred between 1995 and 2001. Patients and diagnosis characteristics were retrieved from medical records. Seven hundred and forty patients were identified with a first diagnosis of VT during 516,405 person-years of follow-up. The incidence rate for all first VT events was 1.43 per 1000 person-years [95% confidence interval (CI): 1.33-1.54], that for deep-vein thrombosis (DVT) was 0.93 per 1000 person-years (95% CI: 0.85-1.02), and that for pulmonary embolism (PE) was 0.50 per 1000 person-years (95% CI: 0.44-0.56). The incidence rates increased exponentially with age, and were slightly higher in women than in men. The 30-day case-fatality rate was higher in patients with PE than in those with DVT [9.7% vs. 4.6%, risk ratio 2.1 (95% CI: 1.2-3.7)]; it was also higher in patients with cancer than in patients without cancer [19.1% vs. 3.6%, risk ratio 3.8 (95% CI 1.6-9.2)]. The risk of dying was highest in the first months subsequent to the VT, after which it gradually approached the mortality rate in the general population. This study provides estimates of incidence and mortality of a first VT event in the general population.
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            The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation.

            The study was conducted to compare risks of adverse cardiovascular and other events associated with the use of drospirenone (DRSP)-containing oral contraceptives (OCs) and other OCs. The European Active Surveillance study (EURAS) was a multinational, prospective, noninterventional cohort study of new users of DRSP, levonorgestrel (LNG) and other progestin-containing OCs. Semiannual follow-up was based on mailed questionnaires, with additional follow-up procedures when needed. Overall, 58,674 women were followed for 142,475 women-years of observation. Loss to follow-up was 2.4%. Serious adverse and fatal events were rare, and rate ratios were close to unity (1.0). Cox regression analysis of cardiovascular outcomes yielded hazard ratios for DRSP-containing vs. LNG-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively. Risks of adverse cardiovascular and other serious events in users of a DRSP-containing OC are similar to those associated with the use of other OCs.
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              Third generation oral contraceptives and risk of venous thrombosis: meta-analysis.

              To evaluate quantitatively articles that compared effects of second and third generation oral contraceptives on risk of venous thrombosis. Meta-analysis. Cohort and case-control studies assessing risk of venous thromboembolism among women using oral contraceptives before October 1995. Pooled adjusted odds ratios calculated by a general variance based random effects method. When possible, two by two tables were extracted and combined by the Mantel-Haenszel method. The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% confidence interval 1.4 to 2.0; seven studies). Similar risks were found when oral contraceptives containing desogestrel or gestodene were compared with those containing levonorgestrel. Among first time users, the odds ratio for third versus second generation preparations was 3.1 (2.0 to 4.6; four studies). The odds ratio was 2.5 (1.6 to 4.1; five studies) for short term users compared with 2.0 (1.4 to 2.7; five studies) for longer term users. The odds ratio was 1.3 (1.0 to 1.7) in studies funded by the pharmaceutical industry and 2.3 (1.7 to 3.2) in other studies. Differences in age and certainty of diagnosis of venous thrombosis did not affect the results. This meta-analysis supports the view that third generation oral contraceptives are associated with an increased risk of venous thrombosis compared with second generation oral contraceptives. The increase cannot be explained by several potential biases.
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                Author and article information

                Contributors
                Role: research fellow
                Role: professor of clinical epidemiology of fertility
                Role: professor of clinical epidemiology
                Role: research fellow
                Role: professor of clinical epidemiology, head of department
                Journal
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1468-5833
                2009
                2009
                13 August 2009
                : 339
                : b2921
                Affiliations
                [1 ]Department of Clinical Epidemiology, Leiden University Medical Center, C7-P, PO Box 9600, NL-2300 RC Leiden, Netherlands
                [2 ]Department of Gynaecology and Reproductive Medicine, Leiden University Medical Center
                [3 ]Department of Thrombosis and Haemostasis, Leiden University Medical Center
                [4 ]Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center
                Author notes
                Correspondence to: F R Rosendaal F.R.Rosendaal@ 123456lumc.nl
                Article
                vana618587
                10.1136/bmj.b2921
                2726929
                19679614
                8d37ed70-b660-409c-92a0-371c3d290dba

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 29 May 2009
                Categories
                Research
                Epidemiologic studies
                Drugs: cardiovascular system
                Stroke
                Contraception
                Drugs: obstetrics and gynaecology
                Menopause (including HRT)
                Pregnancy
                Reproductive medicine
                Venous thromboembolism
                Pulmonary embolism
                Sexual health
                Drugs: endocrine system

                Medicine
                Medicine

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