gestodene and Venous-Thrombosis

Combined oral contraceptive (COC) use has been associated with venous thrombosis (VT) (i.e., deep venous thrombosis and pulmonary embolism). The VT risk has been evaluated for many estrogen doses and progestagen types contained in COC but no comprehensive comparison involving commonly used COC is available.. To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.. Electronic databases (Pubmed, Embase, Web of Science, Cochrane, CINAHL, Academic Search Premier and ScienceDirect) were searched in 22 April 2013 for eligible studies, without language restrictions.. We selected studies including healthy women taking COC with VT as outcome.. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported.Two independent reviewers extracted data from selected studies.. 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 0.19 and 0.37 per 1 000 person years, in line with previously reported incidences of 0,16 per 1 000 person years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol 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.. All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol. Risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and gestodene, desogestrel, cyproterone acetate and drospirenone were similar, and about 50-80% higher than with levonorgestrel. The combined oral contraceptive with the lowest possible dose of ethinylestradiol and good compliance should be prescribed-that is, 30 μg ethinylestradiol with levonorgestrel.

Topics: Androstenes; Contraceptives, Oral, Combined; Cyproterone; Desogestrel; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Norpregnenes; Pulmonary Embolism; Randomized Controlled Trials as Topic; Venous Thrombosis

Topics: Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Meta-Analysis as Topic; Norpregnenes; Risk Factors; Thromboembolism; Venous Thrombosis

The use of oral contraceptives is a well-established acquired risk factor for venous thrombosis. In 1995, a number of epidemiological studies were published which suggested that women who use third generation oral contraceptives that contain desogestrel or gestodene as progestagen are exposed to a two- to threefold higher risk for venous thrombosis than women using second generation oral contraceptives which contain levonorgestrel. In this paper, the effects of oral contraceptives on the haemostatic system are discussed. It appears that plasma from oral contraceptive users is resistant to the anticoagulant action of activated protein C (APC). This phenomenon, called acquired APC resistance, is more pronounced in users of desogestrel or gestodene-containing oral contraceptives than in women who use oral contraceptive pills with levonorgestrel. On the basis of these observations, it was proposed that acquired APC resistance may be the mechanistic basis of the increased risk for venous thrombosis during oral contraceptive use and for the further increased thrombotic risk of third generation oral contraceptive users. Furthermore, the results of a recent cross-over study are discussed. This study indicated that a large number of other haemostatic parameters were changed during oral contraceptive use. Some of these changes were more pronounced on desogestrel-containing oral contraceptives. The cross-over study also showed that the increased fibrinolytic activity during OC use is counterbalanced by an enhanced activity of thrombin-activatable fibrinolysis inhibitor (TAFI), a protein that participates in the inhibition of fibrinolysis.

Topics: Activated Protein C Resistance; Contraceptives, Oral; Desogestrel; Female; Hemostasis; Humans; Norpregnenes; Risk Factors; Venous Thrombosis

Controversy exists regarding whether oral contraceptives (OCs) containing desogestrel and gestodene are associated with an increased risk of venous thromboembolism (VTE) versus OCs containing levonorgestrel. We were interested in synthesizing the available data, exploring explanations for mixed results, and characterizing the degree of uncontrolled confounding that could have produced a spurious association. We performed a meta-analysis and formal sensitivity analysis of studies that examined the relative risk of VTE for desogestrel and gestodene versus levonorgestrel. Twelve studies, all observational, were included. The summary relative risk (95% CI) was 1.7 (1.3-2.1; heterogeneity p = 0.09). If real, the incremental risk of VTE would be about 11 per 100,000 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. However, in the sensitivity analysis, the association abated in many, but not all, scenarios in which an unmeasured confounding factor increased the risk of VTE three to fivefold and in nearly all examined scenarios in which the factor increased the risk 10-fold. The summary relative risk of 1.7 does not appear to be caused by depletion of susceptibles, but is sensitive to a modest degree of unmeasured confounding. Whether such confounding occurred is unknown. However, given this sensitivity, this issue probably cannot be settled unequivocally with observational data. In the absence of a definitive answer, this apparent increased risk, together with its uncertainty and small magnitude and its important consequences, should be considered when selecting an OC for a given woman.

Topics: Contraceptives, Oral; Desogestrel; Female; Humans; Levonorgestrel; Norpregnenes; Odds Ratio; Risk Factors; Venous Thrombosis

The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin.. In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E2) 50 microg (tE2 group, n=33), oral E2 1 mg (oE2 group, n=37), or oral E2 1 mg combined with gestodene 25 microg (oE2+G group, n=33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE2, +26.9%; oE2, +102.7%; oE2+G, +69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE2, -4.1%; oE2, -7.9%; oE2+G, -5.8%), free protein S (tE2, -7.1%; oE2, -8.4%; oE2+G, -5.2%), and protein C in the oE2+G group (-6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr.. Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy.

Topics: Activated Protein C Resistance; Administration, Cutaneous; Administration, Oral; Aged; Biomarkers; C-Reactive Protein; Double-Blind Method; Estradiol; Estrogen Replacement Therapy; Female; Hemostasis; Humans; Middle Aged; Norpregnenes; Postmenopause; Protein C; Protein S; Prothrombin; Risk Factors; Venous Thrombosis

Complementary to the epidemiological knowledge on the association between oral contraceptive use and the occurrence of venous thromboembolism, a study was designed to obtain more conclusive data regarding the effect of estrogen dose and progestogen type of oral contraceptives on risk markers for the occurrence of venous thromboembolism. The protocol for this multicenter, randomized, open label, parallel group, comparative study is outlined in the present article. A total of 730 healthy, nonsmoking, mulliparous women were treated for six cycles with one of the seven monophasic oral contraceptives tested in this study. The effects of progestogen type (desogestrel, gestodene, levonorgestrel, and norgestimate) and the effects of ethinyl estradiol dose (50, 30, and 20 micrograms) on various hemostatic variables was assessed, including the key components of the anticoagulant and fibrinolytic system, as well as the coagulation system. The primary outcome variables in the study were prothrombin fragment 1 + 2 and D-dimer.

Topics: Blood Coagulation; Contraceptives, Oral; Desogestrel; Ethinyl Estradiol; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Hemostasis; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Peptide Fragments; Prothrombin; Thrombin; Venous Thrombosis

Oral contraceptives (OC) are a definite risk for venous thrombosis. It is commonly accepted that they cause a fourfold increased risk of thrombosis compared to non-users. The prescription patterns were evaluated from 1990 to 2000 in a northern Italian province (province of Padua). This province is typical of other northern Italian provinces. As a consequence, it can be safely assumed that the observations gathered may apply to the entire north of Italy. During these years, a sharp increase in the use of OC was noted. Furthermore, around 1995 to 1996, a marked switch toward the use of preparations containing third-generation progestins was noted. During the past few years of the observation period, approximately 80% of women use preparations containing third-generation progestins. During the same period, an increased incidence of episodes of venous thromboembolism (VTE) was noted. The increase in the prevalence of VTE episodes appeared to be proportional to the increased use of OC, regardless of the type of progestin contained in the oral contraceptive preparations.

Topics: Adolescent; Adult; Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Desogestrel; Drug Prescriptions; Drug Utilization; Female; Humans; Incidence; Italy; Middle Aged; Norpregnenes; Progesterone Congeners; Risk Factors; Thromboembolism; Thrombophilia; Venous Thrombosis

Recent studies have indicated that the risk of thromboembolic disease (VTE) in users of combined oral contraceptive pills (COCs) varies not only with estrogen dose, but also with the progestogen in pills with the same estrogen dose. The aim of this article is to discuss sex hormone binding globulin (SHBG) as a marker of estrogenicity and as a surrogate indicator for the potential risk of VTE in users of COC.. Using data from the literature, we investigated the relationship between the risk of VTE with various COCs and their effects on SHBG. We also collected data on the effects on SHBG by some combined preparations, where there are no VTE data.. There appears to be a relationship between the risk of VTE and the effect on SHBG. Monophasic preparations containing levonorgestrel, having the lowest risk of VTE, cause an average SHBG increase of around 50%. COCs containing desogestrel or gestodene cause an average SHBG increase of 200-300%. A preparation with cyproterone acetate, carrying a higher risk of VTE than desogestrel and gestodene, cause a 300-400% SHBG increase. With the recently developed combined preparations, there is a 150% SHBG increase with norgestimate and a 250-300% increase with drosperinone and dienogest.. We propose that the change in SHBG with a COC could be interpreted as a measure of total estrogenicity and used as a predictor of the risk of VTE. Preparations containing drosperinone, dienogest, cyproterone acetate and norgestimate are equally or more estrogenic than the more thoroughly studied COCs, containing desogestrel or gestodene and should not be considered a safer substitute.

Topics: Biomarkers; Contraceptives, Oral, Combined; Cyproterone Acetate; Desogestrel; Female; Humans; Levonorgestrel; Norgestrel; Norpregnenes; Predictive Value of Tests; Risk Factors; Sex Hormone-Binding Globulin; Venous Thrombosis

To estimate the risk of venous thromboembolism among women prescribed the oral contraceptive pill who have acute clinical conditions such as lower limb fractures, compared with women with idiopathic venous thromboembolism.. A nested case-control analysis using the General Practice Research Database, January 1993 to December 1999 was carried out. The participants were women aged 15-39 years, prescribed third generation oral contraceptives (gestodene and desogestrel) or oral contraceptives containing levonorgestrel. The main outcome measures were odds ratios as a measure of the relative risk estimate for venous thromboembolism in women with clinical conditions that predispose to VTE.. The adjusted relative risk estimate for venous thromboembolism among patients with the acute clinical conditions, compared with those without such illness, and adjusted for oral contraceptive use, was 17 (95% CI 6.5, 46).. This paper documents the strong independent association between certain acute clinical conditions and venous thromboembolism in women prescribed oral contraceptives. Failure to accurately identify and exclude such patients from a study of the effect of oral contraceptives on the risk of venous thromboembolism would result in an underestimate of the risk of venous thromboembolism associated with oral contraceptives.

Topics: Adolescent; Adult; Case-Control Studies; Contraceptives, Oral, Combined; Desogestrel; Female; Humans; Levonorgestrel; Norpregnenes; Odds Ratio; Risk Factors; Thromboembolism; Venous Thrombosis

Topics: Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Desogestrel; Humans; Levonorgestrel; Norpregnenes; Progesterone Congeners; Risk Factors; Thromboembolism; Venous Thrombosis

The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use.

Topics: Adult; Body Mass Index; Case-Control Studies; Contraceptives, Oral, Synthetic; Desogestrel; Estrogens; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Logistic Models; Norgestrel; Norpregnenes; Risk Factors; Venous Thrombosis

Recent data indicate that users of third-generation oral contraceptives, those containing the new progestins desogestrel, gestodene, and norgestimate, have 2 to 3 times the risk of venous thromboembolism faced by users of second-generation oral contraceptives. The risk of development of deep vein thrombosis was also found to be 2 to 5 times greater with a low-estrogen, desogestrel-containing oral contraceptive than with second-generation monophasic and triphasic preparations. Investigators point to an acquired resistance to the anticoagulation effects of activated protein C, the most common cause of hereditary thrombophilia, as a possible mechanism. The American College of Obstetrics and Gynecology's Committee on Gynecologic Practice reconfirms the increased risk of venous thromboembolism associated with third-generation progestins versus other progestins. Because the third-generation oral contraceptives may have benefit for some patients, however, it defers to the individual clinician's and patient's judgment regarding the use of a desogestrel-containing formulation (the only third-generation progestin available in the United States).

Topics: Clinical Trials as Topic; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Levonorgestrel; Norpregnenes; Risk Factors; Thromboembolism; Venous Thrombosis

The restriction on the use of third-generation oral contraceptives, pills which contain gestodene and desogestrel, has been lifted, and the pills can now be offered to women who want to use the method. The Committee on Safety of Medicine imposed the 1995 restriction after a study suggested a small increase in the risk of deep vein thrombosis. But after extensive research, the Medicines Commission stated that third generation pills can be prescribed to women provided that they will be informed of the greater risk involved. In addition, third-generation pills would contain new package inserts, explaining the risks of deep vein thrombosis. The warning will state that the risk of deep vein thrombosis in women not taking the pill is 5/100,000 women/year. This risk increases to 15/100,000 women/year in women taking second-generation pills, while it is 25/100,000 women/year in women taking third-generation pills.

Topics: Contraceptives, Oral, Combined; Desogestrel; Female; Humans; Norpregnenes; Patient Education as Topic; Risk Factors; Venous Thrombosis

In October 1995 the Committee on Safety of Medicines advised UK doctors and pharmacists that oral contraceptives containing desogestrel and gestodene were associated with double the risk of venous thromboembolic events (VTE) compared to pills containing other progestogens. In 1997 data was analysed from the MediPlus database of UK general practitioner records, which reported odds ratios for desogestrel and gestodene lower than that for levonorgestrel. Here the results of a more stringent nested case control analysis on the MediPlus database are reported. The study was larger and cases were verified. A crude incidence of idiopathic VTE was found amongst users of combined oral contraceptives of 4.6 per 10 000 exposed women years. Using levonorgestrel 150 microg + ethinyloestradiol 30 microg as reference, non-significant odds ratios of 1.1 (0.5-2.6) for desogestrel 150 microg + ethinyloestradiol 30 microg and 1.1 (0.5-2.4) for gestodene 75 microg + ethinyloestradiol 30 microg were found. The results of this study show no significant difference in risk between different formulations of combined oral contraceptive.

Topics: Adolescent; Adult; Body Mass Index; Case-Control Studies; Cohort Studies; Contraceptives, Oral, Combined; Contraceptives, Oral, Synthetic; Databases, Factual; Desogestrel; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Middle Aged; Norpregnenes; Odds Ratio; Risk Factors; Smoking; United Kingdom; Venous Thrombosis

Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptives.. This transnational study examined the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (OCs). The study analyzed data on 502 women aged 16-44 years with VTE and 1864 controls from 10 centers in Germany and the UK from 1 January, 1993, to 20 October, 1995. Information on lifetime exposure history from all subjects was added to the data set used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17,622 continuous exposure episodes comprising 47914 person-years of observation, the adjusted hazard ratio of VTE for the comparison of current users of third-generation versus current users of second-generation combined OCs was 0.8 (0.5-1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1-2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the transnational study data show no evidence for an increased risk of VTE with third-generation compared with second-generation combined OCs.

Topics: Adolescent; Adult; Age Factors; Alcohol Drinking; Bias; Body Mass Index; Case-Control Studies; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Norpregnenes; Regression Analysis; Risk Factors; Smoking; Venous Thrombosis

Topics: Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Norpregnenes; Venous Thrombosis