Combined Oral Contraceptives and Venous Thromboembolism Risk
Combined Oral Contraceptives and Venous Thromboembolism Risk
Objective To investigate the association between use of combined oral contraceptives and risk of venous thromboembolism, taking the type of progestogen into account.
Design Two nested case-control studies.
Setting General practices in the United Kingdom contributing to the Clinical Practice Research Datalink (CPRD; 618 practices) and QResearch primary care database (722 practices).
Participants Women aged 15–49 years with a first diagnosis of venous thromboembolism in 2001–13, each matched with up to five controls by age, practice, and calendar year.
Main outcome measures Odds ratios for incident venous thromboembolism and use of combined oral contraceptives in the previous year, adjusted for smoking status, alcohol consumption, ethnic group, body mass index, comorbidities, and other contraceptive drugs. Results were combined across the two datasets.
Results 5062 cases of venous thromboembolism from CPRD and 5500 from QResearch were analysed. Current exposure to any combined oral contraceptive was associated with an increased risk of venous thromboembolism (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives levonorgestrel (2.38, 2.18 to 2.59) and norethisterone (2.56, 2.15 to 3.06), and for norgestimate (2.53, 2.17 to 2.96). The number of extra cases of venous thromboembolism per year per 10 000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17).
Conclusions In these population based, case-control studies using two large primary care databases, risks of venous thromboembolism associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs.
About 9% of women of reproductive age worldwide use oral contraceptives. This percentage rises to 18% of women in developed countries and 28% of women in the United Kingdom. Combined oral contraceptives form a substantial proportion of these, particularly in more developed nations. Although combined oral contraceptives are generally effective in preventing pregnancy, they have measurable side effects such as venous thromboembolism (VTE). VTE is important, not only because of the prolonged time over which women might be exposed to such contraceptives, but also because VTEs are potentially avoidable and can be fatal.
Previous studies have shown varying risks for different types of oral contraceptives (such as third generation pills compared with first or second generation pills), but such studies were done some years ago, and tended not to include new preparations containing drospirenone. Also, previous studies have generally had insufficient power to analyse the risks for more recent formulations such as norgestimate. Few studies—only four of those referenced here—have included any detailed analyses of dosage and, of these, only Lidegaard and colleagues have covered a full range of prescribed drugs. Some studies did not control for all potential confounders (such as body mass index or smoking), while others analysed only healthy users. Different methodological approaches in studies have also made it difficult to compare and combine the results. Therefore, although the increased VTE risk associated with combined oral contraceptive drugs is established, the relative risks associated with different combinations remain inconclusive, especially for newer formulations.
The UK has some of the largest sources of routinely collected data in the world, with longitudinal primary care records spanning up to 25 years and linked to secondary care data and mortality records. These databases cover many millions of patients, include data both on exposure and outcomes, and therefore are representative of the setting in which drugs are used. This makes the databases ideally suited to large scale safety studies of commonly used drugs. In this study, we have used the two largest of these databases, QResearch (www.qresearch.org) and Clinical Practice Research Datalink (CPRD, www.cprd.com). Both have been used for earlier studies of associations between drug prescribing and VTE risks.
Our objective was to quantify the associations between use of combined oral contraceptives and risk of VTE, adjusting for comorbidities and other available confounding factors. In particular, we were interested to analyse risks associated with newer or less used preparations such as drospirenone or norgestimate, quantify risks associated with various types of progestogen, and analyse the effect of different doses of oestrogen on VTE risks. To make the study more comparable with previous studies, we also replicated analyses for different subgroups by age and health status and for VTE cases with anticoagulation prescriptions.
Abstract and Introduction
Abstract
Objective To investigate the association between use of combined oral contraceptives and risk of venous thromboembolism, taking the type of progestogen into account.
Design Two nested case-control studies.
Setting General practices in the United Kingdom contributing to the Clinical Practice Research Datalink (CPRD; 618 practices) and QResearch primary care database (722 practices).
Participants Women aged 15–49 years with a first diagnosis of venous thromboembolism in 2001–13, each matched with up to five controls by age, practice, and calendar year.
Main outcome measures Odds ratios for incident venous thromboembolism and use of combined oral contraceptives in the previous year, adjusted for smoking status, alcohol consumption, ethnic group, body mass index, comorbidities, and other contraceptive drugs. Results were combined across the two datasets.
Results 5062 cases of venous thromboembolism from CPRD and 5500 from QResearch were analysed. Current exposure to any combined oral contraceptive was associated with an increased risk of venous thromboembolism (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives levonorgestrel (2.38, 2.18 to 2.59) and norethisterone (2.56, 2.15 to 3.06), and for norgestimate (2.53, 2.17 to 2.96). The number of extra cases of venous thromboembolism per year per 10 000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17).
Conclusions In these population based, case-control studies using two large primary care databases, risks of venous thromboembolism associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs.
Introduction
About 9% of women of reproductive age worldwide use oral contraceptives. This percentage rises to 18% of women in developed countries and 28% of women in the United Kingdom. Combined oral contraceptives form a substantial proportion of these, particularly in more developed nations. Although combined oral contraceptives are generally effective in preventing pregnancy, they have measurable side effects such as venous thromboembolism (VTE). VTE is important, not only because of the prolonged time over which women might be exposed to such contraceptives, but also because VTEs are potentially avoidable and can be fatal.
Previous studies have shown varying risks for different types of oral contraceptives (such as third generation pills compared with first or second generation pills), but such studies were done some years ago, and tended not to include new preparations containing drospirenone. Also, previous studies have generally had insufficient power to analyse the risks for more recent formulations such as norgestimate. Few studies—only four of those referenced here—have included any detailed analyses of dosage and, of these, only Lidegaard and colleagues have covered a full range of prescribed drugs. Some studies did not control for all potential confounders (such as body mass index or smoking), while others analysed only healthy users. Different methodological approaches in studies have also made it difficult to compare and combine the results. Therefore, although the increased VTE risk associated with combined oral contraceptive drugs is established, the relative risks associated with different combinations remain inconclusive, especially for newer formulations.
The UK has some of the largest sources of routinely collected data in the world, with longitudinal primary care records spanning up to 25 years and linked to secondary care data and mortality records. These databases cover many millions of patients, include data both on exposure and outcomes, and therefore are representative of the setting in which drugs are used. This makes the databases ideally suited to large scale safety studies of commonly used drugs. In this study, we have used the two largest of these databases, QResearch (www.qresearch.org) and Clinical Practice Research Datalink (CPRD, www.cprd.com). Both have been used for earlier studies of associations between drug prescribing and VTE risks.
Our objective was to quantify the associations between use of combined oral contraceptives and risk of VTE, adjusting for comorbidities and other available confounding factors. In particular, we were interested to analyse risks associated with newer or less used preparations such as drospirenone or norgestimate, quantify risks associated with various types of progestogen, and analyse the effect of different doses of oestrogen on VTE risks. To make the study more comparable with previous studies, we also replicated analyses for different subgroups by age and health status and for VTE cases with anticoagulation prescriptions.
