Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2135 (Published 26 May 2015) Cite this as: BMJ 2015;350:h2135
- Yana Vinogradova, research fellow in medical statistics1,
- Carol Coupland, associate professor and reader in medical statistics1,
- Julia Hippisley-Cox, professor of clinical epidemiology and general practice1
- Correspondence to: Y Vinogradova yana.vinogradova{at}nottingham.ac.uk
- Accepted 19 March 2015
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.
Footnotes
We acknowledge the contribution of Egton Medical Information System (EMIS) and the University of Nottingham for expertise in creating and maintaining QResearch and to the EMIS practices which contribute data; we thank CPRD and Vision Practices for allowing access to the CPRD for this study.
Contributors: JHC had the original idea for this study. CC contributed to the development of the idea and the study design. YV reviewed the literature, contributed to the study design, undertook the primary analysis as well as the first interpretation and wrote the first draft of the paper. JHC and CC critically reviewed the paper. All authors approved the submitted version.
Funding: This research received no external funding.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any additional organisation for the submitted work; JHC is professor of clinical epidemiology at the University of Nottingham and unpaid director of QResearch, a not-for-profit organisation which is a joint partnership between the University of Nottingham and EMIS (commercial IT supplier for 60% of general practices in the UK); JHC is also a paid director of ClinRisk, which produces open and closed source software to ensure the reliable and updatable implementation of clinical risk algorithms within clinical computer systems to help improve patient care; no other relationships or activities that could appear to have influenced the submitted work.
Ethics and dissemination: The protocol for this study has been published in BMJ Open. It has also been independently peer reviewed by the QResearch Scientific Board and has been reported to Trent research ethics committee in accordance with the agreed procedure (reference no MREC/03/4/021). For CPRD data analysis, the protocol was approved by Independent Scientific Advisory Committee (reference no ISAC 13_118RA2).
Data sharing: Results for all additional analyses and descriptive statistics are already published in the web tables. Any further requests are available from the corresponding author.
The lead author and the manuscript’s guarantor (YV) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.
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