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
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These studies confirm with a sufficient power most of the previous conclusions relating to the risk of venous thromboembolism of COC.
Nevertheless the data for norgestimate are subject to heterogeneity considering the CPRD and the QResearch databases.
The adjusted odds ratio for current use of Norgestimate versus Levonorgestrel is lower considering the data sourced from the CPRD whereas the Odds ratio sourced from the data of Q Research is 1.25 with a P value at the hedge of significant level. Is O.05 a rounded value and what is the real one?
In your opinion, is there any significant factor likely to explain such a difference, what is the most powerful analysis and the reliable odds ratio?
Regards
Competing interests: No competing interests
Recent evidence from long term observations of hundreds of thousands of women, in 10 European Countries, clearly demonstrated that the use of oral contraceptives reduced mortality by roughly 10%. Despite all thromboembolism risks, apparently.
Reference
doi: 10.1186/s12916-015-0484-3.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627614/
Competing interests: No competing interests
Venous thrombosis risk varies with different doses of the same progestogen combined with different doses of the same oestrogen.
Five dose combinations of norethisterone acetate (NA) and ethinyl estradiol (EE) were tested in 4mg, 2 mg and 1mg doses of NA and 50 to 90 µg doses of EE.1 The incidence of vein changes ranged from 3% of women taking 2 mg NA plus 50 µg EE to 55% of women taking 1 mg NA plus 75µg EE. The incidence of migraine ranged from 40 to 60% with all dose combinations and 30% of women reported depression with the highest 4 mg NA dose combination. 2,3
The incidence of vein changes ranged from 10 to 17% with 6 doses of norgestrel (0.1 mg to 3 mg) plus EE 50 µg but the incidence of migraine ranged from 10 to 50% and depression from 10 to 44%.
It is simplistic and misleading to ignore all the adverse effects of progestogens and oestrogens.
1 Grant ECG. Venous effects of oral contraceptives. BMJ 1969;2:73-7.
2 Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968; 3: 402-5.
3 Grant ECG, Pryse Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. BMJ 1968;3:777-80.
Competing interests: No competing interests
Although the large number of cases of VTE (10,562) and linkage to details of co-morbid conditions and BMI allowing adjustment for many important confounders are major strengths of the analysis by Vinogradova and colleagues, it is unlikely that these adjustments completely corrected for the core problem with database and case-control studies; healthy user effect and preferential prescription of low androgen progestogens to women at higher risk of VTE [1, 2]. It is of interest that in the duration of use analysis, a significantly increased risk for new users and restarters was seen only for levonorgestrel products. One likely explanation is that providers have responded to negative publicity concerning low-androgen progestogens by switching patients to levonorgestrel (LNG) pills, increasing the high risk pool among LNG users.
Preferential prescribing of newer low dose/low androgen products to high risk women is also the likely explanation for the findings seen with respect to estrogen dose. Farmer initially pointed out the “inverse-dose response” for ethinyl estradiol (EE) and VTE risk during the first pill scare in the 1990s [3]. Similar results are observed in the Vinogradova paper. I calculated the crude OR for VTE (relative to LNG) for 20 mcg EE norethisterone at 1.25 (0.95, 1.64), while for 30/40 mcg the OR is 1.02 (0.82, 1.27). For 20 mcg gestodene the OR is 2.24 (1.46, 3.44) while for 30 mcg the OR is reduced at 1.46 (1.18, 1.80). Only with the desogestrel preparations was the risk marginally higher with 30/40 mcg EE (OR 1.87 (1.54, 2.25) than for 20 mcg (1.71 (1.34, 2.17). Data for 20 and 30 mcg drospirenone was not provided. This provides strong evidence that the observed differential effect of progestogen type observed by Vinogradova and colleagues also reflects preferential prescribing of newer low androgen pills to high risk women.
References
[1] Rowlands S, Devalia H, Lawrenson R. Preferential prescribing of type of combined oral contraceptive pill by general practitioners to teenagers with acne. Eur J Contracept Reprod Health Care. 2001;6:9-13.
[2] Heinemann LA, Lewis MA, Assmann A, Gravens L, Guggenmoos-Holzmann I, Working Group for Pharmacoepidemiology B-B. Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives? Pharmacoepidemiol Drug Saf. 1996;5:285-94.
[3] Farmer RD, Lawrenson RA. Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany. American journal of obstetrics and gynecology. 1998;179:S78-86.
Competing interests: I have received payments for consulting from Agile Pharmaceuticals, Abbvie Pharmaceuticals, Bayer Healthcare, ContraMed, Evofem Inc, HRA Pharma, Merck Pharmaceuticals, Microchips, Teva Pharmaceuticals and the Population Council. I have also received research funding from Abbvie, Bayer, the Population Council, and the Bill & Melinda Gates Foundation. These companies and organizations may have a commercial or financial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by my employer, OHSU.
Zagarella asks whether risks of venous thromboembolism may be different in women with potential symptoms of polycystic ovarian disease (such as acne and hirsuitism) but without a formal diagnosis of polycystic ovary syndrome (PCOS). Menstrual disorders and acne were recorded for a large proportion of cases and controls across the databases: 23% to 36% for menstrual disorders, 9% to 13% for acne and 1% to 2% had hirsutism recorded. Although all are possible symptoms of PCOS, we could not simply assume that a woman with these symptoms had PCOS in the absence of a record for it. There was also no evidence to date that these symptoms in themselves were associated with increased risk of venous thromboembolism, so there was no justification for including them into the model.
Between countries and studies, diagnostic criteria differ, with the prevalence of PCOS ranging from 4% to 20%.[1] In our study, the age-standardised prevalence rate for PCOS in controls was 3.1% for QResearch and 3.6% for CPRD, suggesting that this condition might be under-recorded. To address this issue as suggested in response by Zagarella we ran a sensitivity analysis adding the possible symptoms of PCOS to the model.
The results were in line with the main analysis with the largest differences for current use cyproterone with reference to no use (pooled odds ratio of 4.32 vs 4.27 in the main analysis) and for drospirenone (4.15 vs 4.12) [Table1]. With reference either to no use or to levonorgestrel use, no other differences between pooled odds ratios from this sensitivity analysis and the main analysis were more than 0.02. The pooled adjusted odds ratio for acne was 0.99 (95%CI 0.91 to 1.07), for menstrual disorders it was 1.13 (95%CI 1.07 to 1.20) and for hirsutism it was 0.98 (95%CI 0.81 to 1.20).
1. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol 2014;6:1-13
Competing interests: No competing interests
The risk of venous thromboembolism (VTE) associated with combined oral contraceptives is not a new issue and the recent study by Vinogradova et al [1] confirms the UK regulatory position, supporting decisions on safe prescribing.
The authors’ conclusions are consistent with findings of a regulatory Europe-wide review of combined hormonal contraceptives (CHCs). In early 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) sent a letter to UK prescribers [2] and published a summary of the European review [3]. This confirmed our previous understanding that the level of VTE risk with all low-dose CHCs (ethinyloestradiol <50μg) is small and stated there is good evidence that the risk of VTE varies, depending on the type of progestogen they contain, as shown in Table 1.
The new analysis by Vinogradova et al. (including over 10,000 cases of VTE) adds further weight to the regulatory advice provided to UK prescribers, that CHCs containing the progestogens levonorgestrel, norethisterone or norgestimate have the lowest risk of VTE.
There is no need for any woman to change her CHC on the basis of this new study. If women have questions, they should discuss them with their GP or contraceptive provider at their next routine appointment, but should keep taking their contraceptive until they have done so.
References
1. Vinogradova Y., Coupland C and Hippisley-Cox J. 2015. Use of combined oral contraceptives and risk of venous thromboembolism: nested case control studies using the QResearch and CDRD databases. BMJ 2015;350:h2135
2. Medicines and Healthcare products Regulatory Agency (MHRA). 2014. Dear Doctor Letter (circulated by NHS Central Alerting System January 2014) Available at: https://www.cas.dh.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=1...
3. MHRA. 2014. Combined hormonal contraceptives and venous thromboembolism: review confirms risk is small. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/combined-hormonal-contraceptives-a...
Competing interests: No competing interests
Vinogradova and colleagues analysed 68% of the cases of venous thromboembolism and 56% of the controls in the QResearch and CPRD UK general practice databases. Any use of combined oral contraceptive had a three-fold increased risk of venous thromboembolism. With the exception of norgestimate, risks were higher for newer third generation drug preparations (x 4) than for second generation drugs (x 2),
Norgestimate (third generation) is converted in the body to norgestrel (first generation). Levonorgestrel (second generation) is the active isomer of norgestrel. Desogestrel and gestodene (third generation) are more powerful substituted derivatives of norgestrel. Synthetic oestrogens are much more powerful than natural oestrogens and are given in much lower doses. All progestogens predominantly act like progesterone whether or not they also have oestrogenic or androgenic activity.
We established by 1969 that changing strengths and doses of progestogens and oestrogens merely switched which adverse effects were most likely.2-9 These varied from irregular bleeding and ovulation, to venous changes and venous thrombosis, to arterial vascular diseases including migraine, strokes and heart attacks to increased monoamine oxidase activity and depressive mood changes. The combinations causing most adverse vascular effects had the most first year discontinuations.5
There has been no improvement in the overall safety of hormonal contraception over the last 50 years. Breast cancer incidences have been matching increases with occasional decreases, in progestogen and/or oestrogen contraceptive or hormone therapy use.10-11 In young women metastatic breast cancer is still increasing and use of progestogen only contraceptives is increasing the use of antidepressants.12-14
1 Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135,
2 Grant ECG. Hormone balance of oral contraceptives. BJOG 1967;74:908-18.
3 Grant ECG. Relation of arterioles in the endometrium to headaches from oral contraceptives. Lancet 1965;1:1143-44
4 Grant ECG, Mears E. Mental effects of oral contraceptives. Lancet 1967;1:945-46.
5 Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968;3:402-5.
6 Grant ECG, Pryce Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. BMJ 1968;3:777-80.
7 Southgate J, Grant ECG, Pollard W, Pryse Davies J, Sandler M. Cyclical variations in endometrial monoamine oxidase: Correlations of histochemical and quantitative biochemical assays. Biochemical Pharmacology 1968;17:21-26.
8 Grant ECG. Venous effects of oral contraceptives. BMJ 1969;2:73-7.
9 Changing oral contraceptives. BMJ 1969;4:789-91 & Today's Drugs
10 Grant ECG. Reduction in mortality from breast cancer: fall in use of hormones could have reduced breast cancer mortality. BMJ. 2005 Apr 30;330(7498):1024; author reply 1025
11 Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res. 2007;9:108.
12 Johnson RH, Chein FL, Bleyer A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA 2013;309(8):800-805.
13 Wiréhn AB, Foldemo A, Josefsson A, Lindberg M. Use of hormonal contraceptives in relation to antidepressant therapy: A nationwide population-based study. Eur J Contracept Reprod Health Care 2010;15:41-7.
14 www.harmfromhormones.co.uk
Competing interests: No competing interests
The authors are to be commended on a well conducted case-control study, however there is an important methodological issue that may impact on the findings.
Although the authors stated that they included polycystic ovarian syndrome as a confounder, they did not include acne, hirsutism in the final analysis because they "failed to change the OR by more than 10%).
However, many young women with acne and hirsutism have undiagnosed polycystic ovarian syndrome, so the data may well be different if all these patients were grouped together with the polycystic ovarian syndrome cases and accounted for in the final analysis.
The fact is that, in recent times, levonorgestrel OCP's are used in healthy women for contraception, whereas newer pills like drosperinone are more likely to be used for young women with polycystic ovaries, acne or hirsutism.
Because drosperinone is used for a different medical use than levonorgestrel, it is crucial that these factors are accounted for.
It may turn out that women with acne and hirsutism have a higher risk for DVT when treated with any OCP , and this is what would be clinically useful to know.
Competing interests: No competing interests
Re: Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases
The study was run separately on two large primary care databases and the results were combined using meta-analysis techniques. Overall, there was good consistency in the results between the two databases. Because of the large number of comparisons in our study, the value for statistical significance was set at the 1% level. For the combined analysis we had 72 pairs of odds ratios, and the only significant heterogeneity discovered was for use of norgestimate compared with no use of combined oral contraceptives.
The findings for norgestimate were of particular interest because of its historical position between second and third generation combined oral contraceptives. Although the results for the direct comparisons between norgestimate and levonorgestrel had different directions of association with VTE risk in the two databases, with a reduced odds ratio in favour of norgestimate) in CPRD (adjusted odds ratio 0.879, 95% confidence interval 0.688 to 1.123, p-value 0.302) and an increased odds ratio in QResearch (adjusted odds ratio 1.252, 95% CI 0.996 to 1.573, p-value 0.054), neither of the findings were statistically significant. Results for these direct comparisons of norgestimate with levonorgestrel were not significantly heterogeneous between the databases (the p-value for this heterogeneity test was 0.038). The most reliable odds ratio is therefore the combined odds ratio from the fixed effect model (combined odds ratio 1.06, 95% CI 0.90 to 1.26, p-value 0.480), which is very similar to that from the random effect model (combined odds ratio 1.08, 95% CI 0.89 to 1.30, p-value 0.443).
We concluded, therefore, that this study had not produced evidence that the risk of VTE associated with norgestimate is significantly different from levonorgestrel.
Competing interests: No competing interests