Hormonal contraception and risk of venous thromboembolism: national follow-up study
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b2890 (Published 13 August 2009) Cite this as: BMJ 2009;339:b2890
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I appreciate the authors initiative to study one of the long
unresolved query of VTE (venous thromboembolism) associated with Oral
contraceptives (OCs). Some prominent features of this study are that it
has analyzed the OC users based on the different types of progesterone and
different dose strengths of ethinyl estradiol. I would like to seek a
clarification- does the method used to evaluate the risk of VTE takes into
account the other causal factors for VTE development, e.g. BMI, family
history of VTE, history of smoking and other predisposing factors?
Additionally, the authors have concluded that the VTE risk can be
stratified based on the type of progesterone and dose of estrogens. I
would appreciate if the authors can also clarify that whether these
differences are statistically significant to draw some conclusions.
This is a good initiative to address the unanswered questions associated
with OC use. A long term randomized controlled trial would help us to
better understand VTE related risk associations. Until more data become
available, all combined OCs are perhaps best used with caution in women
with predisposing factors for VTE.
Competing interests: I work as Medical Advisor in Pfizer India managing womens health portfolio.
Øjvind Lidegaard et al (1) report that combined contraception by
oestrogen and progestogen increases the risk of venous-thromboembolism.
Therefore, combined contraception should not be used in the post partum
which is a period with an increased risk of thromboembolism (2). As
progestogen only contraception is not associated with a higher risk of
venous thromboembolism (1), it could be used in the post-partum.
References
1. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C.
Hormonal contraception and risk of venous thromboembolism: national follow
-up study. BMJ. 2009;339:b2890. doi: 10.1136/bmj.b2890.
2. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton
LJ 3rd.
Trends in the incidence of venous thromboembolism during pregnancy or
postpartum: a 30-year population-based study. Ann Intern Med. 2005;
143:697-706
Competing interests:
None declared
Competing interests: No competing interests
COCs and VTE risks
Szarewski and Mansour distract from the carcinogenic effects and
inherent thrombotic risks of COCs by mentioning synergistic factors such
as obesity and smoking.1
However, they miss two important points.
Firstly, use of the Pill is a main cause of obesity in younger women.
Secondly, smoking usually takes decades to increase serious vascular
risks compared with an immediate adverse vascular effect of progesterones
with or without oestrogens.
I was involved with the clinical and pathological testing of over 60
dose combinations of seven progestogens (including norethisterone and
norgestrel) with or without two oestrogens. First year attrition
(discontinuations of hormones) was mostly due to arterial and venous
effects, mood changes, weight gain and irregular bleeding. Thrombosis is
caused by changes in vessel walls, blood flow and blood clotting factors.
No progestogen contraceptive regimes, with or without oestrogens, were
free from such problems. However, small variations in doses changed which
of these adverse effects was most prominent.2 Most of these original
research publications are available for free.
Dr Ellen C G Grant, Council for the Investigation of Fertility
Control, London 1961-1969.
1 Szarewski A, Mansour D.
http://www.bmj.com/cgi/eletters/339/aug13_2/b2890.
2 Editorial Changing Oral Contraceptives. BMJ 1969;4:789-791.
Competing interests:
None declared
Competing interests: No competing interests
Thanks to Anne Szarewski and Diana Mansour for their comments to our recent publication on oral contraceptives (OC) and risk of venous thromboembolism (VTE)( http://www.bmj.com/cgi/eletters/339/aug13_2/b2890).
Previous pill scares:
It is true that we have been working in this epidemiological field for decades. Therefore we also know very well the many methodological issues to be aware off when conducting observational research in this field. Nevertheless, it is also an obligation (at least for clinical scientists) to put the findings in a large new study into perspective and to try to guide the readers on how these new findings could or should influence our clinical practice. We stated, however, that further studies should confirm our results before firm conclusions could be drawn. Coincidently, another independent study came out with the same results at the same time, validating our findings further.
Attrition of susceptibles:
While this phenomenon sounds very logic, the fact is that so few women experience a VTE during their first year of use, that the a priori risk in the cohort of users the next year will be essentially unchanged. About 10% of women are genetically predisposed for VTE, and they have an average relative risk of about 4 of VTE when compared with women without genetic predispositions. In a population of 1 million young women, 100,000 will have such a predisposition. With a baseline risk of VTE of 1 in 10,000 per year, in women not on OC about 40 will suffer a VTE during a year, leaving a cohort with 99.960 women at an increased risk. If one half of these women at risk had been on OC, which increases their risk of VTE further 4 fold, 20 + 80 = 100 women wound experience a VTE, leaving 99.900 women at an increased risk in the cohort.
So the attrition is in fact so tiny that in practice it would not be possible to measure after one year.
This circumstance does not, however, change the fact the risk of VTE decreases by length of use, just that we still have difficulties in explaining this fall in risk within the first year. Some kind of biological adaptation is more likely, an adaptation, which takes few months to accomplish.
Besides these reflections, we did control for length of use, and still found a differential risk of VTE with different progestogens.
Confounder control:
We have dealt with the missing control of BMI and family disposition in detail in our paper. An important risk factor is not the same as an important confounder. When 3rd generation OC were introduced they were perceived as safer than the older products. At that time it was important to control for family history. When OC with drospirenon were introduced, they were not perceived as safer, and the Euras study documented that “..the differences [in risk factors Øli] were small and the preferential prescribing pattern identified here could only slightly increase the incidence of VTE in the DRSP cohort” to use the authors own formulation. This was confirmed in our previous study, in which we had information about these variables, and no confounding influence was found at all (2). Finally, the Dutch study had this information, controlled for it, and found the same increased risk of OC with drospirenone as compared with OC with levonorgestrel products as we did (3).
So for several reasons the increased risk in users of OC with drospirenon is unlikely to be due to confounding – unfortunately.
Smoking is a (weak) risk factor of VTE in older and even less in middle-aged women, but not in young women, as demonstrated in our previous publications and in the Dutch study. Even less likely it is a confounder, as no data points to a differential per cent of smokers among users of different types of oral contraceptives, at least not in Denmark.
1. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890
2. Lidegaard Ø, Edström B, Kreiner S. Oral contraceptives and venous thromboembolism. A five-year national case-control study. Contraception 2002; 65: 187-96.
3. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. Effects of oestrogen dose and progestogen type on venous thrombotic risk associated with oral contraceptives: results of the MEGA case-control study. BMJ 2009:339:b2921.
Competing interests:
The author has previously received grants from pharmaceutical companies for cover of research expenses, and has received fees for speeches in pharmacoepidemiological issues.
Competing interests: No competing interests
We are astonished at the conclusions and claims being made in the two
studies and Commentary published in this week’s BMJ 1,2,3. Given the mass
of research, published following the ‘pill scare’ of 1995, showing how
difficult it is to draw conclusions without careful control for bias and
confounding, we would have expected a much more circumspect approach from
these authors.
While Lidegaard et al note that there is a higher risk of VTE during
the first year of COC use, they have failed to notice that this does not
apply to products which came on the market well before their study
starting date of 1995 (levonorgestrel-containing COCs in particular). It
has been well documented that ‘attrition of susceptibles’ occurs 4 when
long-term (by definition lower risk) users of older pills are compared
with new (by definition higher risk) users of newer pills. Indeed they
have corroborated the finding of Suissa et al5, that every new COC
introduced onto the market appears to have a higher VTE risk than those
that came before it.
The authors of this study admit they have not been able to control
for family history of VTE, nor for obesity, both of which are extremely
important confounders6,7,8. And it has also been well documented (by the
authors themselves among others) that doctors preferentially prescribe
newer COCs to women they perceive as being at greater risk8,9,10. A
striking example of this has been the preferential prescribing of Yasmin
(the 30mcg drospirenone COC) to women with a BMI over 30 ref8. In
addition, they have not controlled for smoking behaviour, nor do they even
mention it. This is most surprising, since the authors’ own previous study
6 not only showed smoking and obesity to be independent risk factors, but
showed a dose-response effect for higher levels of smoking and increasing
BMI.
A recent Danish national registry cohort study found a positive
association between smoking and VTE, which was greater for women (OR 1.52
95% CI 1,15-2.00) than for men (OR 1.32 95% CI 1.00-1.74)ref 11. Indeed,
there was a dose-response relationship for both genders in this study;
smoking more than 20 grams of tobacco per day among women and 30 grams per
day among men was associated with a 150-300% higher risk of VTE. The
authors noted that there are different thresholds of risk for men and
women, which may be explained by gender differences in metabolism. It is
interesting that this concurs with results published only last year12 by
the group which carried out the second study in the current BMJ2. Using
data from the same MEGA case control study, they showed a synergistic dose
response relationship with smoking, COC use and VTE incidence. Like the
Danish group, they found that the effect of smoking on VTE risk was more
pronounced in women than in men. In addition, this group7 found a greatly
increased risk of VTE (OR 23.78 (95% CI 13.35 - 42.34) in women who used
the COC and had a BMI over 30, compared to those with a BMI under 25, who
did not use the COC. Indeed, in their paper, the authors state ‘The
association between BMI and venous thrombosis is likely to be causal
because it is consistent over studies, shows a dose–response relationship
and is biologically plausible.’
In the light of their previous findings, it is surprising that van
Hylckama Vlieg et al did not appear to control for either BMI or smoking
in their sub-analyses of VTE risk by COC type, only in the overall
analysis of COC use. Given the preferential prescribing described above,
we would have thought this was important. Although the overall size of
their study is quite large, in the sub-analyses of different COC types,
the numbers are in fact very small, (under 20 in both cases and controls
for COCs containing drospirenone, norgestimate and norethisterone) and
therefore the odds ratios are accompanied by wide confidence intervals.
Finally, we find Professor Dunn’s remarks about the VTE risks
associated with smoking and obesity to be ill-informed and detrimental to
the health of women.7,8,12, 13,14 We ask those engaged in analysing
registries and databases to heed the lessons of the past two decades and
ensure accurate and measured reporting of new findings.
References
1. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal
contraception and risk of venous thromboembolism: national follow-up
study. BMJ 2009;339:b2890
2. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen
CJM, Rosendaal FR. Effects of oestrogen dose and progestogen type on
venous thrombotic risk associated with oral contraceptives: results of the
MEGA case-control study. BMJ 2009:339:b2921.
3. Dunn N. Oral contraceptives and venous thromboembolism. BMJ
2009;339:b3164
4. Lewis MA, MacRae KD, Kühl-Habich D, Bruppacher R, Heinemann LAJ,
Spitzer WO. The differential risk of oral contraceptives: the impact of
full exposure history. Hum Reprod 1999;14:1493-9
5. Suissa, S., Blais, L., Spitzer, W.O. et al. (1997) First-time use
of newer oral contraceptives and the risk of venous thromboembolism.
Contraception, 56, 141–146.
6. Lidegaard Ø, Edström B, Kreiner S. Oral contraceptives and venous
thromboembolism. A five-year national case-control study. Contraception
2002;65:187-96.
7. Pomp ER, Le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous
thrombosis: obesity and its joint effect with oral contraceptive use and
prothrombotic mutations. Br J Haematol 2007; 139: 289-29
8. Dinger JC, Heinemann LAJ, Kühl-Habich D. 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. Contraception 2007;75:344-54.
9. Lidegaard Ø. The influence of thrombotic risk factors when oral
contraceptives are prescribed. Acta Obstet Gynaecol Scand 1997;76:252-60.
10. Shulman LP, Goldzieher JW. The truth about oral contraceptives
and venous thromboembolism. J Reprod Med 2003;48(11 suppl):930-8.
11. Severinsen MT, Kristensen SR, Johnsen SP, Dethlefsen C,
Tjonneland A, Overvad K. Smoking and venous thromboembolism: a Danish
follow-up study J Thromb Haemost 2009; 7: 1297–303.
12. Pomp ER, Rosendaal FR, Doggen CJM. Smoking increases the risk of
venous thrombosis and acts synergistically with oral contraceptive use. Am
J Haematol 2008; 83: 97-102
13. Lowe GD. Common risk factors for both arterial and venous
thrombosis, Br J Haematol, 2008; 140 (5): 48-95
Competing interests:
AS has received honoraria, consultancy fees and conference sponsorship from Bayer Schering (formerly Schering HealthCare), Schering Plough (formerly Organon), Janssen-Cilag and Wyeth.
DM has received honoraria, consultancy fees and conference sponsorship from Bayer Schering (formerly Schering HealthCare), Schering Plough (formerly Organon), Janssen-CIilag, HRA Pharma and Wyeth.
Competing interests: No competing interests
It is not news that progestogen/oestrogen contraceptives have a high
risk of venous thrombosis.1,2,3 However it is cancer and not thrombosis
which is the main cause of premature death in hormone users. Hormonal
contraceptives are listed as Group 1 carcinogens by the International
Agency for Cancer Research and evidence is gathering that progestogens are
more carcinogenic than oestrogens.4,5 Advice to use long-acting
progestogens for contraception could be disastrous for many women.3
1 Grant ECG. Venous effects of oral contraceptives, BMJ 1969;4:73-
77.
2 van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP , Doggen
CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives,
effects of oestrogen dose and progestogen type: results of the MEGA case-
control study. BMJ 2009; 339: b2921
3 Lidegaard O, Løkkegaard E, Svendsen AL, Agger C. Hormonal
contraception and risk of venous thromboembolism: national follow-up
study. BMJ 2009:339:b2890.
4 IARC Monographs Vol. 91. Combined Estrogen-Progestogen
Contraceptives and Combined Estrogen-Progestogen Menopausal
Therapy.2007;528 pages.
5 Giersig C. Progestin and breast cancer. The missing pieces of a
puzzle.
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2008;51:782
-786.
Competing interests:
None declared
Competing interests: No competing interests
Oral contreceptives make women live longer
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