Hormonal contraception and risk of venous thromboembolism: national follow-up study

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.

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

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.