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Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

BMJ 2011; 343 doi: (Published 25 October 2011) Cite this as: BMJ 2011;343:d6423

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Authors' reply to Professor Shapiro

Thanks to Professor emeritus Samuel Shapiro (SS) for his
considerations on our new study on venous thrombosis in users of different
types of oral contraceptives (1).

Already after we published our first report in BMJ in 2009 (2) SS and
Dinger published a six-page long critique of our (and a Dutch) study, in
which they postulated that we underestimated the risk of venous thrombosis
for levonorgestrel resulting in a systematic overestimation of the rate
ratio between other oral contraceptives and levonorgestrel due to left
censoring bias, and concluded that "the increased risk of VTE in OC users
is .... independent of the progestogen used" (3).

In our new study we eliminated left censoring bias by putting current
users of OC at the beginning of the study period 2001-2009 into the
correct length of use category. This was possible due to information about
use of hormonal contraception back to 1995. Thus women who had used OC
with levonorgestrel for more than four years before and up to 2001 were
placed in the category use of >4 years use already from January 1,
2001. Use even longer back in time would not change the category as by
January 2001. The secular change in diagnostic precision was accounted for
by adjusting for calendar year.

We also restricted the new study to confirmed events of venous
thromboembolism by assessing anticoagulation therapy after the diagnosis.

Finally we added four new study years (2006-2009) in our new study.

The results of the new study rejected the accusations brought in
print by SS and Dinger. First the rate ratio estimates
of venous thrombosis between users of OC with drospirenone versus OC with
levonorgestrel (LNG) increased from 1.6 (1.3-2.1) to 2.1 (1.6-2.8) in the
new study, proving that we underestimated the risk of OC with drospirenone
versus OC with LNG in our primary study and not the opposite.

Next, we made indeed sub-analyses restricted to starters and new
users of different types of OC. New users were defined as women who had a
pause of at least 12 weeks without use of hormonal contraception prior to
current use. These results were reported with the new publication as
appendix 4. Restricted to starters in the period 2001-2009 brought a rate
ratio between users of OC with drospirenone versus OC with LNG of 2.69
(1.76-4.10) and restricted to starters + new users of 2.05 (1.56-2.70). In
other words, results quite consistent with the overall results.

We also elaborated these results to EMA in an in some respect more
restricted analysis (e.g. we did not report results on combined pills with
20 microgram ethinylestradiol in the EMA report). In other respects the EMA
report included dozens of additional tables, requested by the Steering
Committee. Having seen the results of these successively elaborated
supplementary tables, SS requested a further analysis, in which he wanted
the starters and new users during the study period 2001-2009 not to have
used any type of hormonal contraception before 2001. The other members of
the steering committee did not find this analysis relevant considering the
fact that such a restriction eliminated 93.6% of the exposure time and
93.4% of the events in users of OC with LNG in the study period 2001-2009.
SS insisted, however, in getting this table, and got it.

As expected the rate ratio estimates between OC with drospirenone
versus OC with LNG were unstable and ranged from 0.5 to 1.9 for different
duration categories, with an overall estimate of 1.0. We concluded this
was due to chance, due to the low number of events (n=11), an
interpretation that was confirmed by the rate ratio of 2.05 by inclusion
of all starters and new users. After a pause of at least 12 weeks nobody
believes that previous use influences the risk of thrombosis with new use.

For these reasons we did not include this unreliable and according to
different duration groups inconsistent results in our BMJ paper, it simply
did not add any further relevant information in addition to what already
is included in Appendix 4.

Surprisingly, SS instead of acknowledging the improvements in our new
analysis founders a single unreliable estimate based on a tiny fraction of
our exposure time and thrombotic events.

After our on-line publication, the FDA published last week the results of
an American historical cohort study including 898,251 women years and 625
venous thromboses in users of hormonal contraception. They found a
significantly higher risk of hospitalized venous thrombosis in users of OC
with drospirenone as compared with users of OC with LNG; Rate ratio 1.49
(1.11-2.01) and if restricted to only new users of 1.72 (1.14-2.59),
results further confirming a differential risk of venous thrombosis with
different progestogen types (4).

On the authors' behalf, Ojvind Lidegaard

1. Lidegaard O, Nielsen LH, Skovlund CV, Skjeldestad FE, Lokkegaard
E. Risk of venous thromboembolism from use of oral contraceptives
containing different progestogens and oestrogen doses: Danish cohort study
2001-9. BMJ 2011; 343: d6423.

2. Lidegaard O, Lokkegaard E, Svendsen Al, Agger C. Hormonal
contraception and risk of venous thromboembolism: national follow-up
study. BMJ 2009; 339: b2890.

3. Shapiro S, Dinger J. Risk of venous thromboembolism among users of
oral contraceptives: a review of two recently published studies. J Fam
Plann Reprod Health Care 2010; 36: 33-8.

4. FDA Office of Surveillance and Epidemiology. Combined hormonal
contraceptives (CHCs) and the risk of cardiovascular disease endpoints.

Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare that: Bayer Schering Pharma is thanked for covering the expenses of the analysis. All funding was given to Rigshospitalet, and the primary investigator received no salary for his work with this study, the EMA report or this manuscript. OL has within the last three years received honorariums for speeches on pharmacoepidemiological issues, including fees from Bayer Pharma Denmark and Novo Nordisk, and will be an expert witness for plaintiffs in a legal US case in 2011-2; FES received compensation for his work in the steering committee of the European Medicines Agency report.

02 November 2011
professor of obstetrics and gynaecology,
on behalf of Lars Hougaard Nielsen, Charlotte Wessel Skovlund, Finn Egil Skjeldestad, Ellen Lokkegaard
Gynaecological Clinic 4232, Rigshospitalet, University of Copenhagen, Denmark