The third generation oral contraceptive controversy
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7213.795 (Published 25 September 1999) Cite this as: BMJ 1999;319:795
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The influence of industrial "competing interests" in the third
generation contraceptive controversy is becoming worrisome. At the end of
last year there were three major studies without industrial sponsoring
that found a higher risk of venous thrombosis for third generation
contraceptives, in contrast to three sponsored studies (1). To date, of
nine un-sponsored studies, one study finds no difference - the other eight
find relative risks from 1.5 to 4-fold (summary relative risk 2.4); four
sponsored studies found relative risks between 0.8 to 1.5 (summary
relative risk 1.1) [references given separately at the end of this response]. The industry-sponsored
study with a relative risk of 1.5 has been reanalysed several times,
yielding lower relative risks; after this failed to convince (2), a new
reanalysis was sponsored by another company (3).
In 1995 four studies found the same risk. That evidence was
sufficient for public health action, since equally reliable pills were
available. For at least one company, the third generation pill secured
more than half their revenues. The companies proclaimed a virtual 100%
certainty that everything was bias and confounding. Even for a skeptic at
the time, that was an unreasonable position: all four studies were
reasonably executed and had withstood criticism with the Committee on
Safety of Medicines and with reviewers of leading journals. Thus, the
company position held a high risk to boomerang and to discredit both their
product and their credibility. Their behaviour reminds of Barabara
Tuchman's "The march of folly" (4): rulers become disjointed from reality
and despite clear warnings continue actions against their own best
interest.
Since 1995, three multinationals have used enormous marketing
resources to sow confusion. An avalanche of special symposia and paid
supplements convinced outsiders that something had to be wrong with the
studies finding the higher risks. Many general practitioners,
gynecologists and family planners were swayed in accepting methodologic
arguments that sounded logical - because of their legitimate concern with
good contraception. However, few are really trained in the intricacies of
epidemiologic arguments. The companies exerted strong legal pressure on
governements. "Irresponsible scientists" were accused to have caused a
pill-scare - by juxtaposing selected figures without showing longer time
trends in unwanted pregnancies. Irrelevant comparisons abounded, as with
the risk of thrombosis in pregnancy.
The industrial view on "bias and confounding" was disproved by a WHO
scientific committee with leading epidemiologists not involved in the
controversy (5). Given the pervasiveness of the industrial "competing
interest", BMJ readers should know whose words they read.
(1) Vandenbroucke JP. Medical journals and the shaping of medical
knowledge. Lancet 1998;352:2001-6.
(2) Walker AM. Newer oral contraceptives and the risk of venous
thromboembolism. Contraception. 1998; 57: 169-181.
(3) Lewis MA, MacRae KD, Kühl-Habich D, Bruppacher R, Heinnemann LAJ,
Spitzer WO. The differential risk of oral contraceptives: the impact of
full exposure history. Hum Reprod 1999;14:1493-9.
(4) Tuchman BW. The march of folly: from Troy to Vietnam. New York :
Knopf, 1984.
(5) Cardiovascular disease and steroid hormone contraception. Report of a
WHO scientific group. Geneva, World Health Organization, 1998 (WHO
Technical Report Series, No. 877).
Jan P Vandenbroucke MD
Department of Clinical Epidemiology
vdbroucke@mail.medfac.leidenuniv.nl
Frans M Helmerhorst MD
Department of Obstetrics, Gynaecology and Reproductive
Medicine
Frits R Rosendaal MD
Thrombosis and Hemostasis Research Center
Leiden University Medical Center, Leiden, the
Netherlands.
The 13 extra references. References 4, 7, 11, 12 are sponsored by
pharmaceutical companies that manufacture third generation oral
contraceptives.
(1) World Health Organization Collaborative Study in Cardiovascular
Disease and Steroid Hormone Contraception. Effect of different
progestogens in low dose oral contraceptives on venous thromboembolic
disease. Lancet 1995; 346: 1582-1593.
(2) Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of
idiopathic cardiovascular death and nonfatal venous thromboembolism in
women using oral contraceptives with differing progestogen components.
Lancet 1995; 346: 1589-1593.
(3) Bloemenkamp KWM, Rosendaal FR, Helmerhorst F, Büller H, Vandenbrouke
JP. Enhancement by factor V Leiden mutation of risk of deep-vein
thrombosis associated with oral contraceptives containing a
third-generation progestogen. Lancet 1995; 346: 1593-1596.
(4) Spitzer W, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD. Third
generation oral contraceptives and risk of venous thromboembolic
disorders: an international case-control study. BMJ 1996; 312:83-88.
(5) Bennet L, Odeberg H. Resistance to activated protein C, highly
prevalent amongst users of oral contraceptives with venous
thromboembolism. J Intern Med 1998;244:27-32
(6) Andersen BS, Olsen J, Nielsen GL, Steffensen FH, Sørensen HT, Baech
J, Gregersen H. Third-generation oral contraceptives and heritable
thrombophilia as risk factors of non-fatal venous thromboembolism.
Thrombosis and haemostasis 1998; 79: 23-31.
(7) Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous
thromboembolism. A case-control study. Contraception 1998; 57: 291-301
(8) Bloemenkamp KWM, Rosendaal FR, Büller HR, Helmerhorst FM, Colly LP,
Vandenbroucke JP. Risk of venous thrombosis with use of current low-dose
oral contraceptives is not explained by diagnostic suspicion and
referral bias. Arch Intern Med 1999; 159: 65-70.
(9) Vasilakis C, Jick SS, Jick H. The risk of venous thromboembolism
in users of postcoital contraceptive pills. Contraception 1999;59:79-83
(10) Herings RMC, Urquhart J, Leufkens HGM. Venous thromboembolism among
new users of different oral contraceptives. Lancet 1999; 354: 127-8.
(11) Farmer RDT, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton JR.
Population- based study of risk of venous thromboembolism associated
with various oral contraceptives. Lancet 1997; 349: 83-88.
(12) Farmer RDT, Todd JC, MacRae KD, Williams TJ, Lewis MA. Oral
contraception was not associated with venous thromboembolic disease in
recent study. BMJ 1998; 316: 1090.
(13) Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM.
Interaction between the G20210A mutation of the prothrombin gene and
oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc
Biol 1999;19:700-3
Competing interests: No competing interests
I think other general readers of the BMJ like me might find it easier
to understand this debate if the advantages of third generation oral
contraceptives over existing formulations could be made clearer. Which
outcomes, desired by women themselves, are more likely to be achieved with
third generation than with second generation preparations? I was unable to
identify a systematic review of the relevant controlled trials in a brief
search of The Cochrane Library.
Competing interests: No competing interests
I stand entirely by our decision to ask Dr O'Brien to write our
editorial on third generation contraceptive pills, and I regret that
Dr Ledger has not declared whether or not he has any competing interests.
I ask him to make clear on our website whether he
does.
I am concerned that in an environment where disclosure of competing
interests is just becoming routine, Dr O'Brien has had his
competing interests declared but previous commentators in the BMJ have
not.
In particular, I'm concerned that we did not make a declaration after
the commentary by Øjvind Lidegaard that we published
in June.(1) Dr Lidegaard has also posted a rapid response to Dr O'Brien's
editorial. I thus emailed Dr Lidegaard and asked him
to make clear any competing interests he might have. This is his response:
"I have received funds for all my epidemiological research during the
last 15 years, the majority from public Danish health funds. The last
one, was an unconditional co-grant from the companies Organon, Wyeth and
Schering (as
indicated in my published papers).
"I have received fees for some speeches from companies. None during
this year, few in
1998 and several in 1996-7 (and further back).
"I have received fees for consultancy in five legal processes during
the last 15 years. In
four cases I have been consultant for plaintiff; In two cases for women
suffering a
thrombotic stroke (one in UK, one in Denmark), in two cases for companies
suing health
boards (Organon/Schering). In one case I have been consultant for the
defendant (a stroke
case in USA).
"I have received no funds for a 'member of staff.'"
These comprise what we mean by competing interests, and we believe
that all such interests should be declared. I'm grateful to
Dr Lidegaard for having declared them now.
Dr Lidegaard also wrote in his email to me:
"I agree that competing interest should be indicated. And I have, as
you mentioned, several potential competing interests. With
the definition of competing interest you indicated, however, every expert
in a certain field will per definition have competing
interests. That fact is a consequence of the circumstance that as soon as
you are considered (by some people) to be an expert,
you are invited to speak about your expert field when it is on the agenda,
and you are often asked about consultancy assistance
in legal processes.
"If competing interests should have any meaningfulness, I think there
should be some
criteria of actuality. E.g. if I made a speech 12 years ago in a meeting
sponsored by a
company - should I then sign all my publications, letters, commentaries,
etc the rest of my
professional life with that 'competing interest'? I have had more than
300 speeches
during the last 15 years. How do you in practice comply with that
circumstance in regard to
'competing interests'. More than 50 different companies, organisations,
scientific boards,
health authorities, lawyers, scientific societies, etc, have been involved
in some of these
speeches. Are you expecting a list of all these?
"The fact is that I consider myself as an independent scientist. My
scientific opinion in the
'third generation pill controversy' is in contrast to that of some of my
sponsors, but
I have had no problem in maintaining what I consider as a 'balanced view'
in this
controversy."
In response, I have two points to make.
Firstly, it is true that most protagonists in a debate eventually
have some competing interest. There are few who are both well
informed and wholly independent but well informed. That is why disclosure
is a better policy than banning anybody with any
competing interest.
Secondly, we urge all those communicating with us--"if in doubt,
disclose."
Richard Smith
Editor, BMJ
1. Lidegaard Ø. Commentary: Oral contraceptives and myocardial
infarction: reassuring new findings . BMJ 1999;318:1584.
Competing interests: No competing interests
In a BMJ editorial of September 25, 1999 (319: 795-6) on the third
generation oral contraceptive controversy, Dr. O'Brien advocated that oral
contraceptives (OCs) with 3rd generation progestagens (desogestrel or
gestodene) are less safe than OCs with 2nd generation progestagens
(levonorgestrel). His arguments for this statement were firstly, that OCs
with 3rd generation progestagens confer a higher risk for venous
thromboembolism (VTE) than do OCs with 2nd generation progestagens, and
secondly that OCs with 3rd generation progestagens imply the same risk of
AMI than do OCs with 2nd generation OCs. Permit me a few comments on these
statements.
Four studies published in late 1995 and early 1996 demonstrated a higher
risk of VTE in current users of OCs with 3rd generation progestagens than
in users of OCs with 2nd gen. progestagens. Since then, four new studies
have found smaller differences or no difference in the risk of VTE between
users of OCs with 2nd and 3rd gen. progestagens1-4. These subsequent
studies are - according to O'Brien - of "lower methodological quality". No
arguments for this statement were given. The fact is that these subsequent
studies tried to control more carefully for confounders, especially
duration of OC use and family disposition of VTE than the primarily
published studies, and two of the papers included re-analysis of data from
the primarily published papers2,4.
Next, he finds support for his statement in newly published incidence data
from Denmark, in which VTE among women 15-49 years old increased by 17%
during the period in which OCs with 3rd gen. progestagens were introduced.
However, the incidence rate of VTE among pregnant Danish women (very few
of whom probably were users of OCs) increased by more than 250% during the
same period5. The authors of the latter paper concluded that this increase
probably was due to the development in diagnostic equipment. It is
difficult to see why an increase of 17% among non-pregnant women
necessarily should be attributed to the introduction of OCs with 3rd
generation progestagens, and the development in diagnostic equipment
should influence only pregnant women.
Of five studies on OCs and AMI conducted after the introduction of 3rd
gen. OCs, four found less risk of AMI among users of OCs with 3rd as
compared with 2nd gen. progestagens6-10. The difference was significant in
one of these studies6. Apparently, O'Brien's statement rely solely upon
the most recently published MICA study, which could be influenced more by
recall bias than any of the previous AMI-studies10.
While an incidence study from Denmark get enormous media coverage, a
recently published paper from the WHO-group confirming an earlier Danish
finding that users of OCs with 3rd gen. progestagens had a lower odds
ratio of thrombotic stroke; 1.8 (0.6-5.2) against an odds ratio among
users of OCs with 2nd gen. progestagens 2.7 (1.8-4.1) did not get any
attention at all11. Where is the balance?
It is understandable that professionals working in clinics managing
only VTE or being consultants in legal processes supporting women
suffering from VTE are focused on this particular aspect of OCs. On the
other hand, it is clearly unacceptable to come out with overall
recommendations based on such a limited aspect, when other clinically more
important aspects which favour OCs with 3rd gen. OCs are omitted. Unless
an approach towards a balanced consideration of all relevant thrombotic as
well as non-thrombotic aspects of OCs is attempted, the 3rd gen. pill
controversy will continue with confused clients, colleagues and lay press
as one of several consequences. Unfortunately, is not that simple that one
product is safer than another, but that each generation has bigger or
smaller advantages and disadvantages.
Ø. Lidegaard
Copenhagen, September 27, 1999
References
1. Farmer RDT, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR.
Population-based study of risk of venous thromboembolism associated with
various oral contraceptives. Lancet 1997; 349: 83-8.
2. Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L.
First-time use of newer oral contraceptives and the risk of venous
thromboembolism. Contraception 1997; 56: 141-6.
3. Lidegaard Ø, Edström B, Kreiner S. Oral contraceptives and venous
thromboembolism. A case-control study. Contraception 1998; 57: 291-301.
4. Lewis MA, MacRae KD, Kühl-Habich D, Bruppacher R, Heinemann LAJ,
Spitzer WO. The diffential risk of oral contraceptives: the impact of full
exposure history. Hum reprod 1999; 14: 1493-9.
5. Andersen BS, Steffensen FH, Sørensen HT, Nielsen GL, Olsen J. The
cumulative incidence of venous thromboembolism during pregnancy and
puerperium. An 11 year Danish population-based study of 63,300
pregnancies. Acta Obstet Gynecol Scand 1998; 77: 170-3.
6. Lewis M, Heinemann LAJ, Spitzer WO, MacRae KD. Bruppacher R. The
use of oral contraceptives and the occurrence of acute myocardial
infarction in young women. Contraception 1997; 56: 129-40.
7. Jick H, Jick SS, Myers MW, Vasilakis C. Risk of acute myocardial
infarction and low-dose combined oral contraceptives. Lancet 1996; 347:
627-8.
8. WHO. Acute myocardial infarction and combined oral contraceptives:
results of an international multicentre case-control study. Lancet 1997;
349: 1202-9.
9. Lidegaard Ø, Edström B. Oral contraceptives and myocardial
infarction. A case-control study. Eur. J Contraception Reprod Health Care
1998, suppl. 1, 72-3.
10. Dunn N, Thorogood M, Faragher B, Caestecker L, MacDonald TM,
McCollum C, Thomas S, Mann R. Oral contraceptives and myocardial
infarction: results of the MICA case-control study. BMJ 1999; 318: 1579-
84.
11. Poulter NR, Chang CL, Farley TMM, Marmot MG, Meirik O, and the
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone
Contraception. Effect on stroke of different progestagens in low oestrogen
dose oral contraceptives.. Lancet 1999; 354: 301-2.
Competing interests: No competing interests
Sir
O'Brien (1) writes for 1 1/2 pages beneath the headline 'The
third generation oral contraceptive controversy' shortly after the UK
Medicines Commission removed restrictions on prescribing this class of
drugs. He
appears guilty of selectively quoting articles that support his contention
that third generation contraceptives are less safe than older
preparations.
We then read that O'Brien is a 'paid consultant to the legal team
representing women who developed a venous thrombosis while using third
generation oral contraceptives'. While publication of this leading
article will no doubt aid his clients' quest for compensation, I doubt
that he is
any more able to present a balanced view of this complex subject than a
representative from the pharmaceutical industry would be.
The BMJ is
frequently quoted by the popular press. There is clear evidence that 'pill
scares' of
this kind result in discontinuation of contraception and increases in
pregnancy terminations. Your editorial board should select less apparently
biased authors when commissioning work of this kind.
William L Ledger
University Department of Obstetrics and Gynaecology,
Jessop Hospital For Women,
Leavygreave Road,
Sheffield S3 7RE
1.O'Brien P BMJ 1999 319 795 -6
Competing interests: No competing interests
Competing interests in relation to science
In the BMJ of 25th September, the editor highlighted the need for
transparency in matters of competing interests. The need for such a
policy is amply illustrated by the recent controversy regarding so-called
third generation oral contraceptives. During the debate huge amounts of
money have been spent rubbishing well-conducted studies with clear a
priori hypotheses and analyses which found unexpected higher relative
risks of venous thrombosis between users of 'third generation' pills
containing desogestrel and gestodene, and users of older preparations. At
the same time, studies of venous thromboembolism using non-validated data,
post priori sub-group analyses, controls of different age recruited for a
study of stroke, and inappropriate statistical adjustments, have been
promoted as providing robust evidence of an absence of risk. The
proponents of such arguments have often been paid consultants of oral
contraceptive manufacturers, or individuals receiving large research
grants from these companies.
To this mixture of claim and counter-claim we have the smokescreen of
whether particular oral contraceptives have different risks of myocardial
infarction. For most women this issue is an irrelevancy. For it is
rarely acknowledged that most women stop the pill (usually before their
early or mid-thirties) well before they are at risk of having a myocardial
infarction. Furthermore, it is conveniently forgotten that low risk women
(i.e. those who do not smoke, without hypertension and who have their
blood pressure measured before using the pill) are not at risk of
myocardial infarction, irrespective of what oral contraceptive they use.
Money is a powerful motivator and as O'Brien points out in his
editorial the stakes have been very high. In this controversy great
efforts have been made to discredit the work of well respected
researchers, regulatory authorities and the World Health Organization. A
skeptic might wonder whether such efforts would have been made if the
first studies had found differences in favour of third generation pills
rather than against them?
Science is not a dispassionate activity. Money, desire for fame,
excessive self-belief in one's work, jealously can all distort one's
perspective. The 'truth' might never be established to the satisfaction
of all parties, and even in the age of evidence-based medicine opinion
guides clinical practice. Having spent much time considering the various
arguments, and having been a paid consultant to the World Health
Organization as Rapporteur for its Scientific Group on Cardiovascular
Disease and Steroid Hormone Contraception, I believe like O'Brien that all
currently available oral contraceptives are safe. I also agree that the
older, so-called second generation formulations have a smaller risk of
venous thromboembolism than the newer preparations containing desogestrel
or gestodene, and for this reason should be the preferred first choice for
most women.
Professor Philip Hannaford
Director
RCGP Centre for Primary Care Research and Epidemiology
Competing interests: The Centre for Primary Care Research and
Epidemiology (formerly the RCGP Manchester Research Unit) has received
funding for its research and education activities from all oral
contraceptive manufacturers. Hannaford has received lecture fees and
hospitality from oral contraceptive manufacturers, he has also been a paid
consultant to the World Health Organization and solicitors acting for the
defense of the oral contraceptive manufacturers.
Competing interests: No competing interests