Comment
The influences of exogenous hormones on risk of We declare that we have no conflict of interest.
ovarian cancer differ either side of menopause. In
premenopausal years, use of oral contraceptives could
help to decrease the number of cells that are likely to
become malignant over a lifetime, whereas HRT after
menopause could have a carcinogenic effect.7 The recent
declines in breast-cancer incidence in older women8
might reflect a parallel drop in HRT prescriptions.9 The
acceleration of the decline in ovarian cancer incidence in
the USA8 could have a similar explanation.
As for the link between oral contraceptives and ovarian
cancer, today’s collaborative analysis brings unequivocal
good news. Women and their health-care providers are
once again at a balancing act of judging risks versus
benefits.
*Eduardo L Franco, Eliane Duarte-Franco
Departments of Oncology and Epidemiology, McGill University,
Montreal, Quebec, Canada H2W1S6 (ELF); and Institut National de
Santé Publique du Québec, Montreal, Quebec, Canada (ED-F)
eduardo.franco@mcgill.ca
Stroke prevention in atrial fibrillation: another step sideways
See Articles page 315 In today’s Lancet, the Amadeus Investigators report their
open-label, randomised, non-inferiority trial in which
they examined whether idraparinux, a long-acting in-
direct inhibitor of factor Xa, was non-inferior to oral
vitamin K antagonists for thromboembolism preven-
tion in nearly 5000 patients with atrial fibrillation.1
Disappointingly, the trial was stopped early because of
excessive major bleeding in those receiving idraparinux.
Patients who were older, had reduced kidney function,
or were concurrently using aspirin were at greatest
risk of bleeding. Amadeus is part of a remarkable wave
of very large trials of new anticoagulants for atrial
fibrillation which are investigating replacements for
vitamin K antagonists (especially warfarin) with agents
that are comparably effective but less likely to cause
bleeding and easier to use and manage. To date, this
goal has proved elusive.
Despite sentinel trials that showed the dramatic
efficacy of vitamin K antagonists (64% risk reduction
compared with control),2 the drug industry’s enthusiasm
to develop alternatives is driven by the epidemiology
of atrial fibrillation and challenges associated with
vitamin K antagonists. About 1% of adults have atrial fibril-
278
1 Taylor T, Keyse L, Bryant A. Contraception and sexual health, 2005/06.
Oct 27, 2006. http://www.statistics.gov.uk/downloads/theme_health/
contraception2005–06.pdf (accessed Nov 25, 2007).
2 Chandra A, Martinez GM, Mosher WD, Abma JC, Jones J. Fertility, family
planning, and reproductive health of U.S. women: data from the 2002
National Survey of Family Growth. Vital Health Stat 2005; 23: 1–160.
3 Lacey JV, Colditz GA, Schottenfeld D. Exogenous hormones. In:
Schottenfeld D, Fraumeni JF, eds. Cancer epidemiology and prevention.
3rd edn. New York, USA: Oxford University Press, 2006: 468–88.
4 International Collaboration of Epidemiological Studies of Cervical Cancer.
Cervical cancer and hormonal contraceptives: collaborative reanalysis of
individual data for 16 573 women with cervical cancer and 35 509 women
without cervical cancer from 24 epidemiological studies. Lancet 2007;
370: 1609–21.
5 Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian
cancer and oral contraceptives: collaborative reanalysis of data from
45 epidemiological studies including 23 257 women with ovarian cancer
and 87 303 controls. Lancet 2008; 371: 303–14.
6 Million Women Study Collaborators. Ovarian cancer and hormone
replacement therapy in the Million Women Study. Lancet 2007; 369: 1703–10.
7 Narod SA. Ovarian cancer and HRT in the Million Women Study.
Lancet 2007; 369: 1667–68.
8 Ries LAG, Melbert D, Krapcho M, eds. SEER cancer statistics review,
1975–2004. 2007. http://seer.cancer.gov/csr/1975_2004 (accessed
Nov 25, 2007).
9 Espey DK, Wu XC, Swan J, et al. Annual report to the nation on the status of
cancer, 1975–2004, featuring cancer in American Indians and Alaska
Natives. Cancer 2007; 110: 2119–52.
lation, whose prevalence is highly age-dependent (10% of
those aged 80 years or older are affected).3 The affected
number worldwide will grow rapidly as populations age.
Atrial fibrillation increases the risk of ischaemic stroke
4–5-fold. Whilst vitamin K antagonists can largely reverse
this risk at an acceptable rate of bleeding, their efficacy
and safety depend on maintaining a narrow range of anti-
coagulation intensity (ie, international normalised ratio
[INR] 2·0–3·0).4 This goal is complicated by the fact that
the effect of these drugs is altered by underlying genotype,
coexisting illnesses, dietary intake, and exposure to
other drugs, which necessitates frequent INR testing and
dose adjustment. Even in recent trials,1,5–7 participants
treated with these drugs spent only 63–68% of the time
in the therapeutic INR range. In many clinical settings,
time within this INR range is much lower.8
In view of the burdens and associated bleeding risks
of vitamin K antagonists, many patients with atrial
fibrillation at higher risk of stroke never receive warfarin
and many who do ultimately discontinue treatment.
The drug industry has seized this apparent opportunity
to discover alternatives. Finding the ideal agent has not
been easy, because what is probably needed is a fixed
www.thelancet.com Vol 371 January 26, 2008

dose that is not affected by patients’ characteristics,
has rapid onset and end of activity, has no dietary or
drug interactions, requires no monitoring, and, most
importantly, has similar or greater efficacy and less
bleeding than vitamin K antagonists do.9
Amadeus represents the third recent unsuccessful
attempt to replace warfarin for atrial fibrillation. The
SPORTIF trials6,7 showed that the direct thrombin
inhibitor ximelagatran was nearly as efficacious with
less bleeding than vitamin K antagonists but had
unacceptable liver toxicity. ACTIVE-W showed superior
efficacy of vitamin K antagonists versus the combination
of aspirin and clopidogrel, which confirms that even
intensive antiplatelet therapy is not adequately effective
in atrial fibrillation.7 In Amadeus, the high risk of
bleeding with idraparinux associated with old age and
kidney dysfunction highlights the challenge of identify-
ing the proper drug and dose, and the need for better
risk stratification for major bleeding.
Worldwide, many thousands of patients are currently
entered in randomised trials of new antithrombotic
strategies for atrial fibrillation. The scale of these
efforts is driven by several factors. First, new agents
must be compared with vitamin K antagonists whose
proven efficacy is a formidable obstacle. Second, stroke
incidence in patients with atrial fibrillation seems to be
declining, with annual rates of about 1·5% in patients
thought to be at higher thromboembolic risk who are
treated with a vitamin K antagonist. Third, the increasing
use of non-inferiority designs (chosen largely because
of the perceived low likelihood of a new drug being
more efficacious than vitamin K antagonists) and asso-
ciated stringent standards for asserting non-inferiority
by regulatory agencies,10 combined with the other
factors, have led to the need for sample sizes of greater
than 10 000. Despite these challenges, we believe that on
the basis of positive features of recent trial experiences,
one or more approaches (eg, inhibition of factor Xa,
thrombin, or other clotting factors) will emerge as an
alternative to vitamin K antagonists and facilitate more
widespread use of effective and acceptably safe stroke
prevention in patients with atrial fibrillation.
Yet, while we wait for the new antithrombotics to
emerge, we still need dedicated innovative efforts to
improve the delivery of vitamin K antagonists for the
growing population with atrial fibrillation. Recent trials
have reinforced how effective vitamin K antagonists
www.thelancet.com Vol 371 January 26, 2008
Comment
Science Photo Library
Freeze-fracture electron micrograph of thrombus
can be in preventing strokes in atrial fibrillation.
However, these drugs are only as good as the quality of
anticoagulation management, which can be improved
by choosing the right patients to treat and maximising
time in the therapeutic INR range.11,12
*Alan S Go, Daniel E Singer
Division of Research, Kaiser Permanente of Northern California,
Oakland, CA 94612, USA (ASG); and Clinical Epidemiology Unit,
General Medicine Division, Massachusetts General Hospital and
Harvard Medical School, Boston, MA, USA (DES)
alan.s.go@kp.org
ASG has received research support from Johnson & Johnson. DES has been
a consultant to AstraZeneca, Boehringer Ingelheim, Bayer HealthCare,
Johnson & Johnson, and sanofi-aventis.
1 The Amadeus Investigators. Comparison of idraparinux with vitamin K
antagonists for prevention of thromboembolism in patients with atrial
fibrillation: a randomised, open-label, non-inferiority trial. Lancet 2008;
371: 315–21.
2 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to
prevent stroke in patients who have nonvalvular atrial fibrillation.
Ann Intern Med 2007; 146: 857–67.
3 Go AS, Hylek EM, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed
atrial fibrillation: national implications for management and stroke
prevention: the ATRIA study. Circulation 1999; 100 (suppl): 1-397.
4 Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation
on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;
349: 1019–26.
5 SPORTIF Executive Steering Committee for the SPORTIF V Investigators.
Ximelagatran vs warfarin for stroke prevention in patients with
nonvalvular atrial fibrillation: a randomized trial. JAMA 2005; 293: 690–98.
6 The Executive Steering Committee on behalf of the SPORTIF III
Investigators. Stroke prevention with the oral direct thrombin inhibitor
ximelagatran compared with warfarin in patients with non-valvular atrial
fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;
362: 1691–98.
7 The ACTIVE Writing Group on behalf of the ACTIVE Investigators.
Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in
the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of
Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;
367: 1903–12.
8 Boulanger L, Kim J, Friedman M, Hauch O, Foster T, Menzin J. Patterns of
use of antithrombotic therapy and quality of anticoagulation among
patients with non-valvular atrial fibrillation in clinical practice.
Int J Clin Pract 2006; 60: 258–64.
279
 Comment
9 Lip GY. Preventing stroke in atrial fibrillation: the SPORTIF programme.
Pathophysiol Haemost Thromb 2005; 34 (suppl 1): 25–30.
10 Snapinn S, Jiang Q. Preservation of effect and the regulatory approval of
new treatments on the basis of non-inferiority trials. Stat Med 2008;
27: 382–91.
11 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology
and management of the vitamin K antagonists: the Seventh ACCP
Mechanisms linking parental education and stunting
See Articles page 322 Growth failure resulting from poor nutrition (stunting)
is a major risk factor for deficits in children’s develop-
ment.1 In addition to confirming previous findings on
mothers’ education and stunting in their children,2 the
results from Richard Semba and colleagues, in today’s
Lancet,3 show that level of education in the father can
also contribute to the risk of stunting. However, far less is
known about the mechanisms (mediators) through which
maternal—and now, with Semba’s results, paternal—
education influences physical growth in children.
Semba and colleagues suggest that increased use of
health-promoting activities by educated parents (eg,
vaccination and vitamin supplementation of offspring)
is one mechanism through which parental education
influences their child’s physical growth. Similar findings
from other studies in developing countries indicate
that higher levels of maternal education are related to
mothers’ increased health knowledge,2 understanding of
health information,4 and use of health services.5 Semba’s
study also highlights an important methodological
The printed journal
includes an image merely
for illustration
Panos Pictures
Health and nutrition worker teaching village women in Bangladesh
280
Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;
126 (suppl 3): 204–33.
12 Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ.
Antithrombotic therapy in atrial fibrillation: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;
126 (suppl 3): 429–56.
issue, namely that association of parental education with
a specific risk or protective factor does not mean that
factor functions as a mediator. Appropriate statistical
tests are needed to confirm that mediation is occurring.6
Studies from developing countries have identified
other mechanisms that could also mediate associations
between mothers’ level of education and the physical
growth of their children. One potential pathway involves
the association between increased maternal education
and greater input by the mother into decisions on
allocation of family resources.7 Because mothers are
more likely than fathers to allocate family resources in
ways that promote their child’s nutrition,8 education
might increase the mother’s decision-making power,
which improves the child’s nutrition and health and
ultimately their physical growth.
Other studies from developing countries have
identified specific maternal factors that can also
function as mediators. One such factor is maternal
depression. In developing countries, more educated
women are at lower risk for depression than are
less educated women,9 and infants of mothers with
depression are at greater risk of growth failure than
are infants whose mothers are not depressed.10 The
mechanism through which depression in the mother
influences the physical growth of their child probably
involves reduced involvement in parental care by
depressed women.10 A second characteristic is the
mother’s intelligence. Increased levels of schooling are
linked to higher levels of maternal intelligence,11 and
children of mothers who are more intelligent have
better physical growth than those of less intelligent
mothers.12 Because intelligence is a marker for adaptive
behaviour,13 women with lower levels of intelligence
might have greater difficulty making appropriate
decisions on resource allocation (eg, what foods to
purchase) than those with higher intelligence, when
the family’s economic resources are limited.
www.thelancet.com Vol 371 January 26, 2008