Correspondence

Authors reply
The RECORD programme compared
rivaroxaban 10 mg once daily with
either the EU or North American
approved regimens of enoxaparin
(40 mg once daily or 30 mg twice
daily). As Nina Raju and colleagues
note, factors such as pharmacological
target and dierences in dose and
frequency, as well as timing of initial
postoperative drug administration,
can aect the safety or ecacy of
anticoagulants. However, RECORD4
and the RECORD programme as a
whole were not designed to compare
dierent enoxaparin regimens or to
provide indirect comparisons on the
ecacy of new anticoagulants.
T Stief raises an interesting point
regarding enoxaparin dose and the
potential undertreatment of patients
with
prothrombotic
conditions.
Although the same concerns would
apply to any anticoagulant, assessment
of an unapproved, investigational,
high-dose enoxaparin regimen was
beyond the scope of this phase 3 clinical
trial. Therefore, it is not possible to draw
conclusions about the relative ecacy
of such investigational regimens.
The RECORD4 trial, like other
phase 3 trials of anticoagulants, was
not designed or intended to provide
long-term data on surgical outcomes
after knee arthroplasty. However,
the study did provide results on
endpoints that can aect long-term
outcomes, such as major bleeding,
haemorrhagic wound complications,
and postoperative wound infections
and wound drainage, and showed low
incidences with both drugs.
Strategies for reversal of the anticoagulant eect should be considered
for every anticoagulant. However,
specic reversal of anticoagulants
with relatively short half-lives, such as
rivaroxaban, is usually not necessary in
clinical practice. Low-molecular-weight
heparins also have no specic antidote
and have been used extensively
for the prevention and treatment
of thromboembolic disorders for
more than 20 years. If rivaroxaban
www.thelancet.com Vol 374 August 29, 2009

discontinuation or delay of next dose,

or appropriate symptomatic treatment
fail to control bleeding, recombinant
activated factor VII might be eective.1
However, as noted by Umile Longo
and colleagues, the risks and benets
of any new anticoagulant can only be
fully assessed by long-term clinical
monitoring, as is the case for any newly
approved medication.
As Antonio Gomez-Outes and
colleagues note, the relatively low rates
of major bleeding in RECORD4 can be
attributed to the denition used, which
excluded surgical-site bleeding events
associated with a fall in haemoglobin
of 20 g/L or more, or requiring
transfusion of two or more units of
blood; this denition was adopted
across the RECORD programme to
allow a better assessment of clinically
important bleeding events, as opposed
to those that are an expected result of
the arthroplasty procedure.
We generally agree with GomezOutes and colleagues that non-signicant results do not imply equality of the
treatment groups. On the other hand,
the RECORD4 case scenarios presented
by Gomez-Outes and colleagues
implicitly assume that the relative
risk of 247, which they calculated
using the RECORD major bleeding
denition, also applies when using the
broader denition of major bleeding
(ie, including surgical-site events
associated with a fall in haemoglobin of
20 g/L or more, or requiring transfusion
of two or more units of blood) used in
other contemporary studies.2 In fact,
in RECORD4, the actual hazard ratio
calculated using the broader major
bleeding denition that included
surgical-site bleeding was 167 (95% CI
090310).3
Furthermore, the US Food and Drug
Administration (FDA) ancillary analyses
referenced by Gomez-Outes and
colleagues used a covariate adjustment
(for active treatment duration) that
resulted in an overestimate of the
rivaroxaban treatment eect on
bleeding due to confounding of the
treatment group with active treatment

duration in RECORD2. This approach

was extensively discussed during the
FDA Advisory Committee meeting
(March 19, 2009) and queried by the
independent biostatistician on the FDA
Advisory Committee panel.4 It should
also be noted that, in the sponsors
brieng document, additional pooled
analyses are presented that take
into account the dierent treatment
durations of rivaroxaban and enoxaparin in RECORD2.3 These results were
consistent with the primary analysis
results as reported by the sponsor.
AGGT receive honoraria as a member of the steering
committee and has served as a consultant to Bayer
Schering Pharma. AB and FM are employees of
Bayer Schering Pharma.

*Alexander G G Turpie, Alice Benson,

Frank Misselwitz
turpiea@mcmaster.ca
McMaster University, Hamilton, Ontario L8L 2X2,
Canada (AGGT); and Bayer Schering Pharma AG,
Wuppertal, Germany (AB, FM)
1

Bayer HealthCare. Xarelto: summary of

product characteristics. http://www.xarelto.
com/scripts/pages/en/information-onxarelto/summary_of_product_characteristics/
index.php (accessed June 26, 2009).
Schulman S, Kearon C. Denition of major
bleeding in clinical investigations of
antihemostatic medicinal products in nonsurgical patients. J Thromb Haemost 2005;
3: 69294.
Johnson & Johnson Pharmaceutical Research &
Development. Rivaroxaban for the prophylaxis
of deep vein thrombosis (DVT) and pulmonary
embolism (PE) in patients undergoing hip or
knee replacement surgery. FDA Advisory
Committee Brieng Book, Feb 12, 2009. http://
www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/Cardiovas
cularandRenalDrugsAdvisoryCommittee/
UCM138385.pdf (accessed Aug 4, 2009).
FDA Cardiovascular & Renal Drugs Advisory
Committee. Meeting ID: 20094418. http://
www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/Cardiovas
cularandRenalDrugsAdvisoryCommittee/
UCM143863.pdf (accessed Aug 4, 2009).

On empathy: another
perspective
Jane Macnaughtons essay on
empathy (June 6, p 1940)1 raises
several controversial issues which
require clarication. First, she does
not provide evidence of how medicine
supposedly hijacked and redened
the concept of empathy. Empathy
683

Correspondence

Science Photo Library

is derived from the Greek word

empathieia, meaning aection, or
the ability to sense and understand
someone elses feelings as if they
were ones own. This is the version
of empathy promoted in Goerge
Engels 1977 biopsychosocial model
of medicine, as well as in the related
concept of narrative medicine.2,3 In
this way, empathy is used to apply
medical knowledge to the wellbeing
needs of each patient.
Second, Macnaughtons assertion
that it is not possible to understand
patients psychologically is perhaps
an extreme position. Yes, it is dicult
to gain a complete understanding
of what a patient is feeling or
experiencing. However, in many
instances, an essential dierence
between a competent doctor and a
good one is that the latter is better
able to use her or his ability to sense
and understand a patients feelings
to work through the patients beliefs,
relationships, and stresses to facilitate
a speedy recovery. To assume that this
ability cannot be mastered is to deny
the testimonies of many patients.
Third, the last sentence of
Macnaughtons essay states: A
doctor who responds to a patients
distress with I understand how
you feel is likely, therefore, to be
both resented by the patient and
self deceiving. I agree. Making
such statements is not consistent
with empathy. By contrast, the art
of empathic understanding in a
physicianpatient setting involves
accomplishing acts of witnessing
a patients distress and establishing
a therapeutic alliance. As time slots
for clinical relationships shrink due
to economic imperatives, physicians
need to learn optimum methods of
achieving therapeutic relationships
that are both empathic and eective.

1
2

Gestational diabetes
and health promotion
In the special issue of The Lancet
dedicated to diabetes (May 23),
and in particular in the three papers
focusing on pregnancy,13 there is
no reference to the power that the
term gestational diabetes has to
transform a happy pregnant woman
into an anxious or depressed one.
Instead of using this term, would it
not be more cost eective to routinely
spend longer than usual discussing
with all pregnant women several
aspects of their lifestyle, in particular
the importance of daily physical
activity and, in the age of soft drinks
and white bread, issues such as high
versus low glycaemic index foods? In
other words, would it not be better to
make antenatal care an opportunity
of a lifetime for reconsidering several
aspects of our modern lifestyle?1
Instead of focusing on the prevention of a limited number of maternal
disorders, would it not be more
advantageous to positively promote
health and to develop long-term
thinking? These questions need to be
raised at a time when we have begun
to realise that our health is to a great
extent shaped in the womb.

684

In their Correspondence letter

(June 27, p 2195),1 Gopal Dabade and
Jacob Puliyel state: Given that the
vaccine costs $250 per child, $250 000
will be spent to prevent...four cases
of pneumonia. In fact, the average
cost to GAVI per dose of advance
market commitment (AMC) vaccines
is US$425 (a conservative estimate
which averages the doses that will be
bought at $7 in the AMC period and
those that will be bought at maximum
$350 in the tail period). Therefore the
cost of vaccinating 1000 children is
$12 750 ($425 multiplied by three
doses per treatment multiplied by
1000 children), and not $250 000.
This gure represents an excellent
investment to help prevent one of
the biggest killers of children in the
poorest parts of the world.

Tania Cernuschi
tcernuschi@gavialliance.org
GAVI Alliance, 2 Chemin des Mines, 1202 Geneva,
Switzerland
1

Dabade G, Puliyel J. Global health and the

Bill & Melinda Gates Foundation. Lancet 2009;
373: 219596.

Michel Odent
modent@aol.com
Primal Health Research Centre, London NW3 2JR, UK
1

niyi.awofeso@uwa.edu.au
University of Western Australia, Crawley, Perth,
WA 6009, Australia; and University of New South
Wales, Sydney, NSW, Australia

Pricing of pneumococcal
vaccines under advance
market commitments

I declare that I have no conicts of interest.

I declare that I have no conicts of interest.

Niyi Awofeso

Macnaughton J. The dangerous practice of

empathy. Lancet 2009; 373: 194041.
Borrell-Carrio F, Suchman AL, Epstein RM.
The biopsychosocial model 25 years later:
principles, practice and scientic inquiry.
Ann Fam Med 2004; 2: 57684.
Charon R. Narrative medicine: a model for
empathy, reection, profession and trust.
JAMA 2001; 286: 1879902.

Bentley-Lewis R. Gestational diabetes mellitus:

an opportunity of a lifetime. Lancet 2009;
373: 173840.
Bellamy L, Casas J-P, Hingorani AD, Williams D.
Type 2 diabetes mellitus after gestational
diabetes: a systematic review and metaanalysis. Lancet 2009; 373: 177379.
Reece EA, Leguizamn G, Wiznitzer A.
Gestational diabetes: the need for a common
ground. Lancet 2009; 373: 178997.

Department of Error
Lees AJ, Hardy J, Revesz T. Parkinsons disease.
Lancet 2009; 373: 205566In this Seminar
(June 13), the authors of reference 37 are
incorrect. They should be: Gan-Or Z, Giladi N,
Rozovski U, et al. Also, the author of reference
99 should be: Parkinson Study Group.

www.thelancet.com Vol 374 August 29, 2009