Title page
Title:Red cell distribution width:A novel predictor of mortality in acute
pancreatitis
Authors:
1. Libing Jiang, BM
Department of Emergency Medicine, Second Affiliated Hospital, School of
Medicine?Institute of emergency Medicine, Zhejiang University, Hangzhou,
China.
Email:13738062354@163.com
2. Yuefeng Ma, PhD, MD, chief physician
Department of Emergency Medicine, Second Affiliated Hospital, School of
Medicin...
Title page
Title:Red cell distribution width:A novel predictor of mortality in acute
pancreatitis
Authors:
1. Libing Jiang, BM
Department of Emergency Medicine, Second Affiliated Hospital, School of
Medicine?Institute of emergency Medicine, Zhejiang University, Hangzhou,
China.
Email:13738062354@163.com
2. Yuefeng Ma, PhD, MD, chief physician
Department of Emergency Medicine, Second Affiliated Hospital, School of
Medicine?Institute
of emergency Medicine, Zhejiang University, Hangzhou, China.
Email:mayuefengbj@163.com
3.Mao Zhang, PhD, MD, chief physician
Department of Emergency Medicine, Second Affiliated Hospital, School of
Medicine?Institute
of emergency Medicine, Zhejiang University, Hangzhou, China.
Email:zmhzjzk@163.com
Corresponding author:
Mao Zhang PhD, MD
Complete postal address or affiliations: Emergency Medicine Research
Institute of Zhejiang University; Emergency Medicine Center, Second
Hospital Affiliated to Medical College, Zhejiang University, 88# Jie Fang
road, Shang Cheng district, Hangzhou, China.
Postcode: 310009
Tel.:+86571-87783921.
E-mail address: zmhzjzk@163.com
Keywords: red cell distribution width, acute pancreatitis
Word count: 625
To the Editor,
We have read with great interest the recently published article titled
"Association between red cell distribution width and acute pancreatitis: a
cross-sectional study" by Yao et al. 1 In that very well-presented
article, the authors aimed to investigate whether red cell distribution
width (RDW) was a predictor of mortality in patients with acute
pancreatitis (AP). They concluded that RDW measured on emergency
department (ED) admission was significantly associated with 90-day
mortality in patients with AP. We would like to thank Yao et al 1 for
their comprehensive contribution.
RDW is a quantitative measure of anisocytosis, any processes result in the
release of immature erythrocytethe or increased destruction of red blood
cell (RBC) will cause the increase of RDW.2 RDW is traditionally used for
the differential diagnosis of anemia (especially iron-deficiency anemia).
2 However, it has been reported recently RDW is an independent predictor
of mortality in various conditions, including chronic and acute heart
failure, acute dyspnea, acute pancreatitis, severe sepsis and septic
shock, trauma, acute pulmonary embolism, and even community-dwelling older
adults. 3-8 Whereas, RDW is an index affected by many factors such as
anemia, renal dysfunction or hepatic dysfunction, thyroid disease,
transfusion, acute or chronic inflammation, neurohumoural activation,
malnutrition (i.e. iron, vitamin B12 and folic acid), ethnicity, bone
marrow depression, and use of some medications ( i.e. erythropoietin use
and antibiotic use). 2, 5 However, in the present study, the authors did
not describe these conditions in detail and also did not exclude relevant
diseases in their exclusion criteria. We believe it would be better if the
authors elaborated on the above mentioned RDW affecting factors in more
detail. In addition, there are several other questions about this article.
Firstly, the time elapsed between blood sampling and RDW measuring was not
clearly defined, because the length of this interval may significantly
alter RDW levels.2 Secondly, this was a small sample size study, and only
8 non-survivors were included, we deduced that there is no enough
statistical power to reach this conclusion and this will increase the
probability of type I error. Meanwhile, in this study, multi-variate
regression analysis was not used to adjust other confounding factors,
therefore, we don't know whether the RDW - mortality association in
patients with AP is independent of other covariates. Thirdly, the reasons
why survivors of patients with AP had lower RDW than the healthy
participants appear to be most of these patients suffered from mild AP,
not only what the authors said in their article. Fourthly, according to
the data in the original report, positive likelihood ratio and negative
likelihood ratio of RDW to predict mortality should be 7.35 and 0.28,
rather than 7.35% and 0.28%. Fifthly, another major limitation of the
study by Yao et al1 is that no comparison of RDW and APACHE? and Ranson
scores has been made. Therefore, it still remains unclear whether the
discriminative power of RDW is better than both APACHE?and Ranson scores.
Moreover, we would like to know whether addition of RDW in the classical
prognostic model (such as APACHE?) may improve prognostic accuracy. All
these questions might be answered by further investigation. In addition to
RDW, many other biomarkers has also been shown to have an independent
association with mortality, such as neutrophil lymphocyte ratio, uric
acid, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), serum
creatine. Therefore, whether the combination of these indices may improve
prognostic accuracy?
In conclusion the study by Yao et al1 will lead to further studies
regarding the association between RDW and mortality or other adverse
outcomes in patients with AP. However, one should keep in mind that RDW
should be evaluated together with other prognostic or inflammatory
markers. Only in this way, can we obtain exact information from these
predictors.
Reference
1. Yao J, Lv G. Association between red cell distribution width and acute
pancreatitis: a cross-sectional study. BMJ open 2014;4:e004721.
2. Karagoz E, Tanoglu A. Red Blood cell distribution width: an emerging
diagnostic factor of acute appendicitis? World journal of emergency
surgery : WJES 2013;8:54.
3. N. Hong, J. Oh, S. M. Kang, et al. Red blood cell distribution width
predicts early mortality in patients with acute dyspnea. Clin Chim Acta
2012; 413: 992-7.
4. K. Senol, B. Saylam, F. Kocaay, et al. Red cell distribution width as a
predictor of mortality in acute pancreatitis. Am J Emerg Med 2013; 31: 687
-9.
5. C. H. Kim, J. T. Park, E. J. Kim, et al. An increase in red blood cell
distribution width from baseline predicts mortality in patients with
severe sepsis or septic shock. Crit Care 2013; 17: R282.
6. S. Majercik, J. Fox, S. Knight, et al. Red cell distribution width is
predictive of mortality in trauma patients. J Trauma Acute Care Surg 2013;
74: 1021-6.
7. H. S. Sen, O. Abakay, A. C. Tanrikulu, et al. Is a complete blood cell
count useful in determining the prognosis of pulmonary embolism? Wien Klin
Wochenschr 2014; 126: 347-354.
8. G. M. Felker, L. A. Allen, S. J. Pocock, et al. Red cell distribution
width as a novel prognostic marker in heart failure: data from the CHARM
Program and the Duke Databank. J Am Coll Cardiol 2007; 50: 40-7.
Olsen (1) has questioned the validity of the stillbirth data used in
Hedegaard et als study based on The Danish Birth Register (DBR). Lidegaard
replies that "We always make our own data retrieval from the raw data in
the National registries, including the birth registry rather than relying
on the official statistics" (2). However, we are concerned that data in
DBR seems very unreliable, and perhaps even compromised....
Olsen (1) has questioned the validity of the stillbirth data used in
Hedegaard et als study based on The Danish Birth Register (DBR). Lidegaard
replies that "We always make our own data retrieval from the raw data in
the National registries, including the birth registry rather than relying
on the official statistics" (2). However, we are concerned that data in
DBR seems very unreliable, and perhaps even compromised.
We check the register regularly and recently noted a dramatic
retrospective change on augmentation during year 2000-2006. The incidence
was suddenly lowered from 16,000 to approximately 10,000 annually. This
means that 6000 oxytocin augmentations a year have been deleted from the
register. No public information is available as to why this change
occurred. We e-mailed DBR (Aug.15 2014) and asked for an explanation but
received no answer. We sent a reminder Aug 27 and the next day the online
access to data from 2000-2006 were removed from the website, again without
any explanation. The Danish Health Authorities offer no public information
on why these changes have occurred. Even though augmentation is not an
outcome used in the study by Hedegaard et al, the changes raises strong
concerns about validity of the data in DBR in general. More importantly
for the validity of the data in the study by Hedegaard et al, we have
recently observed changes in DBR on induction rates for the year 2010
where 1033 induction had been added. Besides these inconsistencies Olsen
(1) draws attention to the discrepancy concerning the data on intra
uterine death, which are the primary outcome of the study by Hedegaard et
al (2).
All these observations make us question the validity of the data in
DBR and in the paper. The unexpected retrospective change in data, the
lack of explanation for these changes, and the closedown of the register
all fuel an uncertainty toward the data in DBR. The problem is, that
nobody knows which data are correct. We urge the authors to document the
validity of all data in their paper.
1. Olsen. O. Stillbirth data seem incorrect. BMJ Open. Epub 2014 Sep
10. http://bmjopen.bmj.com/content/4/8/e005785.short/reply#bmjopen_el_8836
2. Hedegaard M, Lidegaard O, Skovlund CW, Morch LS, Hedegaard M.
Reduction in stillbirths at term after new birth induction paradigm:
results of a national intervention. BMJ Open. 2014 Aug 14;4(8)
We read with interest the article regarding UK newspaper coverage of
common cancers by Konfortion et al [1] and were pleased that this
confirmed similar findings to our previous work [2]. We had previously
looked at the UK's print media coverage of the top ten most common cancers
in 2009: this found similar discrepancies between the prevalence of
disease and the number of articles about each cancer, wi...
We read with interest the article regarding UK newspaper coverage of
common cancers by Konfortion et al [1] and were pleased that this
confirmed similar findings to our previous work [2]. We had previously
looked at the UK's print media coverage of the top ten most common cancers
in 2009: this found similar discrepancies between the prevalence of
disease and the number of articles about each cancer, with over
representation of breast and prostate cancer and under representation of
colorectal and lung cancer [2]. We noted that coverage of breast and
prostate cancer was influenced by the illness of Kylie Monogue and Mr Al-
Megrahi (the Lockerbie bomber) in keeping with the work of Konfortion, et
al. We agree that the 'human element' articles may be key to
representation of cancer within the media, as shown by coverage of Kylie
Minogue, Jade Goody and Patrick Swayze (breast, cervical and pancreatic
cancer respectively), and we have referred to this phenomenon as the
'Swayze Shift' [3-5].
We believe that media coverage of disease is one of the most
important sources of health information to the general population and
greatly influences both public perception and awareness of disease [6-9].
Whilst cancer awareness months do improve awareness of disease, it is
clear from Konfortion et althat this strategy may not result in increased
media coverage. We believe that a policy of media advocacy - positive
engagement with health journalists - may greatly improve the quality and
accuracy of health information within media articles. We have also
suggested that media articles could be linked with 'red flag' symptoms to
improve awareness and encourage patients to present earlier [2]; we are
pleased to see this occurring in a recent article by the BBC (British
Broadcasting Corporation) that linked an article on pancreatic cancer to
the associated presenting symptoms [10].
Yours Sincerely
James Williamson and David Hocken
References
1: Konfortion J, Jack RH, Davies EA. Coverage of common cancer types in UK
national newspapers: a content analysis. BMJ Open 2014;4:e004677
2: Williamson JML, Jones IH, Hocken DB. How does the media profile of
cancer compare with prevalence? Annals of the Royal College of Surgeons of
England 2011;93:9-12
3: Chapman S, McLeod K, Wakefield M, Holding S. Impact of celebrity
illness on
breast cancer screening: Kylie Minogue's breast cancer diagnosis. Med J
Aust
2005; 183: 247-50.
4: Casey GM, Morris B, Burnell M, Parberry A, Singh N, Rosenthal AN.
Celebrities and screening: a measurable impact on high-grade cervical
neoplasia diagnosis from the 'Jade Goody effect' in the UK. Br J Cancer
2013;109:1192-7
5: Williamson JML, Hocken DB. Pancreatic cancer in the media: the Swayze
shift. Annals of the Royal College of Surgeons of England 2010;92:537-8
6: The PLoS Medicine editors. False hopes, unwarranted fears: the trouble
with medical news stories. PLoS Medicine 2008; 5: 681-3.
7: Williamson JML, Skinner CI, Hocken DB. Death and illness as depicted in
the media. International journal of clinical practice 2011;65:547-551
8: Jones IH, Williamson JML, Hocken DB. How informative is the print media
coverage of colorectal cancer? Colorectal Disease 2012;14:250-2
9: Williamson JML, Rink J, Hewin D. The portrayal of Bariatric Surgery in
the UK print media. Obesity Surgery 2012;22:1690-1694
10: Mountjoy S. Pancreatic cancer 'missed 19 times by NHS'. BBC news
website 7 July 2014. http://www.bbc.co.uk/news/uk-england-devon-28171117
Rydahl and Clausen are right about problems with the validity of some
official statistics published by central institutions or on the home page
of the State Serum Institute (SSI). These processed data are, however, not
the same as raw data from the Danish Birth Registry (DBR).
Today, official statistics are typically made by data managers in
severely understaffed units in our central administration, often without...
Rydahl and Clausen are right about problems with the validity of some
official statistics published by central institutions or on the home page
of the State Serum Institute (SSI). These processed data are, however, not
the same as raw data from the Danish Birth Registry (DBR).
Today, official statistics are typically made by data managers in
severely understaffed units in our central administration, often without
the possibility of knowledge sharing with clinical expertise. Please don't
make us accountable for these flawed statistics and the changes made in
them over time.
Misinterpretation of DBR data is, however, not the same as unreliable
DBR data. Making reliable statistics from raw diagnosis, procedural or
surgical codes is indeed not simple, even with a hard end point such as
stillbirth. For this reason, we have argued that such statistics should be
made at least in collaboration with clinicians with research experience in
handling registry data. Unfortunately, the central administrative units do
not always (in contrast to good old days) have budget for this proposal to
be effected.
Some people, e.g. Rydahl and Clausen apparently do not discriminate
between flawed analyses of valid registry data on the one hand, and the
baseline validity of the analysed data on the other hand, leading to the
rambling conclusion that all analyses based upon DBR data necessarily are
flawed.
For some years, the DBR has been provided with data from the National
Health Registry, supplemented by chart data from home deliveries (which
are not recorded in the National Health Registry) and by a separate feed
from death certificates which are not always included in the National
Health Registry. To achieve valid numbers of stillbirths demands all of
these three sources of death data to be collected and analysed together.
By doing so, provides in our opinion rather precise estimates of the real
number of stillbirths. And our guess is that one or two of these sources
of data may be missing in some of the official statistics. But that is
nothing but a qualified guess.
Considering all these challenges, it is a little hard to understand
why Rydahl and Clausen get so incensed that someone now publishes
carefully prepared analyses on stillbirths, since such qualified analyses
according to Rydahl and Clausen have been missing.
Thank you for your comments on the published paper.
C1) Recruitment:
In Bissau the majority of TB patients are diagnosed at a laboratory at the
local health centre, where the patient upon a positive smear is referred
to the TB nurse at the same facility who will then start treatment
immediately. Patients with smear negative TB are diagnosed at the national
TB hospital upon x-ray and physician consultation, and are also f...
Thank you for your comments on the published paper.
C1) Recruitment:
In Bissau the majority of TB patients are diagnosed at a laboratory at the
local health centre, where the patient upon a positive smear is referred
to the TB nurse at the same facility who will then start treatment
immediately. Patients with smear negative TB are diagnosed at the national
TB hospital upon x-ray and physician consultation, and are also from there
given treatment on the same day. There is therefore no delay in this part
of the process except in rare events of drug stock-outs etc, but in
general day of diagnosis and day of treatment initiation will be the same.
C2) Censoring:
As it is described in the paper the patient inclusion stopped at 4th of
June 2010. From then patients were followed through the treatment period.
The mortality data follow up was censored at 27th of April 2011 when the
final data-analysis was done. The details of this censoring could
definitely have been described in more detail in the manuscript and we
thank the eLetter authors for pointing this out.
C3) Lost to follow up:
In mortality studies the lost to follow up data are always important and
can be essential to evaluate the data strength and weaknesses of the data
collection.
In our case the focus of the paper was on treatment delay, clinical
severity at the diagnosis of TB and the risk factor analysis. The
mortality data was included to confirm the effect of long-term anti-TB
treatment for presumed smear negative TB patients.
It is important to understand that the follow up data mentioned concerning
effects of treatment assessed by change in clinical severity (e.g.
TBscore) is taken from the six months trial clinical examinations - at the
end of treatment.
When it comes to treatment delay and mortality the results are
inconclusive. The mortality analysis was done over the entire mortality
follow up time at 24 months but because of the significant challenges with
infrastructure and mobility of the population in a country like Guinea
Bissau there was a substantial number of "lost to follow up" cases after 2
years. This would probably explain at least part of the missing
association between treatment delay and mortality.
C4) Beta coefficient vs. relative risk
The risk factor analysis has been done on categorical independent
variables and the treatment delay variable (dependent) is continuous
(though logtransformed because of outliers). It is a simple linear
regression as it is described in the paper.
We did a search on a proper cutoff for delay and found differing
information in the literature and therefore decided to use the continuous
variable instead as to not "loose" too much data strength. The results are
as you correctly point out given as a beta-coefficient and should have
been described as such in the paper.
C5) Observation time on smear-negative TB-cases:
This is a helpful argument and we thank the authors of the E-letter. We
could have pointed this out in more detail in the discussion session. It
is widely accepted and well known that the diagnosis of TB-smear negative
TB is a process where there is a natural and inevitable delay in the
diagnosis and treatment of TB. The results of the paper only present the
difference in time whether it being a delay or a natural cause of TB-smear
negative diagnosis could always be discussed.
As a physician licensed in the state of California, where this study
was conducted, I would like to see each hospital identified by name, and
ranked by order of the prices they charge for each test. I request the
authors of this study please issue a supplementary data table exposing the
billing practices of each hospital by name. As a result of the Affordable
Care Act, many patients now have high-deductible medical insura...
As a physician licensed in the state of California, where this study
was conducted, I would like to see each hospital identified by name, and
ranked by order of the prices they charge for each test. I request the
authors of this study please issue a supplementary data table exposing the
billing practices of each hospital by name. As a result of the Affordable
Care Act, many patients now have high-deductible medical insurance, and
are effectively cash-paying patients, and may fail to comply with my test
orders if they are overcharged.
This protocol is enterprising, interesting and important, but it
nowhere refers to adverse events that might be effects of medication, or
of failure of a medicine to work.
Research on 'patient safety' in hospital has developed quite
separately from pharmacovigilance and the elucidation of harms possibly
caused by medicines and their prevention, but they are related both
conceptually and in practice. They need...
This protocol is enterprising, interesting and important, but it
nowhere refers to adverse events that might be effects of medication, or
of failure of a medicine to work.
Research on 'patient safety' in hospital has developed quite
separately from pharmacovigilance and the elucidation of harms possibly
caused by medicines and their prevention, but they are related both
conceptually and in practice. They need integration, or at least to take
notice of one another. This study could take a big step in that direction.
A further valuable dimension would be added by including all events
['incidents'] that might be attributable to a medication or a diagnostic
or therapeutic procedure. I very much hope this
will be put into the protocol. It would in any case be very useful also
to collect all reports of suspected and reported adverse drug reactions in
the study cohort, with their timelines, and to examine them as fully as
the other events that will be collected.
One other aspect is not clear from the protocol: who first noticed
and mentioned the 'incident', and how did the conversations about it
develop? (For example: patient> nurse> doctor; pharmacist>
doctor>; nurse> doctor >patient) That could influence how to set
about improving detection, reporting, analysis and communication.
We read with great interest the recently published National cohort
study of Hedegaard et al (1). The authors rightly indicate in their
introduction that women with foetal growth restriction or preeclampsia are
at high risk for stillbirth, and that in these women induction before term
is often recommended; these authors also stress that since 2009, Denmark
has had a more proactive policy including early intervention in wome...
We read with great interest the recently published National cohort
study of Hedegaard et al (1). The authors rightly indicate in their
introduction that women with foetal growth restriction or preeclampsia are
at high risk for stillbirth, and that in these women induction before term
is often recommended; these authors also stress that since 2009, Denmark
has had a more proactive policy including early intervention in women with
preeclampsia. However, no data are given in the article about the rates of
preeclampsia, small for gestational age babies, or foetal growth
restriction, although, as stated by the authors, the increased quality of
screening for ultrasound foetal growth and Doppler during the last decade
may have improved the monitoring of foetuses in utero, making it easier to
detect foetal growth restricted foetuses and to induce labour to avoid
foetal death or preeclampsia. Without these data, it is difficult to agree
with Hedegaard et al that "these circumstances are probably of minor
importance for the decrease in stillbirths" from the comparison of Danish
figures with the whole proportion of deliveries after 42 weeks in Sweden,
or the whole stillbirth rate after 37 gestational weeks in Norway. Indeed,
using the ReCoDe ("relevant condition at death") classification for
stillbirth, Gardosi et al confirmed that the most common cause of foetal
death was precisely foetal growth restriction (43.0%) in West Midlands
region of the UK (2) as it is observed worldwide (3), and the incidence of
this condition is probably similar in Denmark. This significant
contribution of foetal growth restriction (and possibly associated
preeclampsia in cases of defective placentation) is all the more plausible
that in the Disproportionate Intrauterine Growth Intervention Trial At
Term (DIGITAT) study (3) comparing the effect of induction of labour with
a policy of expectant monitoring for intrauterine growth restriction near
term in the Netherlands, even in the "expectant monitoring group" labour
had to be induced in as high as 50% of the patients at gestational age 277
(269-283) days [versus 95.6% at gestational age 266 (261-271) days in the
"Induction of labour group"]. Furthermore, taking into account the
possible impact of the message delivered by Hedegaard et al's article in
daily practice, the historical design (and not true intervention design)
of this study, with the inherent limitations, should have been clearly
specified in the clinical message.
1.Hedegaard M, Lidegaard O, Skovlund CW, M?rch LS, Hedegaard M.
Reduction in stillbirths at term after new birth induction paradigm:
results of a national intervention. BMJ Open. 2014;4:e005785.
2.Gardosi J, Kady SM, McGeown P, Francis A, Tonks A. Classification of
stillbirth by relevant condition at death (ReCoDe): population based
cohort study. BMJ. 2005;331(7525):1113-7.
3.Lawn JE, Blencowe H, Oza S et al and Lancet Every Newborn Study Group.
Every Newborn: progress, priorities, and potential beyond survival.
Lancet. 2014;384(9938):189-205.
4.Boers KE, Vijgen SM, Bijlenga D et al. Induction versus expectant
monitoring for intrauterine growth restriction at term: randomised
equivalence trial (DIGITAT). BMJ. 2010;341:c7087.
How Lundbeck's conclusion "Nalmefene can be seen as a cost-effective
treatment for alcohol dependence, with substantial public health benefits"
can have been published?(1) Should "Open" in BMJ Open means open to
aggressive marketing from the drug industry, open not to hope but to hype,
open without proper discussion despite several gross limitations.
First, the piece apply a mathematical model to three trials tha...
How Lundbeck's conclusion "Nalmefene can be seen as a cost-effective
treatment for alcohol dependence, with substantial public health benefits"
can have been published?(1) Should "Open" in BMJ Open means open to
aggressive marketing from the drug industry, open not to hope but to hype,
open without proper discussion despite several gross limitations.
First, the piece apply a mathematical model to three trials that were
sponsored by Lundbeck with authors who were on its payrolls. The first two
trials of six months' duration (ESENSE 1 and 2) are negative, however the
EuropeanMedicines Agency granted a marketing authorization on a subgroup
analysis comprising only a quarter of the patients, with half of the data
missing in the nalmefene group.(2) The thrid study (SENSE) is also
negative in intention to treat analysis.(3) The publication has little to
do with science as it associated per protocol analysis, sub group
analysis, post hoc analysis, and added to 16 end points of the genuine
protocol (which failed to evidence a relevant effect), a 17 and 18th end
points (heavy drinking days and reduction of total alcohol consumption)
at 13 months.(3) Both editors of the journal failed to respond a proposal to comment these major
flaws.(personal experience) Last, Laram?e failed to included results from
previous trials.(1) In 1998 Contral Pharma Ltd tried to develop nalmefene
for alcohol related problems but in 2003 nalmefene didn't succeed to meet
phase III clinical end points statistically significant. Lundbeck must
have the data, it paid for it when buying the patent to Contral Pharma.
Other previous nalmefene unsuccessful development included interstitial
cystitis, schizophrenic patients ...P values must be corrected for
multiple testings.
Second, the three studies are limited to surrogate endpoints: heavy
drinking days and total alcohol consumption. Although the European
Medicines Agency has accepted a reduction in drinking at 6 months as an
end point, the US Food and Drug Administration (FDA) does not accept it
yet. FDA is right, this surrogate endpoint has not been validated. Harm
reduction strategy used to minimize the personal harm and adverse societal
effects of alcohol dependence is not yet evidence based.(5,6). Moreover
theses surrogate end points in the nalmefene trials were obtained from
patient reports, a non reliable method.(6,7) Approving an alcohol misuse
drug on the basis of an increase in non-drinking days is similar to
approving a weight reduction intervention on the basis of reducing the
number of cakes consumed daily rather than the weight loss achieved or
ideally obesity related complications or obesity related death.(4) At
best, daily alcohol consumption is 5 to 9 grams lower with nalmefene than
with placebo and the impact of nalmefene on the complications of alcohol
dependence is not known. The crucial first step in the management of
alcohol-dependent patients is to establish a relationship built on trust
and to provide psychological and social support. When medication is
considered, it is better to choose acamprosate or naltrexone, drugs that
are only moderately effective but better-assessed.(8)
Third, regarding ethics, the lack of effective treatment in the
controlled group is a serious concern. Three treatments are validated
(acamprosate, naltrexone, disulfiram) to treat alcohol use disorders. Why
patients were deemed effective treatments for six months or even a year?
To avoid comparisons with an effective comparator? Indeed nalmefene do not
perform better than naltrexone but exhibits greater side effects.(9) This
is a breach in Helsinki declaration! Nalmefene should have been studied on
relevant clinical end points vs one of the usual treaments.
Last, despite Markov is a random process usually characterized as
memoryless, we must not forget Lundbeck's records. On June 19, 2013, the
European Commission imposed a fine of 93.8 million euros on Lundbeck and fined
several producers of generic pharmaceuticals a total of 52.2 million euros
after Lundbeck made agreements with the other companies to delay less
expensive generics of Lundbeck's branded citalopram, it best-selling
product at the time, from entering the market. In return for the ability
to maintain a monopoly on the drug's manufacture, Lundbeck offered
payments and other kickbacks. These violated EU antitrust rules that
prohibit anticompetitive agreements (Article 101 of the Treaty on the
Functioning of the European Union - TFEU). Commission Vice-President
Joaqu?n Almunia: "Agreements of this type directly harm patients and
national health systems, which are already under tight budgetary
constraints".(10)
In conclusion, Markov chain Monte Carlo, named after Andrey Markov, a
Russian mathematician, now evokes me the exaggeration of a russian
oligarch gambling in the small tax haven of the French Riviera, not an
hypothesis to be tested on robust data for the patients' benefit.
1 Laram?e P, Brodtkorb TH, Rahhali N, et al. The cost-effectiveness
and public health benefit of nalmefene added to psychosocial support for
the reduction of alcohol consumption in alcohol-dependent patients with
high/very high drinking risk levels: a Markov model. BMJ Open
2014;4:e005376.
2 Braillon A.Nalmefene in alcohol misuse: junk evaluation by the
European Medicines Agency. BMJ 2014;348:g2017.
3 van den Brink W, S?rensen P, Torup L, Mann K, Gual A; for the SENSE
Study Group. Long-term efficacy, tolerability and safety of nalmefene as-
needed in patients with alcohol dependence: A 1-year, randomised
controlled study. J Psychopharmacol 2014;28:733-744.
4 McNulty SJ1, Williams P. Bad medicine: using surrogate markers. BMJ
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I enjoyed reading the paper "Reduction in stillbirths at term after
new birth induction paradigm: results of a national intervention" by
Hedegaard et al with the encouraging message that the mortality rate for
Danish newborns has declined to a historically low number.
The authors' conclusions seem, however, a bit too far-reaching when
they claim that earlier induction has reduced the still...
I enjoyed reading the paper "Reduction in stillbirths at term after
new birth induction paradigm: results of a national intervention" by
Hedegaard et al with the encouraging message that the mortality rate for
Danish newborns has declined to a historically low number.
The authors' conclusions seem, however, a bit too far-reaching when
they claim that earlier induction has reduced the stillbirth rate and may
be self-accountable for up to 15 % of the reduction of stillbirths. The
study by Hedegaard et al. is an observational study and a causal
relationship can therefore not be established. Moreover, the lack of
adjustment for birth defect, intra uterine growth restriction (IUGR),
medical diseases before and during pregnancy, ultrasound scans, and socio-
economic status in analysis may introduce to bias in the risk estimates
due to residual confounding.
The continuing decline in stillbirths in the study period is probably
a result of several concurrent interventions. In particular, the
comprehensive surveillance program introduced during the year 2011 may
relevant. A total of 17 of the 24 Danish maternity wards implemented
routine antenatal surveillance of pregnancies that exceeded 41 weeks of
gestation. This practice included ultrasound monitoring of foetal well-
being as well as cardiotocography and clinical examinations at each visit
after 41 weeks of gestation (the visits are normally scheduled at
gestational age 41+3 and 41+5). This surveillance program is not mentioned
by Hedegaard et al.
The present study provide clear and solid evidence that the
stillbirth rate in Denmark have declined during the study period from 2000
- 2012 but provides little data to support the authors conclusion that
earlier induction is a major explanation for the decline in stillbirths.
Title page Title:Red cell distribution width:A novel predictor of mortality in acute pancreatitis Authors: 1. Libing Jiang, BM Department of Emergency Medicine, Second Affiliated Hospital, School of Medicine?Institute of emergency Medicine, Zhejiang University, Hangzhou, China. Email:13738062354@163.com 2. Yuefeng Ma, PhD, MD, chief physician Department of Emergency Medicine, Second Affiliated Hospital, School of Medicin...
Olsen (1) has questioned the validity of the stillbirth data used in Hedegaard et als study based on The Danish Birth Register (DBR). Lidegaard replies that "We always make our own data retrieval from the raw data in the National registries, including the birth registry rather than relying on the official statistics" (2). However, we are concerned that data in DBR seems very unreliable, and perhaps even compromised....
Dear Sir,
We read with interest the article regarding UK newspaper coverage of common cancers by Konfortion et al [1] and were pleased that this confirmed similar findings to our previous work [2]. We had previously looked at the UK's print media coverage of the top ten most common cancers in 2009: this found similar discrepancies between the prevalence of disease and the number of articles about each cancer, wi...
Rydahl and Clausen are right about problems with the validity of some official statistics published by central institutions or on the home page of the State Serum Institute (SSI). These processed data are, however, not the same as raw data from the Danish Birth Registry (DBR).
Today, official statistics are typically made by data managers in severely understaffed units in our central administration, often without...
Thank you for your comments on the published paper. C1) Recruitment: In Bissau the majority of TB patients are diagnosed at a laboratory at the local health centre, where the patient upon a positive smear is referred to the TB nurse at the same facility who will then start treatment immediately. Patients with smear negative TB are diagnosed at the national TB hospital upon x-ray and physician consultation, and are also f...
As a physician licensed in the state of California, where this study was conducted, I would like to see each hospital identified by name, and ranked by order of the prices they charge for each test. I request the authors of this study please issue a supplementary data table exposing the billing practices of each hospital by name. As a result of the Affordable Care Act, many patients now have high-deductible medical insura...
This protocol is enterprising, interesting and important, but it nowhere refers to adverse events that might be effects of medication, or of failure of a medicine to work.
Research on 'patient safety' in hospital has developed quite separately from pharmacovigilance and the elucidation of harms possibly caused by medicines and their prevention, but they are related both conceptually and in practice. They need...
We read with great interest the recently published National cohort study of Hedegaard et al (1). The authors rightly indicate in their introduction that women with foetal growth restriction or preeclampsia are at high risk for stillbirth, and that in these women induction before term is often recommended; these authors also stress that since 2009, Denmark has had a more proactive policy including early intervention in wome...
How Lundbeck's conclusion "Nalmefene can be seen as a cost-effective treatment for alcohol dependence, with substantial public health benefits" can have been published?(1) Should "Open" in BMJ Open means open to aggressive marketing from the drug industry, open not to hope but to hype, open without proper discussion despite several gross limitations.
First, the piece apply a mathematical model to three trials tha...
Dear Sirs,
I enjoyed reading the paper "Reduction in stillbirths at term after new birth induction paradigm: results of a national intervention" by Hedegaard et al with the encouraging message that the mortality rate for Danish newborns has declined to a historically low number.
The authors' conclusions seem, however, a bit too far-reaching when they claim that earlier induction has reduced the still...
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