We can hardly disagree about the limitations pointed out by Dr Chang
et al and by Roger Marshall. We emphasized in the discussion section that
the postponements (or increment in restricted mean survival) calculated by
us were restricted to the trials' running time, usually in the order of 5
years. We fully agree - and have emphasized in our paper - that they do
not answer the question on what would be the benefit from a l...
We can hardly disagree about the limitations pointed out by Dr Chang
et al and by Roger Marshall. We emphasized in the discussion section that
the postponements (or increment in restricted mean survival) calculated by
us were restricted to the trials' running time, usually in the order of 5
years. We fully agree - and have emphasized in our paper - that they do
not answer the question on what would be the benefit from a lifelong
statin treatment.
However, the problem is that we can only know about the benefit
accrued during the trial. Benefit beyond the trial has to be modelled on
the basis of assumptions. Dr Marshall has kindly shared his calculations
with us. They are based on extrapolations from two readings on the
survival curve two years apart from each other in the LIPID trial. These
extrapolations, based on the Weibull distribution, yielded an average
survival of 27.1 years in the pravastatin group and 19.2 years in the
placebo, for an average gain of 7.9 years. Mathematically correct as it
is, it may be a stretch to extrapolate more than twenty years from two
close readings. It is unclear to us whether the model takes the increase
in mortality by age in to account, which would have limited the
postponement achieved. We have performed a simulation, using real-life age
-specific mortality rates from the Danish population in 2014. If we
reduced the mortality rate by 22% from age 62 onwards as in the LIPID
trial, we arrived at 1.8 years' longer survival with lifelong statin
treatment. One may note that the LIPID trial is an outlier. It had the
second longest postponement and the second lowest hazard ratio of all
trials, only surpassed by the 4S trial. If we applied a hazard ratio of
0.89 as we found in the meta-analysis of included trials, we arrived at
0.8 years' postponement of death for lifelong statin users, starting at
age 62. Stovring et al found with a model that incorporated mortality in
different risk strata, postponements between 3 and 11 month for lifelong
statin treatment, depending on the baseline risk and age at statin
initiation (1). Chang arrived at 3.0 years for the LIPID trial. Without
necessarily arguing which is correct, at least we can note that these
values are highly variable and seem to be strongly dependent on
assumptions.
In clinical practice, statin treatments often have a fairly limited
duration, either because of non-adherence (2,3) or because users are
already old when they initiate therapy. We carefully phrased our
conclusions and recommendations as to reflect that the benefit in statin
treatment would be limited for patients whose life-expectancy was short
and that the patient or physician might reconsider the treatment if the
patient had intolerance to statins.
References
1. Stovring H, Harmsen CG, Wisloff T, Jarbol DE, Nexoe J, Nielsen
JB, et al. A competing risk approach for the European Heart SCORE model
based on cause-specific and all-cause mortality. Eur J Prev Cardiol. 2013
Oct;20(5):827-36.
2. Monaldi B, Bologna G, Costa GG, D'Agostino C, Ferrante F, Filice
M, et al. Adherence to statin treatment following a myocardial infarction:
an Italian population-based survey. Clin Outcomes Res CEOR. 2015;7:273-80.
3. Shah ND, Dunlay SM, Ting HH, Montori VM, Thomas RJ, Wagie AE, et
al. Long-term medication adherence after myocardial infarction: experience
of a community. Am J Med. 2009 Oct;122(10):961.e7-13.
Guest et al are to be congratulated on a well-conducted study
providing further insight into the economic burden of chronic wounds in
the UK.
I assume that random sampling was chosen because of the considerable
work required just to assess the economic resources used in the 1,000
patients sampled in each group. The authors then chose to employ
sensitivity analysis in regard to the number of comorbidities rather...
Guest et al are to be congratulated on a well-conducted study
providing further insight into the economic burden of chronic wounds in
the UK.
I assume that random sampling was chosen because of the considerable
work required just to assess the economic resources used in the 1,000
patients sampled in each group. The authors then chose to employ
sensitivity analysis in regard to the number of comorbidities rather than
other approaches. This begs some questions. For example, did the authors
considered weighting comorbidities in terms of severity and likely
resources consumed? Did the authors attempt to determine the variance of
the random sampling technique--for example by resampling 100 times and
determining the 95% confidence intervals of the percentages of the listed
comorbidities? Last, did the author settle on 1,000 as a reasonable number
or was some prior research employed to choose this number over (for
example) 500 or even 5,000?
The article by Miller et al. published on 12th November (1) took a
similar approach to previous studies by Rawal and Deane (2, 3) that
also set out to examine the clinical trial evidence related to recently
approved medicines. The article therefore requires some qualification;
while the study examines some of the industry-sponsored clinical trials
related to 15 selected new medicines approved by the FDA in 2012, their
st...
The article by Miller et al. published on 12th November (1) took a
similar approach to previous studies by Rawal and Deane (2, 3) that
also set out to examine the clinical trial evidence related to recently
approved medicines. The article therefore requires some qualification;
while the study examines some of the industry-sponsored clinical trials
related to 15 selected new medicines approved by the FDA in 2012, their
study methodology is not 'unique' or 'novel', but was preceded by two
publications (the earliest in November 2013) which together assessed all
the industry-sponsored trials in patients related to all 76 new medicines
approved by the EMA during 2009, 2010, 2011 and 2012 (2, 3).
The Miller et al. report focused on trials related to the FDA
approvals, and it includes the early phase I trials, which are not
'applicable trials' under the FDAAA reporting requirements. Conversely,
our studies assessed all completed clinical trials in patients, (in line
with industry commitments since 2005), covering a wider range of
clinically important trials available at the time - not just those
completed and submitted to regulatory bodies such as the EMA or FDA.
The variance in reported numbers are a direct consequence of these
differences in methodology, and the cut-off dates for data collection. For
example, Eliquis (apixaban) was approved by the EMA in May 2011 and by the
FDA in December 2012; data collected by Rawal and Deane up to 31st January
2013 included 12 trials in patients completed by the end of January 2012
(allowing 12 months for reporting) and excluding trials in healthy
subjects, while data collected by Miller et al. up to April 2014 included
39 trials submitted to the FDA of which at least 29 were phase I trials in
healthy subjects.
Miller et al. reported an overall disclosure rate for Eliquis of
17/39 (44%, including phase I trials not required under the FDAAA), while
Rawal and Deane reported 12/12 (100%, excluding trials in volunteers). In
addition, a quick search of ClinicalTrials.gov on 12th December 2015
revealed 21 completed, industry sponsored phase II, III or IV trials
(twice as many as covered by Miller et al.) - and it is immediately
obvious (without exploring other data sources) that results of at least 18
of these (86%) have been disclosed.
This is another reminder of the complexity of this topic (which is
inextricably linked to the complicated global process of new drug
development), and the difficulty of comparing disclosure figures from
study to study, especially when the timing of data collection varies.
References
1. Jennifer E Miller, David Korn, Joseph S Ross. Clinical trial
registration, reporting, publication and FDAAA compliance: a cross-
sectional analysis and ranking of new drugs approved by the FDA in 2012.
BMJ Open 2015;5:11 e009758 doi:10.1136/bmjopen-2015-009758
2. Rawal B, Deane BR. Clinical trial transparency: an assessment of
the disclosure of results of company-sponsored trials associated with new
medicines approved recently in Europe. Curr Med Res Opin; 2014 Mar;
30(3):395-405. Epub 2013 Nov 11
3. Rawal B, Deane BR. Clinical trial transparency update: an
assessment of the disclosure of results of company-sponsored trials
associated with new medicines approved in Europe in 2012. Curr Med Res
Opin; 2015 Jul; 31(7):1431-1435. Epub 2015 Jun 9
Conflict of Interest:
As a consultant, I undertake a variety of projects for pharmaceutical companies and for agencies providing services to the industry
I note with interest that your population cohort covers a 16 year
time period.
In this respect may I direct you to some research I have been
conducting on a time-series of infectious like outbreaks affecting both
medical admissions and all-cause mortality (1-17).
I have recently demonstrated these events across the whole of Europe
(10) and Australia (14), they are condition specific (1,3-9,11,13), and...
I note with interest that your population cohort covers a 16 year
time period.
In this respect may I direct you to some research I have been
conducting on a time-series of infectious like outbreaks affecting both
medical admissions and all-cause mortality (1-17).
I have recently demonstrated these events across the whole of Europe
(10) and Australia (14), they are condition specific (1,3-9,11,13), and
show infectious-like small area spread (5,8,14,15).
Preliminary evidence suggests that cardiovascular conditions are also
affected (1,11,17).
Can I suggest that your long time series presents an ideal
opportunity to determine if these events are as wide-spread and wide-
reaching, as seems to be indicated.
References
1. Jones R. Could cytomegalovirus be causing widespread
outbreaks of chronic poor health? Hypotheses in Clinical Medicine, 2013, pp
37-79, Eds M. Shoja, et al. New York: Nova Science Publishers Inc.
Available from: http://www.hcaf.biz/2013/CMV_Read.pdf
2. Jones R. Widespread outbreaks of a subtle condition leading
to hospitalization and death. Epidemiology: Open access, 2013, 4(3): 137.
3. Jones R. Increased deaths in 2012: which conditions? BJHCM, 2014, 20(1): 45-47.
4. Jones R, Goldeck D. Unexpected and unexplained increase in
death due to neurological disorders in 2012 in England and Wales:Is
cytomegalovirus implicated? Medical Hypotheses, 2014, 83(1): 25-31.
5. Jones R. Infectious-like Spread of an Agent Leading to
Increased Medical Admissions and Deaths in Wigan (England), during 2011
and 2012. British Journal of Medicine and Medical Research, 2014, 4(28): 4723
-4741.
6. Jones R. A Study of an Unexplained and Large Increase in
Respiratory Deaths in England and Wales: Is the Pattern of Diagnoses
Consistent with the Potential Involvement of Cytomegalovirus? British
Journal of Medicine and Medical Research, 2014, 4(33): 5179-5192.
7. Jones R. An unexpected increase in adult appendicitis in
England (2000/01 to 2012/13): Could cytomegalovirus (CMV) be a risk
factor? British Journal of Medicine and Medical Research, 2015, 5(5): 579-603.
8. Jones R, Beauchant S. Spread of a new type of infectious
condition across Berkshire in England between June 2011 and March 2013:
Effect on medical emergency admissions. British Journal of Medicine and
Medical Research, 2015, 6(1): 126-148.
9. Jones R. Unexpected and Disruptive Changes in Admissions
Associated with an Infectious-like Event Experienced at a Hospital in
Berkshire, England around May of 2012. British Journal of Medicine and
Medical Research, 2015, 6(1): 56-76.
10. Jones R. Recurring Outbreaks of an Infection Apparently
Targeting Immune Function, and Consequent Unprecedented Growth in Medical
Admission and Costs in the United Kingdom: A Review. British Journal of
Medicine and Medical Research, 2015, 6(8): 735-770.
11. Jones R. A new type of infectious outbreak? SMU Medical
Journal, 2015, 2(1): 19-25.
12. Jones R. Are emergency admissions contagious? BJHCM, 2015, 21(5):
227-235.
13. Jones R. Unexpected Increase in Deaths from Alzheimer's,
Dementia and Other Neurological Disorders in England and Wales during 2012
and 2013. Journal of Neuroinfectious Diseases, 2015, 6:172.
14. Jones R. A time series of infectious-like events in
Australia between 2000 and 2013 leading to extended periods of increased
deaths (all-cause mortality) with possible links to increased hospital
medical admissions. International Journal of Epidemiologic Research, 2015, 2(2):
53-67.
15. Jones R. Small area spread and step-like changes in
emergency medical admissions in response to an apparently new type of
infectious event. FGNAMB, 2015, 1(2): 42-54.
16. Jones R. Is cytomegalovirus involved in recurring periods
of higher than expected death and medical admissions, occurring as
clustered outbreaks in the northern and southern hemispheres? British
Journal of Medicine and Medical Research, 2015, 11(2): 1-31.
17. Jones R. A 'fatal' flaw in hospital mortality models: How
spatiotemporal variation in all-cause mortality invalidates hidden
assumptions in the models. FGNAMB, 2015 1(3): in press
There was never any intention to match the wound patients with their
matched controls on the basis of their comorbidities, since differences in
comorbidities between the groups is an outcome we wanted to measure. The
patients' records did not describe the severity of their comorbidities in
all cases. Furthermore, it would have been difficult to disentangle
resource use for the comorbidities from that associated with wound...
There was never any intention to match the wound patients with their
matched controls on the basis of their comorbidities, since differences in
comorbidities between the groups is an outcome we wanted to measure. The
patients' records did not describe the severity of their comorbidities in
all cases. Furthermore, it would have been difficult to disentangle
resource use for the comorbidities from that associated with wound care in
all instances. It would also have proved very challenging to identify
which resources were used to manage individual comorbidities as many
patients in both groups had two or more comorbidities. Hence, we employed
the two methods described in the article to separate the cost of
comorbidities from that of wound care. We recognise this is
methodologically limited and we state in the article that the possibility
of resource use associated with managing a comorbidity being conflated
with that of wound management cannot be excluded. Previous experience
working with the THIN database indicated that the population size of 1,000
patients per group would be sufficient to address the study's objectives.
Beneficial effect of moderate alcohol intake on a variety of health
issues should be limited to people with normal acetaldehyde-metabolizing
capacity from intact aldehyde dehydrogenase 2 (ALDH2), which is true of
the majority of western people like the subjects in Berntsen's study [1].
However, Asians, particularly East Asians (Korean, Chinese, and Japanese)
include significant numbers of the population with inactive ALDH...
Beneficial effect of moderate alcohol intake on a variety of health
issues should be limited to people with normal acetaldehyde-metabolizing
capacity from intact aldehyde dehydrogenase 2 (ALDH2), which is true of
the majority of western people like the subjects in Berntsen's study [1].
However, Asians, particularly East Asians (Korean, Chinese, and Japanese)
include significant numbers of the population with inactive ALDH2,
approximately 30 to 40% of the whole population, which is encoded by the
genotype - either homozygous (ALDH2*2/*2) or heterozygous (ALDH2*1/*2) -
of the mutant ALDH2 allele (ALDH2*2), leading to loss of ALDH2 activity
[2,3]. This point mutation in ALDH2 is the most frequent variant in humans
and is present in 8% of the world's population, or approximately 560
million people, who show a distinctive physiological response to drinking
even a small amount of alcohol. This phenomenon includes facial flushing,
nausea, palpitation, headache, pruritus, and a hangover the next morning.
[3,4] Thus, such bad experiences with alcohol produced a lot of non-
drinkers in East Asia, which is predominantly caused by immediate and
prolonged acetaldehyde exposure with an inherited deficiency of ALDH2
enzyme. Moreover, this genetic polymorphism has been indicated to be
closely associated with digestive tract cancer, neurodegenerative disease,
metabolic syndrome, and atherosclerotic vascular disease [5], which
potentially gives some new insights into the mechanism of health
protective effects of moderate alcohol intake, and future research
directions.
References
1. Berntsen S, Kragstrup J, Siersma V, Waldemar G, Waldorff FB.
Alcohol consumption and mortality in patients with mild Alzheimer's
disease: a prospective cohort study. BMJ Open 2015;5(12):e007851.
2. Eng MY, Luczak SE, Wall TL. ALDH2, ADH1B, and ADH1C genotypes in
Asians: A literature review. Alcohol Res Health 2007;30:22-27.
3. Yokoyama A, Omori T, Yokoyama T. Alcohol and aldehyde dehydrogenase
polymorphisms and a new strategy for prevention and screening for cancer
in the upper aerodigestive tract in East Asians. Keio J Med 2010;59:115-
130.
4. Gross ER, Zambelli VO, Small BA, et al. A personalized medicine
approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.
Annu Rev Pharmacol Toxicol 2015;55:107-27.
5. Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D. Targeting aldehyde
dehydrogenase 2: new therapeutic opportunities. Physiol Rev 2014;94:1-34.
In a recent paper published in BMJ Open, Jang et al. reported that
extreme obesity [body mass index (BMI) >= 30] is an independent
predictive factor for good functional outcomes in stroke survivors 6
months after onset [1]. These results are consistent with previous studies
[2-5] and are important in the stroke rehabilitation setting because
weight management of obese patients has been a critical issue for
improving p...
In a recent paper published in BMJ Open, Jang et al. reported that
extreme obesity [body mass index (BMI) >= 30] is an independent
predictive factor for good functional outcomes in stroke survivors 6
months after onset [1]. These results are consistent with previous studies
[2-5] and are important in the stroke rehabilitation setting because
weight management of obese patients has been a critical issue for
improving physical function and preventing future cerebrovascular
diseases. However, we have some concerns regarding the study.
First, the authors did not include age in the multiple regression
analysis. Although the study participants were stratified into two groups
based on age (>= 65 years and < 65 years), previous reports have
shown a significant correlation between age per year and functional
outcomes [2-5]. The results of the current study [1] also showed that the
mean age tended to decrease among BMI stratification groups, such as 79.1,
75.7, 74.3, 73.6, and 72.6 years in the underweight, normal, overweight,
obese, and extremely obese groups, respectively, in participants >= 65
years of age. Thus, the authors should have included age as a continuous
variable in the multiple regression analysis.
Second, the pre-stroke physical and cognitive function was not
described. Stroke patients have often experienced functional difficulties
before stroke onset due to various conditions, such as dementia,
particularly in older patients. These problems usually limit the patients'
functional recovery. Some articles have suggested that pre-stroke
functional conditions are independent risk factors for functional outcomes
or mortality [2-4]. Therefore, the pre-stroke activities of daily living
or the residential situation status, such as living at home or in an
institution, should be investigated.
Third, the length of the hospital stay, implementation of
rehabilitation, and destination at discharge were not shown in this paper.
This study used the functional independence measure (FIM) at discharge as
a confounder for the 6-month FIM; however, the length of hospital stay
also affects FIM at discharge [6]. In addition, rehabilitation
implementation and discharge destination correlate with functional
recovery. We consider that describing the length of hospital stay,
implementation of rehabilitation, and destination at discharge would be
helpful in interpreting the results.
Fourth, the National Institutes of Health Stroke Scale (NIHSS) scores
were measured at 7 days after stroke onset. However, the initial NIHSS
score is a stronger independent predictor for functional outcomes than BMI
[7]. From this perspective, the NIHSS scores at admission could be a more
effective factor for functional recovery than those at 7 days after stroke
onset.
Finally, whether extremely obese stroke patients should lose weight
or not is still unclear. We recognize that extremely obese stroke patients
have often been encouraged to lose weight because extreme obesity,
particularly excessive fat deposition, has been associated with metabolic
disorders and functional disabilities. Moreover, the existence of an
obesity paradox among stroke survivors remains controversial [7-9]. To
maximize functionality in stroke patients, we believe that optimal
rehabilitation nutrition as a combination of rehabilitation and nutrition
care management [10] should emphasize on body composition rather than BMI
in the rehabilitation setting. Further studies investigating the
proportion or distribution of body mass and weight changes after stroke
are required.
We believe that these concerns should be addressed to confirm the
reported findings from this study.
References
[1] Jang SY, Shin Y-I, Kim DY, et al. Effect of obesity on functional
outcomes at 6 months post-stroke among elderly Koreans: a prospective
multicentre study. BMJ Open. 2015;5(12):e008712. doi:10.1136/bmjopen-2015-
008712.
[2] Doehner W, Schenkel J, Anker SD, Springer J, Audebert H.
Overweight and obesity are associated with improved survival, functional
outcome, and stroke recurrence after acute stroke or transient ischaemic
attack: Observations from the TEMPiS trial. Eur Heart J. 2013;34(4):268-
277.
[3] Zhao L, Du W, Zhao X, et al. Favorable functional recovery in
overweight ischemic stroke survivors: Findings from the China National
Stroke Registry. J Stroke Cerebrovasc Dis. 2014;23(3):e201-e206.
[4] Nishioka S, Wakabayashi H, Yoshida T, Mori N, Watanabe R,
Nishioka E. Obese Japanese Patients with Stroke Have Higher Functional
Recovery in Convalescent Rehabilitation Wards: A Retrospective Cohort
Study. J Stroke Cerebrovasc Dis. 2015.
doi:10.1016/j.jstrokecerebrovasdis.2015.08.029.
[5] Andersen KK, Olsen TS. Body mass index and stroke: Overweight and
obesity less often associated with stroke recurrence. J Stroke Cerebrovasc
Dis. 2013;22(8):e576-e581.
[6] Miyai I, Sonoda S, Nagai S, et al. Results of new policies for
inpatient rehabilitation coverage in Japan. Neurorehabil Neural Repair.
2011;25(6):540-547.
[7] Kim Y, Kim CK, Jung S, Yoon B-W, Lee S-H. Obesity-stroke paradox
and initial neurological severity. J Neurol Neurosurg Psychiatry.
2014;308664. doi:10.1136/jnnp-2014-308664.
[8] Dehlendorff C, Andersen KK, Olsen TS. Body Mass Index and Death
by Stroke: No Obesity Paradox. JAMA Neurol. 2014;71(8):1-7.
[9] Razinia T, Saver JL, Liebeskind DS, Ali LK, Buck B, Ovbiagele B.
Body mass index and hospital discharge outcomes after ischemic stroke.
Arch Neurol. 2007;64(3):388-391.
[10] Wakabayashi H, Sakuma K. Rehabilitation nutrition for sarcopenia
with disability: a combination of both rehabilitation and nutrition care
management. J Cachexia Sarcopenia Muscle. 2014;5(4):269-77.
We would like to confirm that the name of the first affiliation: Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China should be: Department of Biostatistics, Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Ministry of Education, Shanghai, China.
I would like to compliment Barnhoorn and colleagues with their recent
results on CPRS type 1 and the resulting publication (1). The paper
demonstrates that the effect of PEPT is at least comparable to
conventional therapy and has no side effects in patients with acute CRPS
type 1. However, with my background in this subject, there are a few
remarks to make about the study and a few more about CRPS type 1 in
general. Sim...
I would like to compliment Barnhoorn and colleagues with their recent
results on CPRS type 1 and the resulting publication (1). The paper
demonstrates that the effect of PEPT is at least comparable to
conventional therapy and has no side effects in patients with acute CRPS
type 1. However, with my background in this subject, there are a few
remarks to make about the study and a few more about CRPS type 1 in
general. Similar remarks I have made before in a reaction to Bass in April
2014 (2). The new study shows no significant differences between populations treated
with either the intervention (PEPT) or conventional therapy. One of the
main reasons may be the natural course of CRPS type 1. The patients
studied did have CPRS type 1 only for 7 months and it is therefore
possible that many of them improved irrespective of the therapy. The functional treatment, now called PEPT, has been used in the
Netherlands since 2004. We introduced it after visiting a local therapist
in Macedonia in the company of six patients suffering from chronic CRPS type
1. Since then, many colleagues have come to take a look at our
rehabilitation department in Hoogeveen (NL) and have copied the therapy. We have published articles and gave lectures about the approach and the
first promising results. In particular, in 2009 we published a case-series
of 106 patients with chronic CRPS type 1 in Clinical Rehabilitation (3). In this case-series the therapy was effective in patients with chronic
CRPS type 1 (mean duration 55 months), most of whom had had 3 or more
therapies. This case-series was followed by a study concerning the safety
of the treatment (4) and a follow-up study of the first study (5). So the
approach is well known and used by many therapists in the country. In this
context the therapists and patients in the Barnhoorn study appear to
represent a biased population: how sure can we be that patients in the
conventional therapy group were not subject to some form of functional
treatment or have acted in daily life more active when they were not in
the clinic? And how blind can an assessor be in such a context? Can an
assessor be blind when neither the patient nor the therapist are blinded? In the Netherlands there was and still is a debate going on whether the
functional treatment has a scientific basis. A useless debate, in my
opinion, especially if there is no effective alternative therapy. It is
the proper scientific approach to debate the diagnosis and ineffective
therapies. The criteria to diagnose CRPS type 1 change regularly, so it is not even
clear what we are looking at. Maybe every research-group defines its own
kingdom by changing the borders every now and then (6). If solid research shows time after time no or small differences between
the intervention and control group, we must reconsider the hypothesis and
not continue with research directed at the periphery of the body, starting
from end organ damage. We must use our common sense instead of believing
the scientific method resolves every problem in the end. Clinical science
is more than trying to prove hypothesis by RCT's. If we don't use our
common sense, we keep digging a hole without finding oil. We are
neglecting other perspectives and sources of evidence when we don't leave
our pit and thereby become dogmatic. CRPS type 1 is the description of a cluster of symptoms. Typically,
physicians will give aetiologic and therapeutic connotations to a wide
range of symptoms and thereby creating a chronic pain syndrome by the
nocebo effect. The constant adaptation of the diagnostic criteria and the
different names of the syndrome that emerged over the last decades, show
the uncertainty of the diagnosis. Moreover, the criterion that all other
diseases must be excluded before diagnosing CRPS type 1, makes it a
questionable diagnosis. Harden (7) stated that criteria are meant to
improve communication between researchers and that they have no
etiopathological meaning. But by grouping symptoms, clinicians and
patients and even researchers can add other meanings (connotations) to a
cluster of symptoms with a particular name. Causal mechanisms and matching
therapies can then be suggested. If doctor and patient start to behave
according to the hypothesis/connotations an iatrogenic circle develops. Ochoa already said: "there is much iatrogenesis in the realm of
misdiagnosed chronic neuropathic pain". A comparable mechanism was
suggested for fibromyalgia by Wolfe (8). Bell, quoted by Ochoa and
Verdugo, said: "The newfound experts developed therapeutic empires with a
vigorous entrepreneurial spirit that was undeterred by the ineffectiveness
of the treatment methods"
I propose to define the symptoms as a normal reaction to immobilisation
(9) with a broad range in manifestations. Chronicity develops in a group
of patients depending on the nature of the trauma, the duration of the
immobilisation, the genetic make-up and the reaction of the physician and
therapist. If we change the name into 'post immobilisation syndrome'
(PIS), we can start to prevent chronicity by stimulating normal use after
immobilisation. Of course we will have to exclude peripheral causes first
(10,11).
References
1. Barmhoorn KJ, van de Meent H, van Dongen RTM, et al. Pain exposure
physical therapy (PEPT) compared to conventional therapy in complex
regional pain syndrome type 1: a randomised controlled trial. BMJ Open, 2015;5:e008283.
3. Ek JW, van Gijn JC, Samwel H, van Egmond J, Klomp FP, van
Dongen RT. Pain exposure physical therapy may be a safe and effective
treatment for longstanding complex regional pain syndrome type 1: a case
series. Clin Rehabil, 2009;23:1059-66.
4. Van de Meent H, Oerlemans M, Bruggeman A, Klomp F, van Dongen R, Oostendorp R, Fr?lke JP.
Safety of "pain exposure" physical therapy in patients with complex regional pain syndrome type 1.
Pain, 2011: 152,1431-8.
5. Van Egmond J, Koen C, Ek JW, van Dongen R, Klomp F, Samwel H.
Draaijer E. Follow up study of the first series treated PEPT CRPS type 1
patients shows further improvement. Presented as poster and published on
F1000research.
6. Ochoa J, Verdugo R. Mechanisms of neuropathic pain: nerve, brain,
and psyche: perhaps the dorsal horn but not the sympathetic system.
Clinical Autonomic Research, 2001;11:335-9
7. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed New
Diagnostic Criteria for Complex Regional Pain Syndrome. Pain Medicine, 2007;4:326-31.
8.Wolfe F. Fibromyalgia wars. J Reumatology 2009;36:671-8.
9. Terkelsen AJ, Bach FB, Jensen TS. Experimental Forearm
Immobilization in Humans Induces
Cold and Mechanical Hyperalgesia. Anesthesiology, 2008;109:297-307.
10. Frolke JP, van Rumund A, de Waardt D, van Dongen RT, Klomp FP,
Verbeek AL, van de Meent H. Complex regional pain syndrome type 1? In 77%
of people had a different diagnosis. Ned Tijdschr Geneeskd, 2009;153:550-3
11. Del Pinal F. Editorial. I have a dream ... reflex sympathetic
dystrophy (RSD or Complex Regional Pain Syndrome - CRPS I) does not exist.
J Hand Surg Eur Vol, 2013;38:595-7
In their warning call to Belgium and other countries in the world to
(re)consider euthanasia legalisation, Claes et al. highlight some
arguments that were also described in our descriptive study, including the
key conditions 'untreatable and unbearable suffering' as subjects of
controversy. However, we would like to react to some of the other
statements in their commentary.
In their warning call to Belgium and other countries in the world to
(re)consider euthanasia legalisation, Claes et al. highlight some
arguments that were also described in our descriptive study, including the
key conditions 'untreatable and unbearable suffering' as subjects of
controversy. However, we would like to react to some of the other
statements in their commentary.
Firstly, Claes et al. wrote "that 35% and probably 50% of the
euthanasia cases have been approved by one single psychiatrist", referring
to psychiatrist Thienpont L. The Belgian Law on Euthanasia (2002) clearly
states that in case of the non-terminally ill, it is a specific legal
requirement of due care that - besides the treating physician - two
'additional' physicians, a psychiatrist or specialist in the disorder
amidst them, have to be involved in careful evaluation of all legal
requirements, including patient's mental capacity and the suffering
experience in the context of patient's (psycho)pathology, before any
advice regarding a euthanasia request can be given to patients' treating
physician. In all cases in our study, these legal requirements were met.
Secondly, Claes et al. focussed on the 38 euthanasia requests that
were withdrawn: we want to clarify that these patients did not withdraw
their request but were referred by the first author for additional
diagnostic test and/or treatment, hence their request can be considered as
pending, not withdrawn. Hence, at the moment of the final analysis of our
study, these euthanasia procedures were still in process as patients
accepted being referred to further testing- or treatment options and were
giving these new perspectives a fair chance for success. Therefore, a final
decision to grant their euthanasia requests could not be reached.
Thirdly, concerning the key factor 'untreatable suffering', Claes et
al. state - and rightly so - that mental disorders could be seen as a
'transient state'. We could not agree more on this. They rightly warn
psychiatrist for having 'a narrow technical view on psychiatry' and
'denying patients' recovering abilities', when 'denying the fact that
psychiatrists do not primarily treat diseases, but persons', by referring
to scientific evidence showing that diseases tend to resolve over time,
and specifically referring to borderline patients in remission 10 years
after their diagnose. While these results are extremely hopeful, this
doesn't mean that every patient can reach the state of being in remission.
As could be read in the result section from our paper it concerned
patients being treatment resistant, due to a comorbid psychiatric
disorder. For example, it is noteworthy that almost every patient (90%)
was diagnosed with more than one disorder at intake, which makes the
effort to remission success a very complex one. Only when no alternative
options are left and only if all legal requirements are complied, we face
the boundaries of medical treatment. As stated in the introduction section
of our paper, a patient can be considered to be in a medically futile
situation, or treatment resistant, if the suffering is unbearable and
untreatable and there is no prospect of any improvement. According to the
Law, both physician and patient have to come to the conclusion that there
is no reasonable alternative left to relieve the patient's suffering. In
practice (and also stated in the introduction section of our paper), the
guidelines from the Dutch Psychiatric Association (NVvP) are then followed
to qualify untreatable suffering (e.g. any therapeutic option for a
particular condition must meet the following three requirements: (i) a
real prospect of improvement, (ii) the possibility to administer adequate
treatment within a reasonable period of time, and (iii) a reasonable
balance between the expected treatment results and the burden of treatment
consequences for the patient, must be reached). Therefore, untreatable
suffering is not vague in its essence.
Fourthly, in response to the vagueness of the key factor 'unbearable
suffering', we have stated in the introduction section of our paper that
the unbearability of suffering cannot easily be defined, as it is a
subjective term by its nature and qualitative research in the context of
death wishes is paid cursory attention to (Dees et al, 2010). Delbeke (2013) described that the evaluation whether
suffering is continuous and unbearable, is up to the patient. The
physician has no solid psychophysical or psychological instruments to
measure the irrefutable degree of physical or mental suffering, but has to
come to a level of mutual and empathic understanding with the patient
about the extend of his or her intolerable, unendurable suffering.
However, the consulted physician can have patient's consent in having
access to patient's medical file that contains information about patients'
suffering history. Moreover, it belongs to the expertise of the advising
specialist (psychiatrist) involved to judge patient's mental competency
and whether there are any opportunities left to alleviate that type,
extend or intensity of patients' suffering (Naudts et al., 2006).
Psychiatrists are expected and supposed to have the knowledge and skills
to decide whether and to estimate the extent to which the mental disorder
is curable or not and whether or not there's a prospect of improvement.
However, the dependence of the actual state of medicine and treatment
options does include a subjective element.
The aim of our paper was to open the discussion about the realised
practice of euthanasia because of psychiatric illness within the Belgian
legal framework. We take note of the considerations of Claes et al. and
fully acknowledge that more research needs to be done in order to improve
the quality of healthcare for this patient group. Therefore, we are already
working on qualitative and quantitative research in order to gain more
insight in this topic and to offer human and legal protection of patients,
friends and relatives involved.
References
Delbeke E. Legal aspects of care at the end of life. Antwerp:
Intersentia; 2012 (in Dutch).
Dees, M, Vernooij-Dassen, M, Dekkers, W, & van Weel, C. (2010).
Unbearable suffering of patients with a request for euthanasia or
physician-assisted suicide: an integrative review. Psycho-Oncology, 19(4),
339-352.
Federal Control and Evaluation Committee on Euthanasia. Fourth report to
the Parliament (2008-2009). Brussels: Federal Control and Evaluation
Committee on Euthanasia; 2010. Available from: http://www.ieb-
eib.org/nl/pdf/rapport-euthanasie-2010-belgique-nl.pdf (in Dutch).
Federal Control and Evaluation Committee on Euthanasia. Fifth report to
the Parliament (2010-2011). Brussels: Federal Control and Evaluation
Committee on Euthanasia; 2012. Available from:
http://www.senate.be/www/webdriver-MItabObj=pdf&MIcolObj=pdf&MInamObj=pdfid&MItypeObj=application/pdf&MIvalObj=83889004
(in Dutch and French).
Ministry of Justice. Law on euthanasia of May 28, 2002. Belgian Official
Gazette: Brussels, 2002. Available from:
http://www.npzl.be/files/107a_B3_Wet_euthanasie.pdf (in Dutch and French).
Naudts, K, Ducatelle, C, Kovacs, J, Laurens, K, Van den Eynde, F, Van Heeringen, C. (2006). Euthanasia: the role of the psychiatrist.
The British Journal of Psychiatry, 188(5), 405-409.
Tholen AJ, Berghmans RLP, Huisman J, Scherders MJ. Guideline dealing with
the request for assisted suicide by patients with a psychiatric disorder.
Utrecht: Dutch Psychiatric Association. De Tijdsstroom; 2009. Available
from: http://steungroeppsychiaters.nl/wp-content/uploads/Richtlijn-hulp-
bij-zelfdoding_NVvP-2009.pdf (in Dutch)
Conflict of Interest:
Authors of the original article 'Euthanasia Requests, Procedures and Outcomes for 100 Belgian Patients Suffering from Psychiatric Disorders: A Retrospective, Descriptive Study'
We can hardly disagree about the limitations pointed out by Dr Chang et al and by Roger Marshall. We emphasized in the discussion section that the postponements (or increment in restricted mean survival) calculated by us were restricted to the trials' running time, usually in the order of 5 years. We fully agree - and have emphasized in our paper - that they do not answer the question on what would be the benefit from a l...
Guest et al are to be congratulated on a well-conducted study providing further insight into the economic burden of chronic wounds in the UK.
I assume that random sampling was chosen because of the considerable work required just to assess the economic resources used in the 1,000 patients sampled in each group. The authors then chose to employ sensitivity analysis in regard to the number of comorbidities rather...
The article by Miller et al. published on 12th November (1) took a similar approach to previous studies by Rawal and Deane (2, 3) that also set out to examine the clinical trial evidence related to recently approved medicines. The article therefore requires some qualification; while the study examines some of the industry-sponsored clinical trials related to 15 selected new medicines approved by the FDA in 2012, their st...
I note with interest that your population cohort covers a 16 year time period.
In this respect may I direct you to some research I have been conducting on a time-series of infectious like outbreaks affecting both medical admissions and all-cause mortality (1-17).
I have recently demonstrated these events across the whole of Europe (10) and Australia (14), they are condition specific (1,3-9,11,13), and...
There was never any intention to match the wound patients with their matched controls on the basis of their comorbidities, since differences in comorbidities between the groups is an outcome we wanted to measure. The patients' records did not describe the severity of their comorbidities in all cases. Furthermore, it would have been difficult to disentangle resource use for the comorbidities from that associated with wound...
Beneficial effect of moderate alcohol intake on a variety of health issues should be limited to people with normal acetaldehyde-metabolizing capacity from intact aldehyde dehydrogenase 2 (ALDH2), which is true of the majority of western people like the subjects in Berntsen's study [1]. However, Asians, particularly East Asians (Korean, Chinese, and Japanese) include significant numbers of the population with inactive ALDH...
In a recent paper published in BMJ Open, Jang et al. reported that extreme obesity [body mass index (BMI) >= 30] is an independent predictive factor for good functional outcomes in stroke survivors 6 months after onset [1]. These results are consistent with previous studies [2-5] and are important in the stroke rehabilitation setting because weight management of obese patients has been a critical issue for improving p...
Conflict of Interest:
None declared
I would like to compliment Barnhoorn and colleagues with their recent results on CPRS type 1 and the resulting publication (1). The paper demonstrates that the effect of PEPT is at least comparable to conventional therapy and has no side effects in patients with acute CRPS type 1. However, with my background in this subject, there are a few remarks to make about the study and a few more about CRPS type 1 in general. Sim...
In their warning call to Belgium and other countries in the world to (re)consider euthanasia legalisation, Claes et al. highlight some arguments that were also described in our descriptive study, including the key conditions 'untreatable and unbearable suffering' as subjects of controversy. However, we would like to react to some of the other statements in their commentary.
Firstly, Claes et al. wrote "that 35%...
Pages