Antipsychotic drugs and risk of venous thromboembolism: nested case-control study
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4245 (Published 22 September 2010) Cite this as: BMJ 2010;341:c4245
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To the editor,
In the article 'Antipsychotic drugs and risk of venous
thromboembolism: nested case-control study' [1] the authors conclude that
there is an association between use of antipsychotic drugs and risk of
venous thromboembolism in a large primary care population. We have some
methodological issues that we would like to discuss with the authors,
before we agree with this conclusion.
The authors mention that 'nearly all use of antipsychotics in the
primary care population we studied was for conditions such as nausea,
vomiting, and vertigo'. Indeed, they found that over 50% of prescriptions
were single prescriptions, and the most commonly prescribed drug (75%) was
prochlorperazine, commonly prescribed for nausea, while the strong anti-
emetics chlorpromazine, trifluoperazine and olanzapine were listed among
the seven most commonly prescribed antipsychotic drugs. Patients with
nausea or vertigo are likely to confine themselves to bed, and immobility
is one of the most important risk factors for venous thrombosis. Nausea
is a common symptom of many diseases. Temporary immobility and / or
current disease may therefore very likely confound the relationship
between current antipsychotic use and venous thrombosis in this study.
Although the authors did include a large number of possible confounders
such as hip fracture, hospital admission etc. in their analysis, it is
very difficult to adjust for this potential confounding by indication.
One way of tackling confounding by indication is by restricting the
analysis to a group with a comparable diagnosis. Unfortunately, the data
provided by the authors in the appendix to the article, only give
additional analyses of the data in which patients with either
schizophrenia or manic depression were excluded, while an analysis
restricted to patients with psychiatric disease would seem more
appropriate.
The title of the article does suggest a nested case-control design,
which would reduce bias by nesting the case control study within a cohort
of patients with comparable baseline-risk (for instance patients with
mental disease). However, cases and controls were extracted from an open
population, which makes this a regular case-control, and not a nested one.
Again, differences in risk for thrombosis might result from differences in
patient groups in this study.
We recently published a case control study with data from the Dutch
Pharmo database [2]. In the Netherlands, antipsychotics are not
recommended and therefore seldom used in primary care to treat nausea and
vertigo. We nested the case control study within a cohort of elderly
antipsychotic users, and used (Cox) conditional logistic regression for
matched data, with each case compared to its own controls. We did not
find an increase in risk of venous thrombosis associated with current
antipsychotic use (OR, 0.9; 95% CI, 0.7- 1.1).
Yours sincerely,
B.C. Kleijer, MD,
GeriMedica Medical Practice for Frail Elderly, Aveant Utrecht, The
Netherlands.
E.R.Heerdink, PhD, Associate Professor of Pharmacoepidemiology
Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands
R.J. van Marum, MD, PhD, Department of Geriatrics, University Medical
Center Utrecht, and Jeroen Bosch Hospital, 's-Hertogenbosch, The
Netherlands
1Parker, C., C. Coupland, et al. (2010). "Antipsychotic drugs and
risk of venous thromboembolism: nested case-control study." BMJ 341:
c4245.
2Kleijer, B. C., E. R. Heerdink, et al. (2010). "Antipsychotic drug
use and the risk of venous thromboembolism in elderly patients." J Clin
Psychopharmacol 30(5): 526-530.
Competing interests: No competing interests
Well, what does this mean to those of us practicing in the long term
care environment? Let me put this in context.
Ten more DVTs per year per
10,000 patients 65 and older treated with anti-psychotics. In my centres
we have 602 seniors living in residential care with a median length of
stay of 20 months, of whom 19% are currently taking anti-psychotics. If we
were to assume that those 114 prescriptions do not change we would have to
wait eight and three quarter years to see one DVT attributable to anti-psychotics.
Hardly seems worth worrying about, yet, a 32% increased risk
in patients already at high risk such as those residing in our facilities
sounds much more significant. Risk of DVT will now be on the list when
deciding about treatment but well behind risk of cerebrovascular events,
aspiration pneumonia, falls, sedation and the possible, albeit small,
benefit of therapy.
Competing interests: No competing interests
When risk adjustments are made for the overall sample the odds ratio
is reduced half-way to unity (from 1.62 to 1.32). A similar change occurs
for conventional antipsychotics (from 1.58 to 1.28) and for patients
receiving both conventionals and atypicals (2.47 to 1.77). There is no
change, however, for patients who only received atypical antipsychotics
(1.74 to 1.73). despite the fact there is substantial reduction in the
odds ratio with adjustment for the most commonly used atypicals:from 1.41
to 1.24 for risperidone, from 1.63 to 1.49 for olanzapine, and from 3.64
to 2.81 for quetiapine. Could the authors explain this anomaly?
Competing interests: No competing interests
This study showed there is increase risk in embolism in patient who
taking anti psychotic medication. While the relative risk for venous
thromboembolism seems high, the absolute risk is low (four extra cases of
venous thromboembolism per 10,000 patients treated over one year). The
absolute risk is higher (10 per 10,000 patients over one year), among
those 65 and older. The clinical decision to prescribe anti psychotic
medication should be very individually. We should perform benefit-harm
analysis of anti psychotic therapy quantify the reduction in psychotic
symptoms and the increase embolism risk in an individual patient,
according to the individual risk profile.
Competing interests: No competing interests
Dear editor,
I read with interest the useful article by Parker and colleagues.
Prolactin and leptin have been found to be potent co-activators of
ADP-dependent platelet aggregation or P-selectin expression(1,2).
Prolactin may also play a role in causing anti-phoshpolipid syndrome(3).
Consequently, higher prolactin levels due to anti-dopaminergic therapy
should be able to cause higher rates of venous (as well as arterial)
thrombotic events.
However in view of published reports that selective blockade of 5HT2A
receptor can have protective effect in cases of recurrent thrombosis (4),
it's difficult to reason why the atypical antipsychotics should entail
higher risk of thrombosis than the conventional drugs. This should
encourage more research into the mechanism of thrombogenesis as well as
the action of the SDA group of antipsychotics.
The authors have shown that the co-existence of other risk factors
like smoking and old-age increase the risk of DVT associated with
antipsychotics. They found no significant difference among various
psychiatric diagnoses for which the drug was prescribed. However more
details on the level of activity, sedation, weight gain and new onset
diabetes/ dyslipidemia in patients receiving particularly the SDAs would
be helpful.
Yours sincerely,
Koushik Dutta
References:
1. Urban A, Masopust J, Maly R, Hosak L, Kalnicka D. Prolactin as a
factor for increased platelet aggregation. Neuro Endocrinol Lett
2007;28(4):518-23.
2. Wallaschofski H, Kobsar A, Sokolova O, Eigenthaler M, Lohmann T.
Co-activation of platelets by prolactin or leptin--pathophysiological
findings and clinical implications. Horm Metab Res 2004;36(1):1-6.
3. Praprotnik S, Agmon-Levin N, Porat-Katz B, Blank M, Meroni PL,
Cervera R, Miesbach W, Stojanovich L, Szyper-Kravitz M, Rozman B, Tomsic
M, Shoenfeld Y. Prolactin's role in the pathogenesis of the
antiphospholipid syndrome. Lupus 2010 Jul 20. [Epub ahead of print]
4. Przyklenk K, Frelinger AL, Linden MD, Whittaker P, Li Y, Barnard
MR, Adams J, Morgan M, Al-Shamma H, Michelson AD. Targeted inhibition of
the serotonin 5HT2A receptor improves coronary patency in an in vivo model
of recurrent thrombosis. J Thromb and Haemost 2010; 8(2): 331-40.
Competing interests: No competing interests
The degree of mobility of these patients and the underlying
comorbidities need to be taken into account before making the conclusions.
The underlying pathophysiology a of possible side effect of antipsychotics
might help to prevent the untoward events of VTE in pyschiatric patients
after elimniating the confounding bias.
Competing interests: No competing interests
At a time when we are generally led to believe that atypical antipsychotics are safer than the conventional ones, it is a bit worrying that this study[1] suggests a greater risk of thromboembolism with 'modern' antipsychotic medication. The fact that Quetiapine carried a higher risk than chlorpromazine, and haloperidol (adjusted odds ratio 2.81 (1.75 to 4.50), 1.77 (1.27 to 2.48), and 2.17 (1.55 to 3.02), respectively)[1], adds to worries about its safety given the recent claims of its association with Diabetes.[2]
Finally, I wonder,how many patients are aware that without their explicit consent(though on an anonymous basis), their personal medical data had been stored on a central database, QResearch[1].It is said, data currently come from "602 general practices"[3] and that "patients can opt out"[3]. I am not quite sure as to how patients could 'opt out';perhaps, patients could discuss with their GPs about this issue.
References
[1]Research:
Antipsychotic drugs and risk of venous thromboembolism: nested case-control study.
Chris Parker, Carol Coupland, and Julia Hippisley-Cox
BMJ 2010 341:c4245; doi:10.1136/bmj.c4245
[2]News:
AstraZeneca to pay $198m to patients over diabetes claims
Janice Hopkins Tanne
BMJ 341:doi:10.1136/bmj.c4422 (Published 13 August 2010)
[3]http://www.qresearch.org/SitePages/What%20Is%20QResearch.aspx
Competing interests: No competing interests
Dear Editor,
The first ever antipsychotic drug, chlorpromazine, was a byproduct of
rocket fuel extraction, which was conveniently passed off as a good drug
to make hallucinating Schizophrenics quiet! Quiet they did become but, the
prize that they had to pay was mild to severe Parkinsonism and eventually
total dementia. They could become real vegetables. That again was argued
as acceptable as a vegetative patient was better than a hallucinating
trouble maker!
Thus was born the new science of anti-psychotics. In a well
researched book, an American psychiatrist, Grace E Jackson, who worked for
the US navy, has bared all the hidden facts behind anti-psychotic drugs.
Her book, Drug Induced Dementia-a perfect crime, is worth its weight in
diamonds. (1) From the time of locking up mad people in large hospitals
for decades to making them vegetables is all that we achieved with our
well meaning efforts!
Recent epidemics of dementia and many other newer syndromes have very
strong connection to our flawed logic in chemical pharmacology. Most
chemical agents are dextrorotatory and the body molecules are levorotatory
- a good mismatch to begin with. The "first pass effect" taught to
students as a step in pharmacodynamics is a warning that the body tries to
reject any chemical compound by detoxicating it in the liver to the extent
possible lest they should damage the body.
Of course, our aim is to administer repeated doses to choke the liver
off to achieve our needed serum levels! This, in itself, is frightening.
Is it anything surprising that these drugs could help bring about venous
thrombo-embolism? The deeper we look into this mess of psychopharmacology
more such side effects will emerge. ADR emerging as one of the leading
causes of death is no surprise at all.
Using the MITCHIP, Douglas C. Wallace had shown that all chemical
reductionist molecules damage the human cells! (2) How does Socrates
define harm? Why does he believe that it is never just to harm anyone? In
medicine we no longer think it is unjust to harm our patients! Primum non
nocere has to be rewritten.
Yours ever,
bmhegde
References:
(1) Jackson GE. Drug induced Dementia-a perfect crime. A Perfect
Crime. Bloomington, IN. AuthorHouse, 2009, 440 pp.,
(2) Wallace DC. Mitochondria as Chi. Genetics 2008; 179: 727-735.
Competing interests: No competing interests
Those taking antipsychotics had higher rates of risk factors for
thrombosis so whether or not there is a true association with venous
thrombosis depends entirely on whether the statistical modelling
adequately accounts for these other risk factors. There is no reason to
suppose that it does. Indeed, the authors themselves state: "There could
still be residual confounding and the true effect of this group of drugs
is probably less than has been estimated in this study." The true effect
being "less" is compatible with the null hypothesis that there is no
effect at all. Additionally, some risk factors were not measured and other
plausible risk factors were not considered. Antipsychotics are prescribed
for a reason. Patients with schizophrenia have low levels of physical
activity, a risk factor for thrombosis which seems to have been ignored.
Patients with dementia who are prescribed antipsychotics may likewise be
more at risk of thrombosis for a variety of other reasons.
In any event, it should be emphasised that the proposed effect, even
if as high as the authors estimate, is very small. Around one extra case
of thrombosis among a thousand patients prescribed antipsychotics. People
are not generally prescribed antipsychotics without very good reason and
this low level of possible risk should not be regarded as a major
consideration when considering whether or not they should be used.
Competing interests: No competing interests
Clinical applications
Further reflection on this article raises some interesting questions
around implications for clinical practice.
For example, on forming a differential diagnosis that includes venous
thromboembolism (VTE), should we now think of current anti-psychotic usage
as on our list of risk factors? Furthermore, if, for example, a younger
patient, were to develop VTE while using anti-psychotics, should the
future usage of anti-psychotic medication then be contra-indicated? Or
would this contra-indication only be for atypical anti-psychotics?
These are all important and valid questions for clinical practice.
While this observational study certainly has its flaws the possible
clinical implications of these findings certainly merit further reflection
and discussion.
Competing interests: No competing interests