Anticholinergic effects of common drugs are associated with increased mortality in over 65sBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d4037 (Published 28 June 2011) Cite this as: BMJ 2011;342:d4037
All rapid responses
I should like to plead for a sober reflection on the true
implications of this news item and ask whether such excited attention from
the media was really justified? Is it acceptable to risk stirring up a
flurry of anxiety amongst patients who are dependent on a class of
medication when the evidence is so very fickle?
These data were presented initially through BBC News headlines, and
other media outlets, during the morning of 24th June 2011. The paper by
Fox, C. et al. (2011) (1) was not made available on the website of the
Journal of the American Geriatrics Society (JAGS) until 16:00 on 24th
June, by which time the media squall had run its course. It would seem
that this was another, regrettable occurrence of presenting data by press
conference first, with publication for peer scrutiny later. Recent history
in the UK should have deterred such actions.
The press reaction arose from a post-hoc analysis of epidemiological
data collected from older adults enrolled in the MRC Cognitive Function
and Ageing Study. Participants were assessed using the Mini-Metal State
Examination (MMSE) with data collected in 1991 and 1993. The paper was
published as an early, on-line, brief report which is succinct and short
The Anticholinergic medication load, administered to the
participants, was measured by reference to a ranked ordinal scale based on
judgements of potency which was used to calculate a crude score. The scale
was missing from the paper, but was available from the BBC website.
Disease burden was measured by counting the number of self-reported health
conditions, from a prescribed list, to a maximum of three. The BBC
website, in a paragraph headed "Deadly consequences" reported an
association between increased mortality and the use of anticholinergic
drugs. Whilst cautioning against confusing correlation with causation, it
claimed that "other factors, such as increased mortality from underlying
diseases, were removed from the analysis". How could such a feat have been
achieved? It must also be acknowledged that a causative association was
implied in press briefings during the day.
The bulk of the Fox et al (2011) paper focuses on identifying a
correlation between the use of anticholinergics and poorer performance on
the Mini-Mental State Examination. It is well known that the
anticholinergics, identified for this study, influence M1, M2 and M3
receptors with varying selectivity. M1 antagonism, most likely to affect
cognition, is contingent on crossing the blood-brain barrier, so molecule
size and fat solubility are important (2). However, patients prove
idiosyncratic, and all these drugs can affect mental function, such that
routine practice includes vigilance for such side effects (3).
There are cogent reasons to consider the claims about mortality with
an eye to the overactive bladder (OAB), a common problem causing urgency
and urge incontinence of urine, particularly in the elderly. It is an
extremely distressing condition, associated with older age, falls and
fractures, urinary tract and skin infections, sleep disturbances,
depression and comorbidity (4). The options for treatment are not great
but one mainstay is anticholinergic medication.
At this point I declare a conflict of interest. I have specialised in
treating urinary incontinence for 30 years and OAB features in 70% of the
3500 consultations I do annually. I worked on the clinical trial
programmes for terodiline, oxybutynin, tolterodine and solifenacin; all
key anticholinergics in the Fox et al (2011) study. My particular
involvement concerned the studies in the elderly. I have had no contacts
with the manufacturers in recent days.
Given what we know about OAB, it was no surprise that Fox et al
(2011) found that exposure to anticholinergic medication was associated
with older age, lower social class, former smoking and more health
conditions. These researchers claim that they adjusted for age, sex,
education, social class, number of self-reported health conditions and
nonanticholinergic medication. This is not possible to achieve for two
compelling reasons: (1) The variance between groups of these variables was
probably not homogenous and (2) the covariates correlated with the
outcome measures. The salient error in the Fox et al (2011) paper was well
described by Miller and Chapman (2001)(5)and lucidly explained by the
estimable Dr Andy Field (6).
Fox et al (2011) court further trouble through their lavish use of
ordinal scales. As Darwin emphasised, nature is inimical to categories
"Natura non facit saltum" (7). Biological variation is dispersed across
continuous spectra. Clinical scientists, enslaved by what Dawkins calls
"the tyranny of the discontinuous mind" (8) impede themselves. Logistic
multiple regression models might guide hypothesis formation, but rigorous
testing, in different samples, should precede wider, extravagant,
After the news bulletins, various organisations representing groups
with interests in this subject, announced in the media that they welcomed
these data. How could they do this if the data were not in the public
domain? The poor, worried patients were advised to consult with their GP.
What were the long suffering GPs supposed to make of this cacophony? The
cliche, "more research is needed", proved as dispiritingly ubiquitous as
ever. I do not agree with this sentiment as the relevant research is
When the anticholinergic drugs such as oxybutynin were introduced for
OAB we realised the elderly would be major consumers. We were certainly
worried about effects on cognition, but a greater concern was the
potential for torsade de pointes, a sometimes lethal cardiac arrhythmia.
Thus, scrutiny of the safety of these drugs in the elderly was intense,
extremely careful, and conducted by intervention studies to the standards
of GCP. Conveniently, the hypothesis that catalysed the scare promoted by
the BBC News, was tested and rejected by several studies some years ago (9
Given the body of evidence, I am confident that the anticholinergic
drugs used to treat the overactive bladder in the elderly are safe and not
a cause of increased mortality. I also believe that this worry has been
most diligently explored.
Correlations should be quarantined from causation until the mandatory
randomised studies be completed. Covariance analysis needs a health
warning. Scientific data should present through the scientific journals
and not our overwrought press.
(1) Fox C, Richardson K, Maidment ID, Savva GM, Matthews FE,
Simthard D et al. Anticholinergic Medication Use and Cognitive Impairment
in the Older Population: The Medical Research Council Cognitive Function
and Ageing Study. JAGS 2011 June 24;Early View (Online Version of Record
published before inclusion in an issue):1-7. Available from: URL:
(2) Callegari E, Malhotra B, Bungay PJ, Webster R, Fenner KS,
Kempshall S et al. A Comprehensive Nonclinical Evaluation of the CNS
Penetration Potential of Antimuscarinic Agents for the Treatment of
Overactive Bladder. Br J Clin Pharmacol 2011 March 11.
(3) Lackner TE, Wyman JF, McCarthy TC, Monigold M, Davey C.
Randomized, placebo-controlled trial of the cognitive effect, safety, and
tolerability of oral extended-release oxybutynin in cognitively impaired
nursing home residents with urge urinary incontinence. J Am Geriatr Soc
(4) Brown JS, McGhan WF, Chokroverty S. Comorbidities associated
with overactive bladder. Am J Manag Care 2000 July;6(11 Suppl):S574-S579.
(5) Miller GA, Chapman JP. Misunderstanding analysis of covariance.
J Abnorm Psychol 2001 February;110(1):40-8.
(6) Field A. Analysis of covariance. Discovering statsitics using
SPSS. 3rd. ed. London: Sage; 2009. p. 395-420.
(7) Darwin C. On the Origin of Species: By Means of Natural
Selection or The Preservation of Favoured Races in the Struggle for Life .
1st ed. London: Penguin; 1859.
(8) Dawkins R. Amphibians - The Salamander's Tale. The Ancestor's
Tale A Pilgrimage to the Dawn of Life. 1 ed. London: Weidenfield &
Nicholoson; 2004. p. 252-62.
(9) Griebling TL, Kraus SR, Richter HE, Glasser DB, Carlsson M.
Tolterodine extended release is well tolerated in older subjects. Int J
Clin Pract 2009 August;63(8):1198-204.
(10) Wagg A, Wyndaele JJ, Sieber P. Efficacy and tolerability of
solifenacin in elderly subjects with overactive bladder syndrome: a pooled
analysis. Am J Geriatr Pharmacother 2006 March;4(1):14-24.
(11) Kraus SR, Ruiz-Cerda JL, Martire D, Wang JT, Wagg AS. Efficacy
and tolerability of fesoterodine in older and younger subjects with
overactive bladder. Urology 2010 December;76(6):1350-7.
(12) Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V
et al. A systematic review and meta-analysis of randomized controlled
trials with antimuscarinic drugs for overactive bladder. Eur Urol 2008
Competing interests: I worked on the clinical trial programmes for terodiline, oxybutynin, tolterodine and solifenacin.I was the chief investigator for the studies that I worked in for terodiline, oxybutynin and tolterodine. All apposite to this rapid response; I wrote the protocols, was involved in the analyses and wrote the relevant papers. I was not paid for that work. My institution was paid, pro-rata, for patients that we entered and supervised in the clinical trials.Prior to 2005 Pfizer contributed to some conference expenses for my academic department. Since 2005, neither I nor my centre has accepted sponsorship from industry, in-line with a general policy adopted by us that year.I have spoken and shall speak in 2011 at postgraduate study events sponsored by Pfizer and Astellas. I was and shall be paid a reasonable fee for such contributions.With other academics, I have a basic science collaboration that includes scientists working for Pfizer. We all contribute to this research enterprise equally.I see private patients and the income earned is paid into academic funds held by UCL
Anticholinergics are associated with increased risk of falls,
cognitive impairment and increased mortality. They increase the risk of
delirium especially in hospitalised patients. Inpatients are exposed to a
wide variety of drugs with anticholinergic properties such as cyclizine,
codeine,morphine and tramadol. Delirium is linked to decreased cholinergic
response and any medication with anticholinergic properties can cause or
worsen delirium. Anticholinergic side effects such as constipation,
urinary retention, dry mouth and blurred vision also contribute to the
risk of delirium.
Anticholinergics have also been linked to cognitive impairment
through various mechanisms. They have been linked with worsening
cognition in Alzheimer's disease and Parkinson's disease. They also
cause decreased reaction time leading to increased risk of falls and poor
rehabilitation potential. They cause depression of the central nervous
system and this leads to fatigue.
Medications with anticholinergic properties should be reviewed during
acute admissions. This will decrease the risk of delirium and cognitive
impairment especially in the elderly patients. Clinicians especially
junior doctors need to be educated about drugs with anticholinergic
1) Lauretani F,Ceda GP,Maggio M,Nardelli A,Saccavini M,Ferrucci L-
Capturing side-effect of medication to identify persons at risk of
delirium - Aging-Clinical & Experimental Research, Oct 2010, vol./is.
2) Jessen F,Kaduszkiewicz H,Daerr M,Bickel H,Pentzek M,Riedel-Heller
S,Wagner M,Weyerer S,Wiese B,van den Bussche H,Broich K,Maier W -
Anticholinergic drug use and risk for dementia: target for dementia
prevention. European Archives of Psychiatry & Clinical Neuroscience,
Nov 2010, vol./is. 260 Suppl 2/(S111-5), 0940-1334;1433-8491.
3)Ehrt U,Broich K,Larsen JP,Ballard C,Aarsland D. Use of drugs with
anticholinergic effect and impact on cognition in Parkinson's disease: a
cohort study Journal of Neurology, Neurosurgery & Psychiatry, Feb
2010, vol./is. 81/2(160-5), 0022-3050;1468-330X.
4) Karatas GK,Gunendi Z. Do anticholinergics affect reaction time? A
possible impact on the course of rehabilitation. Neurorehabilitation,
2010, vol./is. 27/2(141-5), 1053-8135;1878-6448.
5) Zlott DA,Byrne M. Mechanisms by which pharmacologic agents may
contribute to fatigue. Pm & R, May 2010, vol./is. 2/5(451-5), 1934-
Competing interests: No competing interests