Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis
BMJ 1999; 318 doi: https://doi.org/10.1136/bmj.318.7190.1031 (Published 17 April 1999) Cite this as: BMJ 1999;318:1031All rapid responses
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As continuous itraconazole is known to be less effective than
continuous terbinafine for onychomycosis, there could be no rational
expectation that giving itraconazole intermittently would make it any
better. So why did Evans et al (1) do their mammoth study to prove the
obvious, at so much cost in patient and research time, let alone sterling?
As consultant to Sandoz in the late 80s when terbinafine was being
developed, I tried to convince them that once nail growth had been shown
to be continuous along the bed (2), intermittent pulse therapy, or even
one or a few administrations , perhaps with a bigger dose , would isolate
the fungus as the nail and bed surface grew out, and therefore be as
effective as continuous therapy (3). I planned various studies, including
in parts of the world where administration of one or two doses might be
all that could be expected but Sandoz finally declined. ("Whilst we, of
course, need to define the correct dose and duration of therapy, we
believe that, at this stage, our submission to the authorities shows that
the drug is both highly effective and relatively safe, given both the dose
and duration applied for. Of course, once the drug is marketed, further
projects both within and outside of Sandoz will further delineate the dose
and duration of treatment in onychomycosis and may even improve upon our
recommendations. However, at this stage…... "). Fortunately Janssen were
more receptive, which is why intermittent Itraconazole took the lead from
Terbinafine, although it is less effective.
The study that Evans et al (1) should have done is no different that
required 10 years ago - continuous versus intermittent terbinafine. The
problem with the study they did instead, apart from being a waste of
resources, is that it may come to be seen as the answer to a question it
didn't address. In no way does it answer the fundamental questions of
optimal frequency or duration, let alone dosage. Indeed it highlights it's
own deficiency by confirming that the response to intermittent
itraconazole is no less than has been found when the drug is given
continuously.
Evans et al have come to realise that the long recommended, continuous
dosing over the 12 to 18 months that a toenail can take to grow out is
unnecessary, but why stop at 12 weeks? The idea of a single or
intermittent pulse dosing has to be considered for all forms of cutaneous
fungal disease that can be effectively walled off by drug. The importance
of this idea is not just therapeutic; it would radically change the
screening of potential antifungal drugs because of vastly reduced toxicity
requirements. Perhaps, too, some previously rejected drugs could be
revived for intermittent therapy.
Clinicians took an inordinately long time to realise that prolonged
continuous antifungal therapy is unnecessary, and this misconception was
too willingly augmented by the pharmaceutical industry. What is now needed
is a complete re-examination of antifungal therapy to establish the
minimal duration, frequency and dose for a drug response for treatment and
for the discovery of new drugs
Sam Shuster
The Medical School
University of Newcastle Upon Tyne
1 Evans EGV, Sigurgeirsson B, LION study group. Double blind,
randomised study of continuous terbinafine compared with intermittent
itraconazole in treatment of toenail onychomycosis. BMJ; 318: 1031-1035
2 Johnson M, Comaish JS, Shuster S. Nail is produced by the normal
nail bed: a controversy resolved. Br J Dermatol 1991; 125: 27-29
3 Munro CS, Rees JL, Shuster S. The unexpectedly rapid response of
fungal nail infection to short duration therapy. Acta Derm Venerol
(Stockh) 1992; 72: 131-133
Competing interests: No competing interests
Editor- The methodolgy of Evans and Sigurgeirsson's paper on the
treatment of toenail infections1 was good and thorough, and the
conclusions generally sound, but does this warrant it being published in
the BMJ?
I am a GP and cannot dream of using terbinafine or itraconazole for
my patients however well they work. Where were the arguments about the
importance of the problem, or the justification for treating it? I am
surprised that the BMJ, usually so down-to-earth, should ignore these
points.
If 2-4% of my 5000 patients have onychomycosis, it would cost £17,864
-£35,728 to treat them according to these findings. For that I could save
between 2 to 5 lives by implementing the Sheffield tables for lipid
lowering therapy for the primary prevention of coronary heart disease,2 or
a hundred other things.
The senior authors declare a conflict of interest- they are both
closely linked to the company that makes the drug they favour. How about
the BMJ- do you all have crinkly toenails?
Jessica Harris general practitioner
Bacon Road Medical Practice, 16 Bacon Road, Norwich, NR2 3QX.
baconrd@aol.com
1. Evans EGV and Sigurgeirsson. Double blind, randomised study of
continuous terbinafine compared with intermittent itraconazole in
treatment of toenail onychomycosis. BMJ 1999;318:1031-5.
2. Ramsay LE, Wallis EJ, Haq IU, Jackson PR, Yeo WW. Policy based on
Sheffield table fully satisfies author's criteria. (Letter). BMJ
1999; 318: 1140-1.
Competing interests: No competing interests
I have reviewed your article and hope you can look at your data for a
different response rate and adverse reaction rate in patients aged 65 and
above please. As you know,Onychomycosis prevalence and severity increase
with age while pedal vascularity skin hydration sensitivity decrease with
age. Is this sub population more difficult to treat effectively? Do
results vary with race or socio-economic status? Any insight would be
appreciated as I am scheduled to discuss the LION study in an upcoming
presentation on oral anti-fungals. Thankyou for your time.
Competing interests: No competing interests
Evans and Sigurgeirsson(1) elegantly demonstrate that one form of
treatment for toenail onychomycosis (continuous terbinafine) is
significantly better than another (intermittent itraconazole). But I find
it disturbing that you have given such prominence (the lead Paper in the
journal and the lead item in "This week in the BMJ") to a comparative drug
trial of two well-established drugs which was financed entirely by the
manufacturers of one of the drugs.
The introduction to the paper cites a prevalence of onychomycosis of
2-4%, yet the study population consisted of patients with "severe
onychomycosis" (on average a 10-year history with six toenails affected;
this fact is tucked away in the last paragraph) and no evidence is
presented to demonstrate the relevance of this study to a wider population
of patients with mild or moderate onychomycosis.
The optimistic "Key message" (repeated in "This week in the BMJ")
that "fungal nail disease is curable" is only correct in the sense that
about 50% of patients who took terbinafine showed a "complete cure" at 72
weeks. This accords with Epstein's recent review of the success of oral
treatment of onychomycosis(2). Would it not have been equally true
(although a bit more pessimistic, and certainly less promotional) to say
"fungal nail disease is incurable"?
The paper states: "As with the mycological cure rates the clinical
cure rates for the continuous terbinafine groups continued to increase
after treatment through to week 72. This was not the case for the
intermittent itraconazole groups." The graphs on page 1034, however, tell
a different story. They show that the cure rates for both forms of
treatment continue to increase substantially after treatment ceased.
I was particularly disturbed to see that the authors acknowledged the
"constant help and guidance throughout this project" of an employee of
Novartis Pharmaceuticals Corporation. Why, I asked myself, was it
necessary to require the constant help and guidance of the manufacturers
of one the drugs being studied?
As a general practitioner who often receives letters from podiatrists
asking me to prescribe 12-16 week courses of systemic terbinafine for
relatively mild and insignificant nail discolouration, I am also concerned
about the cost (£134-178) and the cost-benefit analysis of such treatment.
I predict that the BMJ's final "Key message" - "Continuous
terbinafine should be the current treatment of choice for onychomycosis" -
will soon appear in promotional material for terbinafine. But is it a
claim that should be made in the scientific pages of the BMJ, or should it
be confined to the advertisements?
1. Evans EG, et al. Double blind, randomised study of continuous
terbinafine compared with intermittent itraconazole in treatment of
toenail onychomycosis. BMJ. 1999 Apr 17;318(7190):1031-1035.
2. Epstein E. How often does oral treatment of toenail onychomycosis
produce a
disease-free nail? An analysis of published data. Arch Dermatol 1998
Dec;134(12):1551-4.
Fred Kavalier
General Practitioner
Kentish Town Health Centre
2 Bartholomew Road
London NW5 2BX
Competing interests: No competing interests
The article by Evans et al (1) raises two issues about the treatment
for toenail onychomycosis.
Firstly, whilst we acknowledge the difficulties associated with long
term follow up in trials, a follow up time of 72 weeks may not be a true
measure of effectiveness of treatment. Our experience in primary care is
that many patients are put into remission rather than cured when followed
up over longer periods.
Secondly, the prescription of terbinafine for toenail onychomycosis
is usually undertaken by GPs. A more important issue for primary care is
which patients actually require treatment? In 1996, terbinafine appeared
in our PACT data amongst the 20 most expensive drugs, reaching number 12
at its high point. The drug was widely advertised and patients consulted
us, often on the advice of their chiropodist (who are unable to prescribe
the drug) asking for a prescription. Most of these patients had a purely
cosmetic problem.
We consulted with the local dermatolgy and podiatry departments and
pharmaceutical adviser. The consensus was that treatment of toenail
onychomycosis was only necessary if it was contributing to a biomechanical
foot problem or if the patient had associated neurological or circulatory
problems. As a result we now explain to patients that they do not need
treatment if the problem is purely cosmetic; most accept this. If
treatment is indicated it is now only instituted after microbiological
confirmation of infection. This policy has reduced our prescription rate
to 3 courses of treatment over a 12 month period compared with 9
prescriptions in a 3 month period in 1996.
We cannot identify any trials in the literature with follow up for
periods greater than 72 weeks. We feel that trials over 3-5 years should
be undertaken before terbinafine can claim to be both an effective and
cost effective treatment. The current cost to the NHS of each patient with
microbiological cure at 72 weeks is 256 pounds sterling. If our 1996
level of 18 courses of treatment per GP per year were repeated across the
country the costs would be staggering.
Yours sincerely
Peter Rose Tim Wilson.
MB, FRCGP. BM,BS. FRCGP.
Mill Stream Surgery
Benson
Oxon OX10 6RL
ICRF General Practice Research Group
Institute of Health Sciences
Old Road
Headington
Oxon OX3 7LF
1 Evans EGV, Sigurgeirsson B for the LION study group. Double blind,
randomised study of continuous terbinafine compared with intermittent
itraconazole in treatment of toenail onychomycosis. BMJ 1999; 318: 1031-5.
Competing interests: No competing interests
Yes- Crinkly nails do matter!!
EDITOR - We have read with interest and dismay the flurry of
correspondence from general practitioners sent in response to your recent
article concerning the treatment of toenail onychomycosis1. Toenail
onychomycosis seems to be regarded by many as a purely cosmetic problem
and relegated to causing no more distress to the patient than a 'Crinkly
nail'2,3.
The letters raise 2 important issues. Firstly the need to high-light the
subsequent possible sequelae from leaving toenail onychomycosis untreated
and secondly the ongoing conflict between meeting this year's drug budget
and the eventual long term costs to the NHS.
Evans4 mentions that toenail onychomycosis is important in patients with
peripheral vascular disease and increases the risks for conditions such as
cellulitis or erysipelas of the lower leg. We believe that toenail
onychomycosis is very important in 2 large groups of the population. Young
adults with physically active jobs, a keen interest in sport or
professional sports people will be at risk of physical distortion of their
toenails in the presence of onychomycosis. This leads to the frequent
occurrence of in growing nails with associated pain, risk of secondary
infection, need for operations and associated time away from work.
The second large group are the elderly. Onychomycosis has been shown to
complicate up to 50% of cases of onychogryphosis. The majority of these
patients recall having dystrophic toenails for many years prior to the
development of onychogryphosis, suggesting that onychomycosis may have a
causative role. The affect of onychogryphosis on the quality of life of
our elderly population cannot be underestimated with respect to pain,
decreased mobility and increased dependence. The cost to the NHS can also
not be underestimated due the costs incurred from podiatry, adapted shoes
and transport for our less mobile patients.
There are many causes for toenails becoming dystrophic or discoloured and
we agree that treatment should be reserved for those nails with a
mycologically proven infection. We would however remind readers that
toenail clippings are often inadequate and that scrapings from beneath the
toenails or from the nail bed yield a higher rate of fungal culture. A
significant minority of cases of onychomycosis will still have negative
mycological culture, but can be diagnosed clinically and proven by other
methods.
Untreated toenail onychomycosis can have a great impact on a patient's
quality of life and cause many expensive long term sequelae. It is vital
that we look beyond this year's drug budget to the future consequences of
ignoring our patient's 'Crinkly nails'.
Natalie Stone
dermatology specialist registrar
Rodney Dawber
dermatology consultant
Churchill Hospital, Oxford, OX3 7LJ
1. Evans EGV, Sigurgeirsson B for the LION study group. Double blind,
randomised study of continuous terbinafine compared with intermittent
itraconazole in the treatment of toenail onychomycosis. BMJ 1999;318:1031-
5. (17 April)
2. Rose P, Wilson T. Prescribing terbinafine to every patient with
the condition would be expensive. BMJ 1999;319:1197. (30 October)
3. Harris J. Do crinkly toenails really matter?. BMJ1999;319:1197.
(30 October)
4. Evans EGV. Author's reply. BMJ1999;319:1197. (30 October)
Competing interests: No competing interests