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					From The British Journal of Dermatology

To Freeze or Not to Freeze: A Cost-effectiveness Analysis of
Wart Treatment
Posted 06/04/2007

M.R. Keogh-Brown; R.J. Fordham; K.S. Thomas; M.O. Bachmann; R.C. Holland; A.J. Avery;
S.J. Armstrong; J.R. Chalmers; A. Howe; S. Rodgers; H.C. Williams; I. Harvey
Author Information



Summary and Introduction

Summary

Background: Several general practitioner (GP)-prescribed and over-the-counter therapies for
warts and verrucae are available. However, the cost-effectiveness of these treatments is
unknown.
Objectives: To compare the cost-effectiveness of different treatments for cutaneous warts.
Methods: We designed a decision-analytic Markov simulation model based on systematic
review evidence to estimate the cost-effectiveness of various treatments. The outcome
measures studied are percentage of patients cured, cost of treatment and incremental cost-
effectiveness ratio for each treatment, compared with no treatment, after 18 weeks.
Results: Duct tape was most cost-effective but published evidence of its effectiveness is
sparse. Salicylic acid was the most cost-effective over-the-counter treatment commonly used.
Cryotherapy administered by a GP was less cost-effective than GP-prescribed salicylic acid
and less cost-effective than cryotherapy administered by a nurse.
Conclusions: Duct tape could be adopted as the primary treatment for cutaneous warts if its
effectiveness is verified by further rigorous trials. Nurse-administered cryotherapy is likely to
be more cost-effective than GP-administered cryotherapy.

Introduction

It is estimated that U.K. general practices treat about 2 million patients for cutaneous
(nongenital) warts each year.[1] If each treatment prescribed in general practice costs the NHS
on average £20,[2] the total annual cost is about £40 million. Many other people treat warts
themselves, using preparations that they buy from pharmacies.

Available treatments include surgical curettage, topically applied treatments and
complementary and alternative therapies. The most commonly used treatments are
professionally administered cryotherapy with liquid nitrogen, and topical salicylic acid. More
recently, duct tape has proven effective in one randomized trial, [3] and patient-administered
ethylene glycol cryotherapy has become available over-the-counter. Most warts tend to
disappear within a few years without treatment.[4,5] A systematic review of randomized trials
found little evidence that the two commonest wart treatments, salicylic acid and cryotherapy,
were of different effectiveness or that cryotherapy was better than no treatment, [6,7] although
the quantity and quality of direct comparative evidence was limited.

Wart treatment is very common and so imposes a substantial cost on health services and on
society, yet there is still uncertainty about which treatment is most effective or cost-effective.
To synthesize the diverse evidence on disease progression, treatment effectiveness and
treatment costs, a quantitative model is needed. The aim of this study was to compare the
cost-effectiveness of different treatments for cutaneous warts. We also aimed to assess
whether, and if so, which, randomized trials were still needed in the light of available evidence
and current practice.


Methods
The study was a cost-effectiveness analysis based on a decision-analysis model. We
estimated incremental cost-effectiveness ratios of each treatment compared with
'spontaneous resolution' (that is, do nothing) and basic advice from the general practitioner
(GP) (without treatment) as the baseline comparators. A brief explanation of incremental cost-
effectiveness is provided in the appendix. The GP no treatment baseline comparator is
included to represent the advice-only management typically offered by the NHS. As salicylic
acid is usually purchased by patients themselves while cryotherapy is predominately supplied
by the NHS, we conducted the cost-effective analysis both from the perspective of the NHS
and of patients using treatment (or no treatment) pathways determined by the survey data in
Thomas et al.[2]

The cost-effectiveness model was built using TreeAge Data Pro software (TreeAge Software
Inc., Williamstown, MA, U.S.A.). The software allows decision-analytic pathways of accepted
treatments to be clearly modelled using estimates of outcomes and costs found in the
literature. These estimates are set out in Table 1 , Table 2 , and Table 3 .[3,8-14]

The model includes a Markov property, to represent recurring events over time (in our case,
imaginary weekly checks of the treatment's progress). At the end of each weekly cycle we
consider all patients to be in one of two situations or 'Markov states': (i) the patient still has a
wart(s) or (ii) the patient has no wart(s), that is, all warts have resolved or been cured. Cycle
length is set at 1 week. The model includes the possibilities that uncured patients pass from
their first-line treatment into a second-line treatment and then, if still uncured, to spontaneous
resolution. Details of the simplifying assumptions used in the model are given in the report by
Thomas et al.[2] and further details on Markov models are given in the appendix.


Treatment Options

Cure probabilities were estimated from the earlier Cochrane review,[7] which was recently
updated, with the average cure rates weighted by each trial's sample size. We used only trials
reporting numbers of patients cured rather than numbers of warts cured. Interquartile ranges
of cure rates for different trials of the same treatment were used in sensitivity analyses. In the
case of duct tape, the uncertainty in probability estimates was expressed in terms of
confidence intervals as the duct tape cure rate was available from only a single trial. To adapt
trial results to the model's weekly cycle, the proportion cured was apportioned equally across
the number of weeks for which the treatments were applied. A summary of the cure
probabilities for different treatments is presented in Table 1 .



Treatment Costs

Treatment costs included in the model are shown in Table 1 . Treatment pathways were
informed by a combination of expert opinion, patient survey, structured observation of practice
and focus group discussion with patients, health professionals and pharmacists. Treatment
costs are usually independent of time to cure. Although patients cured before completing a
course of treatment can then cease treatment, costs of treatment are not usually determined
by duration of treatment because it is generally not sensible to receive only part of a session
of cryotherapy, or to purchase a fraction of a bottle or tube of salicylic acid. We therefore
assumed that warts remaining uncured after a full course of treatment pass into the
spontaneous resolution (no treatment) branch of the model. The spontaneous resolution
branch of the model permits people's warts to resolve gradually over weekly cycles. In this
way, spontaneous resolution is modelled in the same way as other treatments, except that the
probability of cure or resolution in any cycle is lower.

The cost of combined treatments was the sum of the costs of the individual treatments. The
combination of cryotherapy and salicylic acid was modelled in the same way as a single
treatment, but the probability of cure was adjusted according to the estimated effectiveness of
the combination.
Some treatments work faster than others and the effectiveness of treatments varies according
to the time and frequency with which they are applied. In order to satisfy the opposing needs
of (i) patients who seek a cure within a reasonable time period, and (ii) the need for a
sufficient duration to allow the treatment (or treatments in the case of combination therapy) to
be completed, 18 weeks was selected as the minimum time period for the resolution of warts
in our model.



Results

Two baseline treatments are considered in our analysis, one for primary care treatments and
the other for over-the-counter treatments. Without treatment, 46% of patients' warts resolve
by week 18 at no cost ( Table 2 ). This represents the first baseline for our cost-effectiveness
analysis. The alternative baseline, of 'advice only' from the GP, has the same cure rate, but
costs £26·90 (including the cost of a GP consultation and travel). Several other treatments
(e.g. three sessions of cryotherapy, over-the-counter cryotherapy and cryotherapy by a nurse)
have the same cure rate as each other, but their costs differ ( Table 3 ).

The lower the incremental cost-effectiveness ratio is, the more cost-effective is the treatment.
The effect of using the 'advice only' baseline instead of the 'do nothing' baseline is to reduce
all incremental cost-effectiveness ratios ( Table 3 ) because of the additional cost of the GP
consultation. Using the former baseline also reverses the ranking of self-administered and
nurse-administered cryotherapy.

Figure 1 (top and bottom) shows the average costs and effects (percentage of patients cured)
of each option. The slope of a line between any two treatments represents the respective
incremental cost-effectiveness ratio, which is lowest when closest to vertical. Thus Figure 1
(top) shows that duct tape is the most cost-effective home treatment when compared with 'do
nothing', dominating all other treatments due to its negligible cost and high cure rate. Over-
the-counter cryotherapy also appears promising in that, if it is shown to be as effective as
professionally administered cryotherapy, it would provide a cost-effective alternative to over-
the-counter salicylic acid.

                           Figure 1. (click image to zoom)
                           (top) Average incremental costs and effects, and
                           incremental cost-effectiveness ratio, compared with
                           'do nothing' option. (bottom) Primary care treatments
                           only. Average costs and effects and incremental cost-
                           effectiveness ratio compared with 'advice only' option.
                           COMB = combination salicylic acid (SA) and
                           cryotherapy; CRSA = cryotherapy followed by SA,
                           CR3, CR2, CR1 (three, two and one applications of
                           cryotherapy, respectively); SACR = SA followed by
                           cryotherapy; CRNurse = cryotherapy administered by
                           a nurse; GP SA = SA prescribed by a general
                           practitioner (GP); OTC SA = SA bought over-the-
                           counter; OTC = cryotherapy bought over-the-counter;
                           DUCT = duct tape treatment; DN = do nothing
                           (baseline), ADVICE = advice only from a GP.



Of the single treatments delivered in primary care, cryotherapy administered by a nurse for
three sessions is the most cost-effective option, followed by salicylic acid prescribed by a GP
(GP SA) (Fig. 1, top). Cost-effectiveness of GP-administered cryotherapy (whether one, two
or three sessions) is less cost-effective than GP SA. A single application of cryotherapy offers
a 6% greater average improvement compared with spontaneous resolution, at a much higher
incremental cost than other treatments (£44·80). This high cost is partly due to the usual
requirement for a GP consultation before referral to a wart clinic. Of the combination
therapies, over-the-counter salicylic acid followed by cryotherapy is similarly cost-effective.
However, over-the-counter salicylic acid followed by cryotherapy appears cost-effective only
because it relies on patients self-treating for a period of 12 weeks prior to visiting the GP. An
explanation for the better cost-effectiveness of second-line cryotherapy is that relatively costly
cryotherapy is restricted to the minority of patients whose warts have not already been cured
by salicylic acid.

It is probably more representative of usual clinical practice to compare the GP-administered
treatments with a GP-administered 'advice only' baseline [ Table 3 and Fig. 1 (bottom)]. By
introducing this treatment as the baseline, all the incremental cost-effectiveness ratios for
alternative treatments decrease substantially. The most favourable incremental cost-
effectiveness ratio is for GP SA. However, three sessions of cryotherapy administered by a
nurse is almost as cost-effective as GP SA and is associated with higher cure rates for
patients. The combinations of salicylic acid and cryotherapy treatments are generally the least
cost-effective.



Sensitivity Analysis

A sensitivity analysis of the treatment cure probabilities was performed in order to determine
the cure values at which the choice of most cost-effective treatment would change. Full
details of this analysis are provided in Thomas et al.[2] and a further explanation of sensitivity
analysis is given in the appendix.

If cryotherapy were shown to be 55% effective (as in our estimate), GP SA would require a
cure rate of only 44% to be more cost-effective than GP-administered cryotherapy and a cure
rate of 52% to be more cost-effective than nurse-administered cryotherapy. Taking into
account the more rapid cure rates with cryotherapy, Figure 2 shows equality of cost-
effectiveness between GP SA and nurse-administered cryotherapy around the 50%
effectiveness threshold. At higher levels of effectiveness for both treatments, cryotherapy
would need to have a higher cure rate than salicylic acid to be equally incrementally cost-
effective (and conversely a lower cure rate below this threshold).

                           Figure 2. (click image to zoom)
                           Plot of cure rates at which general practitioner (GP)-
                           administered salicylic acid and nurse-administered
                           cryotherapy have equal incremental cost-effectiveness
                           ratios.




Discussion

Current available evidence suggests that there is little difference in effectiveness between
many commonly used wart treatments, suggesting that the cheapest treatments may be the
most cost-effective. But convenience, speed of cure and pain of different treatments are
highly relevant to patients. For example, cryotherapy can be painful and requires a general
practice visit. In such cases—where the direct costs to patients are relatively small, formal
healthcare costs are high, and outcomes are not significantly improved by professional
intervention—patients may prefer self-treatment. If there is good evidence of a natural
resolution of the illness within a reasonably short time period, or where a patient's quality of
life is not particularly reduced, then any intervention may be deemed unnecessary and not
taken up.[15] As two-thirds of warts are estimated to resolve within 2 years,[4,5] no treatment
may be the best option for those whose warts do not cause discomfort or affect employment
and are not cosmetically undesirable.
The most cost-effective treatments considered in the model are those that are bought by
patients and applied in their homes, namely over-the-counter salicylic acid, over-the-counter
cryotherapy and duct tape. This is not surprising, as the treatments do not require a costly
initial consultation with the GP, and appear to be of comparable efficacy to similar prescribed
treatments.

Some of the newly emerging home treatments such as duct tape and home cryotherapy with
ethylene glycol may prove to be highly cost-effective, but effectiveness evidence for these
treatments is limited. Salicylic acid remains the most cost-effective over-the-counter option
but the advent of a reliable and effective self-administered form of cryotherapy could be
advantageous. Routine use of cryotherapy for the treatment of warts in primary care may not
be justified on the grounds of cost-effectiveness. However, nurse-led cryotherapy clinics
would be a more cost-effective way of delivering this intervention if the number of cryotherapy
sessions is limited to a maximum of three and if subsequent studies show that nurses are as
effective as GPs when using liquid nitrogen cryotherapy. A recent survey showed that just
12% of cryotherapy treatments were currently conducted by nurses.[2] Although the evidence
suggests that cryotherapy and salicylic acid are of broadly comparable efficacy, it is possible
that cryotherapy delivers cures more quickly. This faster speed of cure of cryotherapy
compared with topical salicylic acid coupled with the low direct cost to patients (as the NHS
meets the main costs) may explain its popularity with patients. However, a shift towards
cheaper self-treatment might be beneficial to both the patients and the NHS.

In practice there is a great deal of variation in the application of wart treatments in terms of
their duration, frequency of application and adherence. Our model reflects 'best practice'
using optimum treatment applications as tend to be used in clinical trials.

Our findings suggest that two clinical trials should be undertaken in primary care settings to fill
important gaps in the current evidence. The first is a randomized trial of nurse-led cryotherapy
vs. salicylic acid in primary care. A total sample size of 872 (allowing for a drop-out rate of
10%) would be required to detect a 10% difference in cure rates in either direction. This
assumes that the cure rate of nurse-led cryotherapy is the same as GP-led cryotherapy, i.e.
54%. A second trial should compare three patient-administered treatments, namely over-the-
counter salicylic acid, duct tape and over-the-counter cryotherapy. A total sample size of 1308
(allowing for a drop-out rate of 10%) would be required to detect a 10% difference in cure
rates in either direction, and assumes a baseline cure rate of 54%.

Although cutaneous viral warts constitute a low morbidity problem they nonetheless use
significant primary care resources. Their management should be guided by further high-
quality randomized trials of new interventions or old interventions delivered in new ways.
Table 1. Cost, Cure Rate and Duration of Warts Treatments

                                                                              Cure rates
Intervention              Costs included            Average cost (£)          [duration]
Home treatments
  Over-the-counter    £4·75 per pack (per 6      £23·30                   57% (IQR 35-
salicylic acid        weeks)                                              68%) [12 weeks]a
                      Travel pharmacy
 Duct tape            £2·50 (10 metres)          £9·40                    85% (95% CI
                      Travel to shop                                      66·5-94%) [8
                                                                          weeks]b
  Over-the-counter    £11 (35-mL can)            £17·90                   54% (IQR 53-
cryotherapy           Travel costs                                        58%) [6 weeks]c
Treatments in primary care
 Advice only          £20 (GP consultation)[14] £26·90                    30% [10 weeks]d
                      Travel to GP
  GP-prescribed       £20 (GP consultation)[14] £40·30                    As for over-the-
salicylic acid        Travel to GP                                        counter salicylic
                      £5·50 (two prescribed                               acid
                      items)[14]
                      Dispensing charge
 Cryotherapy          £20 (initial GP            £80·60 for three GP      As for over-the-
                      consultation)[14]          sessions; £55·10 for     counter
                      Travel to surgery (each    three nurse sessions     cryotherapy
                      consultation or session)
                      £11 per 5-min GP
                      cryotherapy session[14]
                      OR
                      £2·50 per 5-min nurse
                      cryotherapy session[14]
Extras
 Travel (to GP,       £6·90 per visit[14]        £6·90                    Not applicable
pharmacy or shop)
GP = general practitioner; IQR = interquartile range.
a
  Cure rates pooled from four studies;[8-11] 12 weeks was the most common duration for
salicylic acid trials.
b
  Cure rates and duration from Focht et al.[3]
c
 Cure rates pooled from five studies.[3,8,11,12,13] Treatment duration of 6 weeks is based on
three sessions at 2-week intervals, which has been shown to be the shortest of the
effective interval lengths in Bunney et al.[8] Ethylene glycol cryotherapy has been
assumed to be of equal effectiveness to liquid nitrogen cryotherapy.
d
  The most common placebo treatment in Gibbs et al.[7] was of 10 weeks' duration with
average resolution of 30%. This has been used to estimate the spontaneous resolution
level.
Table 2. Home Treatment Effects and Total Cost at 18 Weeks

                    Effect (%    Cost     Incremental         Incremental        Incremental cost-
Treatment            cured)       (£)      effect (%)           cost (£)         effectiveness ratio
Do nothing            45·92      0·00            0·00              0·00
Over-the-counter      64·22      20·47          18·30              20·47                  1·12
salicylic acid
Over-the-counter      69·51      17·90          23·59              17·90                  0·76
cryotherapy
Duct tape             88·27      9·40           42·35              9·40                   0·22



Table 3. Primary Care Effect and Total Cost at 18 Weeksa
Compared With Both 'Do Nothing' and 'Advice Only' Baselines

                                                                                  Compared with
                                                        Compared with 'do          'advice only'
                                                         nothing' baseline           baseline
                   Effect
                     (%       Cost   Incremental        Incremental              Incremental
Treatment          cured)      (£)    effect (%)          cost (£)     ICER        cost (£)      ICER
Advice only        45·92    26·90        0·00              26·90           -          -           -
GP-prescribed      64·22    40·30        18·30             40·30          2·20      13·40        0·73
salicylic acid
Cryotherapy 1      52·27    44·80        6·35              44·80          7·06      17·90        2·82
application
Cryotherapy 2      64·85    59·41        18·93             59·41          3·14      32·51        1·72
applications
Cryotherapy 3      69·51    70·67        23·59             70·67          3·00      43·77        1·86
applications
Nurse              69·51    49·27        23·59             49·27          2·09      22·37        0·95
cryotherapy
Salicylic acid     80·00    66·33        34·08             66·33          1·95      39·43        1·16
then
cryotherapy
Cryotherapy        80·13    80·01        34·21             80·01          2·34      53·11        1·56
then salicylic
acid
Combined           69·51    82·32        23·59             82·32          3·49      55·42        2·35
salicylic acid
and
cryotherapy
ICER = incremental cost-effectiveness ratio in £ per patient cured.
a
  Costs and outcomes do not reflect the totals outlined in Table 1 as those patients who
are cured at each weekly cycle no longer incur further costs.
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