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. If each treatment prescribed in general practice costs the NHS on average £20, 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,  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. 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. and further details on Markov models are given in the appendix. Treatment Options Cure probabilities were estimated from the earlier Cochrane review, 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. 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. 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. 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) £26·90 30% [10 weeks]d Travel to GP GP-prescribed £20 (GP consultation) £40·30 As for over-the- salicylic acid Travel to GP counter salicylic £5·50 (two prescribed acid items) Dispensing charge Cryotherapy £20 (initial GP £80·60 for three GP As for over-the- consultation) sessions; £55·10 for counter Travel to surgery (each three nurse sessions cryotherapy consultation or session) £11 per 5-min GP cryotherapy session OR £2·50 per 5-min nurse cryotherapy session Extras Travel (to GP, £6·90 per visit £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. 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. 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. 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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