Journal reference: Bruggink SC, Gussekloo J, Berger M, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: a randomized controlled trial. CMAJ. October 19, 2010; 182 (15) ^[1]

Link: http://dx.doi.org/10.1503/cmaj.092194

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Cryotherapy with liquid nitrogen is more effective than topical salicylic acid ointment for treatment of cutaneous common warts. In the Dutch primary health care study participants, it achieved over double the cure rate (49% vs 15%) at 13 weeks. The study cryotherapy treatment protocol [1]: treatment session every fortnight until warts resolve in each session, application of a wad of cotton wool saturated with liquid nitrogen until a frozen halo of 2 mm around the base of the wart three serial applications of cryotherapy per session There is no significant difference between cryotherapy, topical salicylic acid, and a “wait and see” approach in the treatment of plantar warts.

More details:

Article details

Study design:

non-blinded randomised controlled trial

Study aim:

to compare efficacy of cryotherapy with liquid nitrogen, against topical salicylic acid or “wait and see” (over the counter or no treatment arm) for the treatment of cutaneous warts

Methods summary:

• randomised controlled trial, set in the Netherlands
• analysis on intention to treat basis
• 30 primary care practices between May 1, 2006 and Jan 26, 2007  from Leiden Primary Care Research Network
  • contacted all patients ≥ 4 years age who had attended clinic with one or more new cutaneous warts
  • method of contact not reported
• exclusion:
  • those patients who had been treated by a physician or dermatologist in previous year for their warts
  • immunocompromised patients
  • patients with genital warts
  • seborrhoeic warts
  • warts > 1 cm in diameter
• inclusive of any over the counter treatments
• consenting participants were visited at home by a trained research nurse
• patients were stratified by
  • wart location
  • wart number (< 6 warts or ≥ 6 warts).
• randomisation of patients was through delivery of opaque sealed envelopes
  • numbered based on a computerised randomisation list
  • delivered by an independent statistician to conceal allocation
• treatment arms:
  • cryotherapy treatment:
    • high intensity regimen of one session every 2 weeks until all warts resolved
    • in each session, 3 serial applications in which a wad of cotton wool saturated with liquid nitrogen was moved around on the wart
    • application until a frozen halo of 2 mm around the base of the wart appeared
  • salicylic acid  treatment:
    • 40% salicylic acid in petroleum jelly applied daily until warts completely resolved
    • filing of wart prior to application of jelly
    • occlusion with tape after application including protective tape on surrounding healthy skin
  • wait and see arm:
    • education about benign natural course of warts
    • advised not to undergo treatment other than over-the-counter treatment for at least 13 weeks
• assessment by trained research nurses by home visit at 4, 13 and 26 weeks
  • nurses were not blinded to treatment arms
  • for quality control, 5% of assessments directly supervised by two researchers who were experienced family physicians

Primary outcome:

• proportion of participants whose warts were cured at 13 weeks

Secondary measures:

• side effects
• newly developed warts
• adherence to treatment
• patient rated treatment burden
• treatment satisfaction
• all measures also assessed at 26 weeks

Statistical analysis:

• power calculation made a priori
• 91 patients required for each treatment arm

Results summary:

• 303 patients were invited to participate
  • 35 were ineligible
  • 18 refused consent
• of the remaining 250 participants, baseline characteristics were similar between the groups

Primary outcome:

• cryotherapy:
  • 80 participants → 4 lost to follow up
  • cure rates:
    • all warts: 39% (95% CI 29-51%)
    • wart duration < 6 months: 63% (46-78)
    • wart duration ≥ 6 months: 24% (14-38)
    • common warts: 49% (34-64)
    • plantar warts: 30% (17-46)
• salicylic acid
  • 84 participants → 2 lost to follow up
  • cure rates:
    • all warts: 24% (95% CI 16-35%)
    • wart duration < 6 months: 38% (24-54)
    • wart duration ≥ 6 months: 13% (6-26)
    • common warts: 15% (7-30)
    • plantar warts: 33% (20-47)
• wait and see
  • 86 participants → 4 lost to follow up
  • cure rates:
    • all warts: 16% (10-25)
    • wart duration < 6 months: 31% (18-49)
    • wart duration ≥ 6 months: 6% (6-16)
    • common warts: 8% (3-21)
    • plantar warts: 23% (13-37)

Other results:

• no significant difference at 26 weeks compared to 13 weeks
• greater side effects reported in cryotherapy arm than topical salicylic acid arm
  • pain: 78% vs 13%
  • blistering: 22% vs 2%
• patient satisfaction was generally greater in the cryotherapy arm for treatment of common wart

Study conclusion:

For common warts, cryotherapy was the most effective therapy in primary care.  For plantar warts, there was no clinically relevant difference in effectiveness between cryotherapy, topical application of salicylic acid or a wait and see approach after 13 weeks.

Participants:

• from 30 Leiden Primary Care Research Network clinics in the Netherlands
• 250 participants:
  • 59% were female
  • 43% were aged 4-12 years
  • 47% were aged > 12 years
  • 7% reported symptoms present for over than one year
  • 35% had tried previous over-the-counter treatment without success:
    • 18% dimethylether propane cryotherapy
    • 12% tried topical salicylic acid (concentration less than study ointment)
    • 6% cutting away wart themselves
    • 6% other measures
• wart characteristics:
  • 122 (49%) common warts
  • 128 (51%) plantar warts

Methodological weaknesses

• specific population group of study is patients attending the Leiden Primary Care Research Network Clinic, in the Netherlands
• ethnic Western European (Dutch) population
  • may not necessarily be extrapolated to all other population groups
• study is underpowered
  • was not able to recruit the minimum number of participants (91) in each treatment arm
  • wide confidence intervals and low number of participants in subgroups made stratified analysis useless
  • in most subgroups, cure rate from cryotherapy was higher than the cure rate in the other two treatment arms but a statistically significant result was not found
  • it is possible that the lack of difference in the primary outcome between cryotherapy and the other treatments represents a type 2 error due to the study being underpowered

Methodological strengths

• similar baseline characteristics between treatment groups
• intention to treat analyses
• power calculation made a priori
• randomised design
• participants from primary health care population with wide inclusion criteria → results likely generalisable to Australian general practice setting
• excellent follow up with low rate of dropouts
• methods well described and study well designed

Biases and conflicts of interests

• nil declared and none obvious

Clinical relevance to primary health care

Cutaneous warts are are common dermatological problem seen in Australian general practice. The evidence for the different treatments has been poor though it seemed to favour salicylic acid application.

This well designed and conducted randomised controlled trial conducted on a primary health care population demonstrated the convincing superiority of liquid nitrogen cryotherapy for common warts. Compared, the cure rate for common warts at 13 weeks:

• cryotherapy: 49%
• salicylic acid: 15%
• wait-and-see: 16%

Comparing cryotherapy to topical salicylic acid, the number needed to treat (NNT) for benefit is only 3.0 (i.e., it only takes three patients with common warts treated with cryotherapy rather than topical salicylic acid to benefit an additional one).  Subgroup comparisons seem to favour cryotherapy but statistical significance was not detected for most. The study was relatively underpowered.

No statistical differences were detected between the three treatments for plantar warts.

From the viewpoint of treatment to cure cutaneous warts in the primary health care setting, liquid nitrogen cryotherapy is the most efficacious and should be recommended.

Note: it should be noted that the cryotherapy intervention in this study is more intense than usual practice for many Australian general practitioners. Please see the treatment protocol in the “methods summary” section above, or in the “morsel”, or in the source article.

References

1. Bruggink SC, Gussekloo J, Berger M, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: a randomized controlled trial. CMAJ. October 19, 2010; 182 (15)