Randomized controlled trial of cryotherapy with liquid nitrogen vs topical salicylic acid vs wait-and-see for cutaneous warts.

Question: In outpatients who present with new cutaneous warts, what is the efficacy of treatment with cryotherapy, topical salicylic acid, and a wait-and-see approach in leading to clearance of baseline lesions at 13 weeks? Design: Unblinded, randomized-controlled trial. Setting: Multipractice, 30 family practices from the Leiden Primary Care Research Network in the Netherlands. Patients: Patients 4 years and older who presented to the general medicine clinic with one or more new cutaneous warts. Immunocompromised patients, those with genital warts, seborrheic warts, or warts larger than 1cm in diameter were excluded from the study. Intervention: Enrolled participants were randomized to 13-week treatment periods with cryotherapy (one session every two weeks until resolution of the wart), salicylic acid (daily self-application of 40% salicylic acid in petroleum jelly daily under occlusion preceded by gentle paring), or wait-and-see (advised not to undergo treatment other than over-the-counter medication). Patients were stratified according to characteristics, notably location of warts (plantar vs common [those with both common and plantar warts were grouped according to where the majority of their warts were located]) and number of warts ( 6 or 6). Outcome: The primary end point was the proportion of patients whose warts present at baseline were all cured at 13 weeks. Secondary analyses and subgroup analyses were predefined. Results: Of 250 randomized patients who received treatment, 10 were lost to follow-up at 13 weeks, and 48 patients stopped the assigned treatment protocol. The intention-to-treat analysis demonstrated cure rates of 39% (30/76) for the cryotherapy arm, 24% (20/82) for the salicylic acid arm, and 16% (13/82) for the wait-and-seen arm; two-sided 2 test, linear-by-linear association, comparing three treatment groups (P=.001). With subgroup analysis based on location of warts, cure rates of 49% (19/39) for cryotherapy, 15% (6/39) for salicylic acid, and 8% (3/38) for wait-and see were demonstrated for common warts; two-sided 2 test, linearby-linear association, comparing three treatment groups (P .001). For plantar warts, cure rates of 30% (11/37) for cryotherapy, 33% (14/43) for salicylic acid, and 23% (10/44) for wait and see two-sided 2 test, linear-bylinear association, comparing three treatment groups (P=.46) were seen. Secondary analyses including 26-week follow-up was performed (after allowing for switching after 13 weeks) and results were noted to be concordant with results at 13 weeks. Likewise, further analyses were performed: exclusion of participants with both common and plantar warts from the analysis, per-protocol analysis, and analysis based on individual warts as the unit rather than patients. All of these secondary analyses showed the same significant results as the primary analysis. Also of note, in the common wart group, patients were more satisfied after treatment with cryotherapy, 69%, compared with 24% after salicylic acid and 22% after wait-and-see (P .001). Assessment of adverse effects showed significantly greater number of adverse effects with cryotherapy than with salicylic acid, including more pain and blistering. When comparing the burden of treatment, fewer patients with common warts reported considerable treatment burden with cryotherapy, 31%, as compared with salicylic acid, 49%, two-sided 2 test, linearby-linear association, comparing two treatment groups (P=.04). No difference in patient satisfaction or treatment burden was seen in the plantar wart group. Conclusions: Use of cryotherapy was significantly more effective than use of salicylic acid treatment for common warts only. For plantar warts, there was no clinically relevant difference in effect favoring the use of cryotherapy, salicylic acid, or a wait-and-see approach.