Efficacy and Safety of Ionic Contra-viral Therapy (Digoxin-furosemide) in the Treatment of Multiple Cutaneous Warts: A Systematic Review, Meta-analysis, and Trial Sequential Analysis.

introductionThe primary objective of this systematic review was to evaluate the therapeutic efficacy and safety profile of intralesional Ionic Contra-Viral Therapy (ICVT)-a combination of digoxin and furosemide-in the treatment of multiple cutaneous warts.

methodsThis meta-analysis was conducted in accordance with PRISMA guidelines and was prospectively registered in PROSPERO (CRD42024544551). A comprehensive literature search was performed up to April 2024 across PubMed, MEDLINE, Scopus, Cochrane CENTRAL, ClinicalTrials.gov, and Google Scholar. Eligible studies included randomized controlled trials involving adults with ≥2 cutaneous warts treated with intralesional digoxin and furosemide, assessing outcomes, such as complete and partial clearance, wart size reduction, and adverse events. Exclusion criteria included case reports, reviews, and preclinical studies. Data extraction was performed independently by two reviewers, with discrepancies resolved through consensus. The Cochrane RoB 2 tool was used for risk of bias assessment. Meta-analyses were conducted using a random-effects model, and heterogeneity was evaluated using the I² statistic. The quality of evidence was graded using the GRADE framework.

resultsSeven randomized trials, including a total of 391 patients, were analyzed. The ICVT group demonstrated significantly higher complete wart clearance compared to placebo (56.8% vs. 2.8%; RR = 13.27, 95% CI = 2.93-60.17; p = 0.0018). Partial response was lower in the ICVT group (5.08% vs. 10%; RR = 0.66, 95% CI = 0.09-5.09; p = 0.69). Adverse events occurred more frequently in the ICVT group (85% vs. 58.8%; RR = 1.33, 95% CI = 0.47-3.79; p = 0.59; I² = 97%). Pain during injection was also more commonly reported in the ICVT group (96.6% vs. 63.3%; RR = 1.45, 95% CI = 0.29-7.22; p = 0.65; I² = 99%). The certainty of evidence was rated as very low for complete clearance, moderate for partial response, and low for adverse events and injection pain. Trial Sequential Analysis (TSA) indicated that the required information size was not met for any of the outcomes. DISCUSSION: While the results suggest that ICVT may be effective in achieving complete clearance of multiple cutaneous warts, the current evidence is limited by small sample sizes, methodological heterogeneity, and potential biases. The higher incidence of adverse events and injectionrelated pain raises safety concerns. The low to very low certainty of evidence, coupled with the TSA findings, underscores the need for more rigorous investigation. Variability in trial design, dosing protocols, and outcome reporting further limits the applicability of current findings.

conclusionIntralesional ICVT shows promise as a therapeutic option for multiple cutaneous warts, particularly in achieving complete clearance. However, due to the limited certainty of available evidence and inconsistent safety data, further large-scale, high-quality randomized controlled trials are necessary to validate these findings and establish standardized treatment protocols.