Harm reduction associated with heated tobacco products: A systematic review and meta-analysis.

Objective: We conducted a systematic review and meta-analysis of randomised studies in humans comparing the outcomes of switching to heated tobacco products (HTPs) versus continuing conventional tobacco smoking by burning. Methods: We searched the electronic databases which included PubMed, Web of Science, Cochrane Controlled Trials Register, and Google Scholar from inception to May 2023. Randomised Controlled Trials (RCTs) in humans comparing HTPs with conventional burnt tobacco products were selected. Our search yielded 4817 search results, of which six RCTs (number of participants 1362, all from high-income countries) were selected. Five of the six included RCTs had low risk in four of five domains of bias; only one study had a high risk of bias in one domain. PRISMA guidelines were followed. Results: There were 40 biomarkers of harm reduction reported categorised into six categories. One cancer biomarker (nitrosamine) and two cardiovascular biomarkers (eosinophils and total bilirubin) showed statistically significant harm reduction (total NNAL SMD=0·82, 95% CI 0·67-0·98, eosinophils SMD=0·38, 95% CI 0·12-0·65, total bilirubin SMD=0·71, 95% CI 0·28-1·31). The remaining biomarkers of harm in cardiovascular, inflammatory, metabolic, pulmonary, and renal categories showed imprecise findings. Conclusions: In RCTs of moderate quality, some biomarkers show harm reduction associated with switching from burnt tobacco smoking to HTPs. The majority of the findings are imprecise due to the small sample sizes of the included studies. Sufficiently powered, robust RCTs targeting key harm reduction biomarkers within both upper and low-middle income country settings are required in the future.