Resolving the debate: A systematic review and network meta-analysis of hydroxyurea vs. newer FDA-approved pharmacological therapies in sickle cell disease

Abstract Introduction: Sickle cell disease (SCD) is a debilitating genetic disorder characterized by vaso-occlusive crises, organ damage, and reduced life expectancy. Hydroxyurea has long been the standard treatment, effectively reducing crisis frequency and improving clinical outcomes. However, recent FDA-approved therapies, including Crizanlizumab, Voxelotor, and L-glutamine, offer alternative mechanisms with promising efficacy and safety profiles. Despite these advances, comparative data regarding the relative clinical effectiveness and safety of these therapies compared to Hydroxyurea remains limited. This meta-analysis aims to synthesize data from randomized controlled trials (RCTs) to provide a comprehensive comparison of these therapies in the management of SCD. Methods: A systematic search across five databases was conducted to identify relevant RCTs. Study screening was performed using Covidence, and the network meta-analysis was conducted using the Netmeta package in R. Forest plots and meta-analyses were generated with Stata 18.0, while the risk of bias was assessed using the RoB 2.0 tool. Results: The analysis included 11 RCTs, with a total of 2,242 participants—1,242 in the treatment group and 1,000 in the control group. The therapies evaluated included Hydroxyurea (390), L-glutamine (182), Voxelotor (404), Crizanlizumab (266), and a placebo (1,000). The greatest reduction in vaso-occlusive crises (VOC) was observed with L-glutamine (OR 0.59, 95% CI [0.08; 4.60]), followed by Crizanlizumab (OR 0.75, 95% CI [0.71; 5.26]), Hydroxyurea (OR 1.60, 95% CI [0.39; 6.48]), and Voxelotor (OR 1.96, 95% CI [0.37; 10.44]). The lowest rate of reduction in hospitalization was seen with Hydroxyurea (OR 3.71, 95% CI [0.13; 105.16]), while the highest reduction was seen with L-glutamine (OR 0.82, 95% CI [0.03; 23.15]). Hemoglobin (Hb) levels were most improved with Hydroxyurea (by 1.1 g/dL), followed by Voxelotor (by 0.5 g/dL). Sucra ranking analysis indicated that L-glutamine had the highest ranking, suggesting superior efficacy, while Hydroxyurea ranked lowest in terms of efficacy. The risk ratios for adverse events were as follows: Hemotoxicity 0.16 (95% CI [-0.47; 0.18]), Hepatotoxicity 0.15 (95% CI [-0.62; 2.30]), and Gastrointestinal toxicity 0.16 (95% CI [0.03; 0.34]). Quality of life was significantly improved with L-glutamine and Crizanlizumab treatments. Additionally, the risk of bias was found to be low across all studies included in the analysis. Conclusion: This meta-analysis suggests that newer therapies, particularly L-glutamine and Crizanlizumab, offer superior clinical outcomes in terms of reducing vaso-occlusive crises and improving quality of life, with a favorable safety profile. Hydroxyurea remains effective but is ranked lower in efficacy compared to these newer agents. Further studies are needed to refine comparative efficacy and long-term safety data.