The Emerging Role Of GDMT And Statins In Chemotherapy-Induced Cardiotoxicity: A Network Meta-Analysis

Introduction Cancer patients receiving chemotherapy have an increased risk of cardiovascular complications. This limits the widespread use of lifesaving therapies, often necessitating alternate lower efficacy regimens, or precluding chemotherapy entirely. Prior studies have suggested that using guideline-directed medical therapy (GDMT) for HF as well as statins, can attenuate chemotherapy-induced cardiotoxicity. However small sample sizes and conflicting outcomes have limited the clinical significance of these results. Hypothesis A comprehensive network meta-analysis using updated and high-quality data can provide more conclusive information to assess which drug has the most significant effect on preventing chemotherapy-induced cardiotoxicity. Methods We performed a literature search for RCTs investigating the effects of GDMT and statins in patients with chemotherapy-induced cardiotoxicity. We used established analytical tools and data extraction formats to analyze the outcome data. To obviate systematic bias for the selection and interpretation of randomized controlled trials, we employed the validated Cochrane risk-of-bias tools. Agents included in the final analysis were statins, aldosterone receptor antagonists (MRAs), ACEIs, ARBs, and beta-blockers. Outcomes examined were improvement in clinical and laboratory parameters of cardiac function: LVEF, clinical HF, troponin-I and B-natriuretic peptide levels. This network meta-analysis was performed using the netmeta package in RStudio. Results Across 33 RCTs including 3,285 patients, spironolactone showed the greatest LVEF improvement among drugs studied when compared with control (MD= 12.80, [7.90; 17.70]), followed by enalapril (MD= 7.62, [5.31; 9.94]), nebivolol (MD= 7.30, [2.39; 12.21]), and statins (MD= 6.72, [3.58; 9.85]). Spironolactone also showed a statistically significant troponin reduction when compared with control (MD= −0.01, [−0.02; −0.01]. Enalapril demonstrated the greatest BNP reduction when compared with control (MD= −49.00, [−68.89; −29.11]), followed by spironolactone (MD= −16.00, [−23.9; −8.10]). Patients on Enalapril also had the lowest risk of developing clinical HF when compared with control (RR= 0.05, [0.00; 0.75]). Conclusion Our analysis reaffirmed that statins, MRAs, ACEIs, and beta-blockers can significantly attenuate chemotherapy-induced cardiotoxicity, while ARBs showed no significant effect. Spironolactone showed the most impressive improvement in LVEF, which best supports its use among this population. In the future we recommend RCTs with longer follow up durations studying clinical outcomes, such as hospitalizations and mortality, when comparing the effects of cardioprotective agents in this population. Cancer patients receiving chemotherapy have an increased risk of cardiovascular complications. This limits the widespread use of lifesaving therapies, often necessitating alternate lower efficacy regimens, or precluding chemotherapy entirely. Prior studies have suggested that using guideline-directed medical therapy (GDMT) for HF as well as statins, can attenuate chemotherapy-induced cardiotoxicity. However small sample sizes and conflicting outcomes have limited the clinical significance of these results. A comprehensive network meta-analysis using updated and high-quality data can provide more conclusive information to assess which drug has the most significant effect on preventing chemotherapy-induced cardiotoxicity. We performed a literature search for RCTs investigating the effects of GDMT and statins in patients with chemotherapy-induced cardiotoxicity. We used established analytical tools and data extraction formats to analyze the outcome data. To obviate systematic bias for the selection and interpretation of randomized controlled trials, we employed the validated Cochrane risk-of-bias tools. Agents included in the final analysis were statins, aldosterone receptor antagonists (MRAs), ACEIs, ARBs, and beta-blockers. Outcomes examined were improvement in clinical and laboratory parameters of cardiac function: LVEF, clinical HF, troponin-I and B-natriuretic peptide levels. This network meta-analysis was performed using the netmeta package in RStudio. Across 33 RCTs including 3,285 patients, spironolactone showed the greatest LVEF improvement among drugs studied when compared with control (MD= 12.80, [7.90; 17.70]), followed by enalapril (MD= 7.62, [5.31; 9.94]), nebivolol (MD= 7.30, [2.39; 12.21]), and statins (MD= 6.72, [3.58; 9.85]). Spironolactone also showed a statistically significant troponin reduction when compared with control (MD= −0.01, [−0.02; −0.01]. Enalapril demonstrated the greatest BNP reduction when compared with control (MD= −49.00, [−68.89; −29.11]), followed by spironolactone (MD= −16.00, [−23.9; −8.10]). Patients on Enalapril also had the lowest risk of developing clinical HF when compared with control (RR= 0.05, [0.00; 0.75]). Our analysis reaffirmed that statins, MRAs, ACEIs, and beta-blockers can significantly attenuate chemotherapy-induced cardiotoxicity, while ARBs showed no significant effect. Spironolactone showed the most impressive improvement in LVEF, which best supports its use among this population. In the future we recommend RCTs with longer follow up durations studying clinical outcomes, such as hospitalizations and mortality, when comparing the effects of cardioprotective agents in this population.