Risk of Statin Toxicity Following Initiation of Sacubitril/Valsartan Among Older Adults With Heart Failure: Protocol for a Population-Based Cohort Study

Clinical Context and Rapid Adoption Sacubitril/valsartan is a cornerstone therapy for heart failure with reduced ejection fraction (HFrEF). Landmark clinical trials, such as PARADIGM-HF, demonstrated significant reductions in cardiovascular mortality and heart failure hospitalizations compared with enalapril.1 As a result, sacubitril/valsartan has been rapidly adopted worldwide and is now widely prescribed among older adults, a population characterized by high rates of multimorbidity and polypharmacy. Pharmacokinetic Signal Despite its therapeutic benefits, sacubitril/valsartan presents a potential for drug–drug interactions (DDIs). Clinical pharmacokinetic (PK) data indicate that sacubitril, via its active metabolite LBQ657, is a potent inhibitor of hepatic organic anion-transporting polypeptides (OATP1B1 and OATP1B3).2,3 These transporters are critical for the hepatic uptake and clearance of several statins, particularly atorvastatin. PK studies in healthy volunteers have shown that co-administration with sacubitril/valsartan increases atorvastatin's peak concentration (Cmax) by up to 34% and overall systemic exposure (AUC) by up to 74%.2,3 Clinical Implications of Statin Toxicity Elevated systemic statin concentrations are associated with a dose-dependent increase in serious adverse events, including hepatotoxicity, acute kidney injury (AKI), and rhabdomyolysis. Older adults with heart failure are especially vulnerable due to age-related declines in renal and hepatic function. Given that approximately one in ten Canadian adults takes a statin, the widespread concurrent use of sacubitril/valsartan and statins means that even modest increases in toxicity risk could have meaningful public health consequences. Knowledge Gap and Study Justification To date, the clinical significance of the sacubitril–statin interaction has not been rigorously evaluated in real-world populations. Current evidence is limited to small PK studies and isolated case reports, leaving a critical knowledge gap for clinicians and regulatory authorities regarding the need for dose adjustments. This study leverages population-based administrative healthcare and laboratory data from Ontario, Canada, to generate high-quality evidence on whether initiating sacubitril/valsartan among chronic statin users increases the short-term risk of severe statin toxicity in routine clinical care.