Lipid-lowering therapy and cause-specific mortality in incident heart failure: A nationwide register study

Background Earlier clinical trials with statin therapy in chronic heart failure (HF) failed to show benefit, yet both CORONA and GISSI-HF trials investigated only hydrophilic statins with limited uptake into cardiac tissue. Lipophilic statins, by contrast, demonstrate superior myocardial penetration and may exert favorable effects on cardiac function and inflammation. These mechanistic insights provide a strong rationale for re-evaluating statin therapy in HF. Purpose To assess the association between lipid lowering therapy (LLT) use and cause-specific mortality both at 1-year and during overall follow-up in patients with incident HF, with additional stratified analyses by ejection fraction and ischemic heart disease (IHD) status. Methods Patients with incident heart failure identified from the Swedish Heart Failure Register (SwedeHF) between 2006 and 2021 [AP1] were linked to the National Patient Register, the Cause of Death Register, and the Prescribed Drug Register. Patients were classified according to LLT use. Causes of death (death due to IHD, HF, other cardiovascular causes, cancer and other causes) were analyzed within one-year and during total observation time with subgroup analyses performed according to ejection fraction and IHD status. Results Of 99,734 patients, 51,083 (51.2%) received LLT and 48,651 (48.8%) did not. In these two groups median age was 73.8 (SD 10.3) vs 74.7 years (SD 14.0), 68.2% vs 56.2% were men, prior IHD was present in 69.4% vs 26.8%, and HF duration >6 months in 47.3% vs 44.9% (all p<0.0001). Total mortality in the LLT group was 10.5% (n=5,356) at 1 year and 53.1% (n=27,137) overall. The non-LLT group had a total mortality of 15.0% (n=7,290) at 1 year, and 58.6% (n=28,515) overall. In the LLT vs non-LLT group, causes of death were among patients with ejection fraction (EF) >=50%, EF 40-<50% and EF <40% respectively; IHD (12.6% vs 9.6%, 13% vs 9.4%, 17.7% vs 10.3%), [AP2] HF (4.1% vs 6.3%, 3.6% vs 5.2%, 4.3% vs 5.5%), other cardiovascular causes (13.4% vs 19.7%, 9.3% vs 14.5%, 8.8% vs 13.1%), cancer (6.4% vs 6.8%, 6.1% vs 6.6%, 5.9% vs 6.8%) and other causes (21.9% vs 23%, 15.7% vs 17.9%, 13.8% vs 14.1%). After adjusting for age, sex, comorbidities, HF duration, EF and IHD at index, hazard ratios (HR) showed a significant reduction of all studied causes of death in the LLT group. These associations were present at 1 year and over the entire follow-up period period. Across the study period, the HR for all-cause mortality in the LLT group was 0.79 (0.77-0.80). HR for death in IHD, HF death and other cardiovascular death were 0.89 (0.86 - 0.93), [AP3] 0.74 (0.70 - 0.79) and 0.73 (0.70 - 0.76), respectively (all p<0.0001). Conclusion Lipid-lowering therapy was associated with lower short- and long-term mortality from all major causes in patients with heart failure.