One-year Prognosis Of Heart Failure Associated With Medical Therapy And Median Ejection Fraction

Background Heart failure is a global public health issue and is also one of the tremendous challenges for medical health care system in China.With aging process and increasing prevalence of cardiovascular diseases,health care and financial burden of heart failure is still on the increase.One strategy to address the impending disease burden is to improve the quality of care,optimize the clinical management and improve the prognosis of heart failure patients.Pharmacologic treatment is the cornerstone of heart failure management and effectively improves the quality of life and prognosis of heart failure patients.Left ventricular ejection fraction(LVEF)is of great value for its prognostic value and utility to inform decision-making on treatment in clinical care.Compared with two intensively investigated phenotypes,heart failure with reduced ejection fraction(HFrEF,LVEF<40%)and heart failure with preserved ejection fraction(HFpEF,LVEF≥50%),heart failure with mid-range ejection fraction(HFmrEF,LVEF 40%-49%)is a novel phenotype which was recently introduced.Although HFmrEF was a phenotype with relatively high proportion,substantial comorbidities and ill prognosis,it was largely excluded or partially included in the clinical trials,and treatment evidence for HFmrEF is limited.Currently guidelines do not provide any separate recommendation for the treatment of HFmrEF.More evidence on pharmacologic treatment for HFmrEF is required to guide clinical practice and improve the prognosis.Objective To assess the association between four classes of pharmacologic therapies,including angiotensin receptor blocker(ARB),angiotensin converting enzyme inhibitor(ACEI),β-blocker and mineralocorticoid receptor blocker(MRA)and risk of one-year all-cause death and cardiovascular death among HFmrEF patients.Methods In a national sample of heart failure patients from a multi-center prospective heart failure cohort,we included HFmrEF patients from 52 Chinese hospitals during the year of 2016-2018.After excluding patients who died or withdrew from treatment at terminal status during hospitalization,as well as those with contraindications at discharge,patients were classified into treated or untreated group according to the documentation of ARB,ACEI,β-blocker or MRA therapy in discharge summaries or prescription records.We analysed the associations between ARB,ACEI,β-blocker and MRA therapy at discharge and risk of one-year all-cause death and cardiovascular death via inverse probability treatment weighting(IPTW)-weighted COX regression model.Patients were categorized into different dose groups according to the percentage of dose at discharge against the guideline recommended daily target dose.We performed dose-effect analyses by applying multivariable COX regression model and analysed the prognosis of different dose groups compared with the untreated group.To validate the robustness of the results,we added two sensitivity analyses by adjusting the concomitant medications in the IPTW-weighted COX regression analysis and multivariable COX regression analysis.Results1.Among 1,053 HFmrEF patients,the average age was 66 years(standard deviation:15 years)and female accounted for 36.8%.The proportions of comorbidity of ischemic heart disease,previous myocardial infarction and coronary revascularization among HFmrEF patients were 64.5%,26.0%and 20.9%.23.6%,33.0%,63.2%and 67.9%of the HFmrEF patients were prescribed with ARB,ACEI,β-blocker and MRA at discharge,with 19.8%of them prescribed with none of the four classes.No patients were lost during the one-year follow-up period.175(16.6%)patients died,with 148(84.6%)of them died of cardiovascular causes.2.After excluding patients who died or withdrew from treatment at terminal status during hospitalization,or those with contraindications at discharge,or those on ACEI therapy at discharge,IPTW-weighted COX regression analyses showed that ARB therapy was significantly associated with lower risk of all-cause death(hazard ratio[HR],0.53,95%confidence interval[CI],0.33-0.85,P=0.01)and cardiovascular death(HR,0.54,95%CI,0.32-0.89,P=0.02).Dose-effect analyses showed that increasing dose of ARB therapy was proportionally associated with lower risk of all-cause death and cardiovascular death.Sensitivity analyses showed similar results.3.After excluding patients who died or withdrew from treatment at terminal status duringhospitalization,or those with contraindications at discharge,IPTW-weighted COX regression analyses showed that β-blocker therapy was significantly associated with lower risk of all-cause death(HR,0.71,95%CI,0.51-0.97,P=0.03)and was associated with marginally significant lower risk of cardio vascular death(HR,0.74,95%CI,0.53-1.05,P=0.09).Dose-effect analyses showed a proportionally decreasing risk of all-cause death and cardiovascular death as dose of β-blocker therapy increased.Sensitivity analyses showed similar results.4.After excluding patients who died or withdrew from treatment at terminal status during hospitalization,or those with contraindications at discharge,or those on ARB therapy at discharge,IPTW-weighted COX regression analyses did not detect association between ACEI therapy and risk of all-cause death(HR,1.10,95%CI,0.77-1.56,P=0.61)or cardiovascular death(HR,1.12,95%CI,0.77-1.64,P=0.55),and nor did sensitivity analyses,but dose-effect analyses suggested a trend of lower risk of all-cause death and cardiovascular death with the increasing dose of ACEI therapy.5.After excluding patients who died or withdrew from treatment at terminal status during hospitalization,or those with contraindications at discharge,IPTW-weighted COX regression analyses did not detect association between MRA and risk of all-cause death(HR,1.10,95%CI,0.77-1.60,P=0.56)or cardiovascular death(HR,0.95,95%CI,0.65-1.40,P=0.80),and nor did sensitivity analyses.5%of the patients on MRA therapy were prescribed with doses exceeding guideline-recommended target dose,and was associated with increasing risk of all-cause death(HR,2.24,95%CI,1.20-4.19,P=0.01).Conclusion Among HFmrEF patients discharged alive without contraindications in this study,ARB and β-blocker therapy was associated with lower risk of all-cause death and cardiovascular death,and risk reduction is proportional to dose increase.Our study did not detect the effectiveness of ACEI and MRA therapy among HFmrEF patients,but overdose of MRA therapy is likely to increase the risk of all-cause death.Our study provided important treatment evidence for clinical management of HFmrEF,and may serve as basis for future guideline recommendations.