Prognostication in heart failure across ejection fraction phenotypes and challenging subgroups : data from the Swedish heart failure registry

Background: The growing prevalence of heart failure (HF) worldwide determines an increasing burden on healthcare systems. HF phenotypes differ for several patient characteristics. Treatments with proven efficacy are mainly available for HF with reduced ejection fraction (HFrEF), whereas for HF with mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction evidence on treatment effect is more recent and limited to a single randomized control trial (RCT) and post-hoc/subgroup analyses of former RCTs. Although therapies affect survival in HFrEF, treatment implementation remains poor in particular in specific and more challenging subgroups.

Aims: The overall purpose is to provide a thorough characterization in terms of prognostication, to explore associations with outcomes and reasons for underuse of HF treatments while focusing on challenging settings underrepresented in RCTs and the different HF phenotypes (HFrEF, HFpEF and HFmrEF). Specific aims are to assess gender-related differences in clinical characteristics, therapeutic strategies and outcomes in order to characterize the specific features of women affected by HF across the HF phenotypes (study I); to evaluate the use and the predictors of use of betablockers in older HFrEF patients, and the association between betablocker therapy and outcomes (study II), to assess the state of implementation of evidence-based treatments for HFrEF in older patients (study III); and to explore the burden of HF on an healthcare system, with particular attention to the impact of the increasing burden of comorbidities on cardiovascular (CV) and non-CV mortality and morbidity (study IV) These specific aims are assessed in a large and unselected contemporary cohort of HF patients, such as the Swedish HF Registry (SwedeHF). Sex-based differences in heart failure across the ejection fraction spectrum: Phenotyping, and prognostic and therapeutic implications. In the SwedeHF Registry population, of 42,987 patients, 37% were females (55% with HFpEF, 39% with HFmrEF, 29% with HFrEF). Females were older, had more symptoms and more likely hypertension and kidney disease. There were differences in treatment use, with higher rates of beta-blocker and digoxin use in women vs men. Females less likely received HF devices. Adjusted risk of mortality/HF hospitalization was lower in females regardless of EF. The observed sex-related differences suggest to implement strategies for higher recruitment of women in RCTs.

Association between beta-blocker use and mortality/morbidity in older patients with heart failure with reduced ejection fraction: A propensity score-matched analysis from the Swedish Heart Failure Registry. We assessed the association between beta-blocker use, all-cause mortality and CV mortality/HF hospitalization in a 1:1 propensity score-matched cohort of patients with HFrEF and aged ≥80 years. Of 6562 patients aged ≥80 years, 5640 (86%) received beta-blocker. In the matched cohort (n=1732) beta-blocker use was associated lower risk of all-cause mortality. There was no signifantly lower risk of CV mortality/HF with vs. without beta-blocker in the matched cohort due to the lack of association between beta-blocker use and the outcome HF hospitalization. However, after adjustment rather than matching for the propensity score in the overall cohort, beta-blocker use was associated with reduced risk of all-cause mortality and CV mortality/HF hospitalization. Use of evidence-based therapy in heart failure with reduced ejection fraction across age strata. We studied 27430 patients with HFrEF: 31% were <70, 34% 70-79 and 35% ≥80 years old. Use of renin-angiotensin-system/angiotensin receptor neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists progressively decreased with increasing age. Older patients were less likely treated with target doses of or combinations of HF medications. Except that for cardiac resynchronization therapy, after extensive adjustments age was inversely associated with the probability of guideline-directed medical therapy (GDMT) use and target dose achievement. Persistent high burden of heart failure across the ejection fraction spectrum in a nationwide setting. A total of 76510 HF patients (53% HFrEF, had reduced EF 23% HFmrEF, 24% HFpEF) from the SwedeHF Registry were compared 1:3 with a sex, age, and county matched non-HF population. The incidence of cardiovascular and non-cardiovascular mortality/morbidity outcomes, as well as the in-hospital length of stay, was up to 5 times higher in HF vs non-HF patients. Across the EF spectrum, HFrEF was more exposed to HF hospitalization, whereas HFpEF to all-cause and non-cardiovascular hospitalization and mortality.

Conclusions: In the overall management of patients with HF, there are challenging subgroups that remain underexplored and frequently under-represented in RCT. Weaker evidence supporting the use of treatments and clinical inertia lead to lower adherence to current therapeutic recommendations. In our study women presented peculiarities in characteristics and treatments across the whole EF spectrum compared with men, with better survival/ morbidity after adjustment for other patient characteristics. Patients in the older age range represent another group with a great representation in the overall real-world HF population, but often poorly considered and represented in clinical trials and by the scientific community in terms of treatment use implementation. Concerns regarding lower or no efficacy of treatments in older groups are not supported by post-hoc analyses of RCTs, and we observed a convincing lower mortality/morbidity risk associated with beta-blockers treatment in HFrEF over 80 years old, without any safety concerns. Despite the available data support evidence-based treatments regardless of age, in our cohort study we demonstrated that, with the exception of cardiac resynchronization therapy, medical treatments and devices are largely under-used and under-dosed in older patients with HFrEF. Finally, the increasing complexity of the contemporary HF population, partially given by the growing age and the increasing number of comorbidities, heavily burdens on the whole healthcare system, with HF patients experiencing a dramatically higher rate of cardiovascular and non-cardiovascular mortality/ morbidity events. This claims for further efforts in the optimization of resources allocation and design of future RCTs.

List of scientific papers

I. Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum. Phenotyping, and Prognostic and Therapeutic Implications. Davide Stolfo, Alicia Uijl, Ola Vedin, Anna Strömberg, Ulrika Ljung Faxén, Giuseppe M.C. Rosano, Gianfranco Sinagra, Ulf Dahlström, Gianluigi Savarese. JACC-HEART FAILURE. 2019;7:505–15.
https://doi.org/10.1016/j.jchf.2019.03.011

II. Association between beta-blocker use and mortality/morbidity in older patients with heart failure with reduced ejection fraction - A propensity score-matched analysis from the Swedish Heart Failure Registry. Davide Stolfo, Alicia Uijl, Lina Benson, Benedikt Schrage, Marat Fudim, Folkert W. Asselbergs, Stefan Koudstaal, Gianfranco Sinagra, Ulf Dahlström, Giuseppe Rosano, Gianluigi Savarese. European Journal of Heart Failure. (2020) 22, 103–112.
https://doi.org/10.1002/ejhf.1615

III. Use of evidence-based therapy in heart failure with reduced ejection fraction across age strata. Davide Stolfo, Lars H Lund, Peter Moritz Becher, Nicola Orsini, Tonje Thorvaldsen, Lina Benson, Camilla Hage, Ulf Dahlström, Gianfranco Sinagra, Gianluigi Savarese. [Submitted]
https://doi.org/10.1002/ejhf.2483

IV. Persistent High Burden of Heart Failure across the Ejection Fraction Spectrum in a Nationwide Setting. Davide Stolfo, Lars H. Lund, Lina Benson, Camilla Hage, Gianfranco Sinagra, Ulf Dahlström, Gianluigi Savarese. [Submitted]