Aims

Guidelines recommend immediate initiation of all four class I guideline-directed medical therapies, renin–angiotensin system inhibitors (RASI) or angiotensin receptor–neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) following the diagnosis of heart failure (HF) with reduced ejection fraction (HFrEF). The extent to which this occurs in new-onset HFrEF is unclear. We assessed guideline-recommended therapies during the first year following a HFrEF diagnosis.

Methods and results

The Swedish HF Registry was linked to additional national registries. In patients with HFrEF (ejection fraction <40%), clinical characteristics and HF treatment from when they were available and recommended in guidelines were assessed according to time from HF diagnosis (<3, 3 to <6, 6–12 and >12 months). Of 55 581 patients with HFrEF enrolled between 2000 and 2021, 54%, 5.8%, 4.8% and 36% had an HF duration of <3, 3 to <6, 6–12 and >12 months, respectively. Patients with shorter HF duration were younger, had lower New York Heart Association class and had fewer cardiovascular comorbidities. Within 3 months, 3 to <6 months, 6–12 months and >12 months from HF diagnosis, 93%, 92%, 90% and 89% were on RASI or ARNI, 9.8%, 17%, 19% and 22% on ARNI alone, 35%, 43%, 44% and 46% on MRA, 92%, 92%, 92% and 91% on beta-blockers, and 26%, 30%, 19% and 28% on SGLT2i, respectively. Additionally, 18% received cardiac resynchronization therapy/implantable cardioverter-defibrillator >12 months after diagnosis.

Conclusions

Most patients received RASI and beta-blockers in the first months following HFrEF diagnosis. Use of ARNI, MRA and SGLT2i was limited, both in the early and later time periods. Our findings suggest that strategies to improve guideline-directed use of HFrEF therapies remain urgently needed.

Aims It is common in heart failure (HF) trials, especially in HF with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF), to select for increased risk of outcomes ('enrichment'). We investigated the association between loop diuretic use and common trial outcomes. Methods and results Patients in the Swedish HF Registry with HFmrEF and HFpEF were divided into three groups: no loop diuretic use, 1-40 mg furosemide equivalent, and &gt;40 mg. Outcomes were assessed for all patients and high risk for exacerbation patients (previous HF hospitalization [HFH] or N-terminal pro-B-type natriuretic peptide &gt;= 300 ng/L). Among 25 986 patients, 41.3% were not taking loop diuretics, 33.5% had 1-40 mg, and 25.2% had &gt;40 mg; 80.7% were at high risk. With increasing diuretic dose, the crude risk of all outcomes increased in both analysis groups. Event rates for cardiovascular death (CVD)/HFH were as follows for total: no loop diuretic: 6, dose 1-40 mg: 17, dose &gt;40 mg: 34 and as follows for high risk: no loop diuretic: 8, dose 1-40 mg: 19, dose &gt;40 mg: 36. Hazard ratios (HRs) for CVD/HFH with no loop diuretic as reference for the total population were: 1-40 mg HR 2.59, &gt;40 mg HR 4.91 (all p &lt; 0.001), and for high risk were: 1-40 mg HR 2.21, &gt;40 mg HR 4.05 (all p &lt; 0.001). Conclusion In HFpEF and HFmrEF, loop diuretics were used in 58.7% of patients. Use of and higher doses were strongly associated with HF trial-relevant outcomes. These associations were similar regardless of other risk markers. In HFpEF/HFmrEF trials, requiring loop diuretics as an enrichment factor will reduce the number of eligible patients but increase event rates considerably.

Background

We explored the association between use of renin–angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF).

Methods and Results

We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young–low comorbidity burden (12%), atrial fibrillation–hypertensive (32%), older–atrial fibrillation (24%), obese–diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin–angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young–low comorbidity burden and atrial fibrillation–hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese–diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar.

Conclusions

In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

Graphical abstract

AF = atrial fibrillation; CI = % confidence interval; CV = cardiovascular; DM = diabetes; HF = heart failure; HFpEF = Heart failure with preserved ejection fraction; HR = hazard ratio; HT = hypertension; RAS = renin–angiotensin system.

Aims Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). Methods and results We studied HFrEF patients from the Swedish HF registry (2000-2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin-angiotensin system (RAS) inhibitors, beta-blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92-0.93), which was less high risk under optimized RAS inhibitor and beta-blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p &lt; 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease &gt;10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease &gt;10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04-1.17) or decreasing (HR 1.29, 95% CI 1.18-1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86-1.02). Conclusions The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization.

Objectives This study is aimed to compare the effectiveness of modern therapy including angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) with conventional heart failure treatment in the real world. Background Since ARNI and SGLT2i were introduced to treat heart failure (HF), its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). However, a comparison between conventional and modern treatment strategies with drugs in combination has not been performed. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n = 20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n = 709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality (adjusted HR [aHR], 0.72 (0.54-0.96); p = 0.024) and a significant 62% reduction in CV mortality (aHR, 0.38 (0.21-0.68); p = 0.0013) compared to conventional HF treatment. Similar results emerged in a sensitivity analysis using propensity score matching. The interaction analyses did not reveal any trends for EF (&lt; 40% and &gt;= 40%), sex, age (&lt; 70 and &gt;= 70 years), eGFR (&lt; 60 and &gt;= 60 ml/min/1.73 m(2)), and etiology of HF subgroups. Conclusion In this nationwide study, modern HF therapy was associated with significantly reduced all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF. [GRAPHICS] .

Aims: In patients with heart failure (HF), we aimed to assess (i) the time trends in N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing; (ii) patient characteristics associated with NT-proBNP testing; (iii) distribution of NT-proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT-proBNP levels over time.Methods and results: NT-proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT-proBNP levels before (in the previous 6 +/- 3 months) and after (in the following 6 +/- 3 months) the index date were categorized as follows: (i) &lt;3000 ng/L at both measurements = stable low; (ii) &lt;3000 ng/L at the first measurement and &gt;= 3000 ng/L at the second measurement = increased; (iii) &gt;= 3000 ng/L at the first measurement and &lt;3000 ng/L at the second measurement = decreased; and (iv) &gt;= 3000 ng/L at both measurements = stable high. Univariable and multivariable logistic regression models, expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs), were performed to assess the associations between (i) clinical characteristics and NT-proBNP testing and (ii) changes in NT-proBNP from 6 months prior to the index date and the index date and a WHFE. Consistency analyses were performed in HF with reduced ejection fraction (HFrEF) alone. A total of 4424 HF patients were included (median age 74 years, women 34%, HFrEF 53%), 33% with a WHFE. NT-proBNP testing increased over time, up to 55% in 2018, and was almost two-fold as frequent, and time to testing was less than half, in patients with WHFE vs. NWHFE. Independent predictors of testing were WHFE, higher heart rate, diuretic use, and preserved ejection fraction. Median NT-proBNP was 3070 ng/L (Q1-Q3: 1220-7395), approximately three-fold higher in WHFE vs. NWHFE. Compared with stable low NT-proBNP levels, increased (OR 4.27, 95% CI 2.47-7.37) and stable high levels (OR 2.48, 95% CI 1.58-3.88) were independently associated with a higher risk of WHFE. Results were consistent in the HFrEF population.Conclusions: NT-proBNP testing increased over time but still was only performed in half of the patients. Testing was associated with a WHFE, with features of more severe HF and for differential diagnosis purposes. Increased and stable high levels were associated with a WHFE. Overall, our data highlight the potential benefits of carrying further implementation of NT-proBNP testing in clinical practice.

AimsThe aim of this analysis was to provide data on the overall comorbidity burden, both cardiovascular (CV) and non-CV, in a large real-world heart failure (HF) population across the ejection fraction (EF).Methods and resultsPatients with HF from the Swedish HF Registry between 2000 and 2021 were included. Of 91 463 patients (median age 76 years [interquartile range 67-82]), 98% had at least one among the 17 explored comorbidities (94% at least one CV and 85% at least one non-CV comorbidity). All comorbidities, except for coronary artery disease (CAD), were more frequent in HF with preserved EF (HFpEF). Patients with multiple comorbidities were older, more likely female, inpatients, with HFpEF, worse New York Heart Association class and higher N-terminal pro-B-type natriuretic peptide levels. In a multivariable Cox model, 12 comorbidities were independently associated with a higher risk of death from any cause. The highest risk was associated with dementia (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.45-1.65), chronic kidney disease (HR 1.37, 95% CI 1.34-1.41), chronic obstructive pulmonary disease (HR 1.32, 95% CI 1.28-1.35). Obesity was associated with a lower risk of all-cause death (HR 0.81, 95% CI 0.79-0.84). CAD and valvular heart disease were associated with a higher risk of all-cause and CV mortality, but not non-CV mortality, whereas cancer and musculo-skeletal disease increased the risk of non-CV mortality. A significant interaction with EF was observed for several comorbidities. Occurrence of CV and non-CV outcomes was related to the number of CV and non-CV comorbidities, respectively.ConclusionThe burden of both CV and non-CV comorbidities was high in HF regardless of EF, but overall higher in HFpEF. Multimorbidity was associated with a high risk of death with a different burden on CV or non-CV outcomes. Prevalence and outcome of cardiovascular and non-cardiovascular comorbidities and of multimorbidity among 91 463 patients from the Swedish Heart Failure Registry. CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; PAD, peripheral artery disease; TIA, transient ischaemic attack.image

Aims To assess the association between combination, dose and use of current guideline-recommended target doses (TD) of renin-angiotensin system inhibitors (RASi), angiotensin receptor-neprilysin inhibitors (ARNi) and beta-blockers, and outcomes in a large and unselected contemporary cohort of patients with heart failure (HF) and reduced ejection fraction. Methods and results Overall, 17 809 outpatients registered in the Swedish Heart Failure Registry (SwedeHF) from May 2000 to December 2018, with ejection fraction &lt;40% and duration of HF &gt;= 90 days were selected. Primary outcome was a composite of time to cardiovascular death and first HF hospitalization. Compared with no use of RASi or ARNi, the adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.83 (0.76-0.91) with &lt;50% of TD, 0.78 (0.71-0.86) with 50%-99%, and 0.73 (0.67-0.80) with &gt;= 100% of TD. Compared with no use of beta-blockers, the adjusted HR (95% CI) was 0.86 (0.76-0.91), 0.81 (0.74-0.89) and 0.74 (0.68-0.82) with &lt;50%, 50%-99% and &gt;= 100% of TD, respectively. Patients receiving both an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)/ARNi and a beta-blocker at 50%-99% of TD had a lower adjusted risk of the primary outcome compared with patients only receiving one drug, i.e. ACEi/ARB/ARNi or beta-blocker, even if this was at &gt;= 100% of TD. Conclusion Heart failure with reduced ejection fraction patients using higher doses of RASi or ARNi and beta-blockers had lower risk of cardiovascular death or HF hospitalization. Use of two drug classes at 50%-99% of TD dose was associated with lower risk than one drug class at 100% of TD.

Aims To evaluate the quality of heart failure (HF) care using the European Society of Cardiology (ESC) quality indicators (QIs) for HF and to assess whether better quality of care is associated with improved outcomes. Methods and results We performed a nationwide cohort study using the Swedish HF registry, consisting of patients with any type of HF at their first outpatient visit or hospitalization. Independent participant data for quality of HF care was evaluated against the ESC QIs for HF, and association with mortality estimated using multivariable Cox regression. In total, 43 704 patients from 80 hospitals across Sweden enrolled between 2013-2019 were included, with median follow-up 23.6 months. Of the 16 QIs for HF, 13 could be measured and 5 were inversely associated with all-cause mortality during follow-up. Higher attainment (&gt;= 50% vs. &lt;50% attainment) of the composite opportunity-based score (combination of QIs into a single score) for patients with reduced ejection fraction was associated with lower all-cause mortality (adjusted hazard ratio 0.81; 95% confidence interval 0.72-0.91). Attainment of the composite score was less in the outpatient than inpatient setting (adjusted odds ratio 0.85; 95% confidence interval 0.72-0.99). Quality of care varied across hospitals, with assessment of health-related quality of life being the indicator with the widest variation in attainment (interquartile range 61.7%). Conclusion Quality of HF care may be measured using the ESC HF QIs. In Sweden, attainment of HF care evaluated using the QIs demonstrated between and within hospital variation, and many QIs were inversely associated with mortality.

Aims Left ventricular ejection fraction (EF) is required to categorize heart failure (HF) [i.e. HF with preserved (HFpEF), mid-range (HFmrEF), and reduced (HFrEF) EF] but is often not captured in population-based cohorts or non-HF registries. The aim was to create an algorithm that identifies EF subphenotypes for research purposes. Methods and results We included 42 061 HF patients from the Swedish Heart Failure Registry. As primary analysis, we performed two logistic regression models including 22 variables to predict (i) EF &gt;= vs. &lt;50% and (ii) EF &gt;= vs. &lt;40%. In the secondary analysis, we performed a multivariable multinomial analysis with 22 variables to create a model for all three separate EF subphenotypes: HFrEF vs. HFmrEF vs. HFpEF. The models were validated in the database from the CHECK-HF study, a cross-sectional survey of 10 627 patients from the Netherlands. The C-statistic (discrimination) was 0.78 [95% confidence interval (CI) 0.77-0.78] for EF &gt;= 50% and 0.76 (95% CI 0.75-0.76) for EF &gt;= 40%. Similar results were achieved for HFrEF and HFpEF in the multinomial model, but the C-statistic for HFmrEF was lower: 0.63 (95% CI 0.63-0.64). The external validation showed similar discriminative ability to the development cohort. Conclusions Routine clinical characteristics could potentially be used to identify different EF subphenotypes in databases where EF is not readily available. Accuracy was good for the prediction of HFpEF and HFrEF but lower for HFmrEF. The proposed algorithm enables more effective research on HF in the big data setting.