Effectiveness of integrated person-centered interventions for older people's care: Review of Swedish experiences and experts' perspective.

Older adults have multiple medical and social care needs, requiring a shift toward an integrated person-centered model of care. Our objective was to describe and summarize Swedish experiences of integrated person-centered care by reviewing studies published between 2000 and 2023, and to identify the main challenges and scientific gaps through expert discussions. Seventy-three publications were identified by searching MEDLINE and contacting experts. Interventions were categorized using two World Health Organization frameworks: (1) Integrated Care for Older People (ICOPE), and (2) Integrated People-Centered Health Services (IPCHS). The included 73 publications were derived from 31 unique and heterogeneous interventions pertaining mainly to the micro- and meso-levels. Among publications measuring mortality, 15% were effective. Subjective health outcomes showed improvement in 24% of publications, morbidity outcomes in 42%, disability outcomes in 48%, and service utilization outcomes in 58%. Workshop discussions in Stockholm (Sweden), March 2023, were recorded, transcribed, and summarized. Experts emphasized: (1) lack of rigorous evaluation methods, (2) need for participatory designs, (3) scarcity of macro-level interventions, and (4) importance of transitioning from person- to people-centered integrated care. These challenges could explain the unexpected weak beneficial effects of the interventions on health outcomes, whereas service utilization outcomes were more positively impacted. Finally, we derived a list of recommendations, including the need to engage care organizations in interventions from their inception and to leverage researchers' scientific expertise. Although this review provides a comprehensive snapshot of interventions in the context of Sweden, the findings offer transferable perspectives on the real-world challenges encountered in this field.

Achieved dose and treatment discontinuation of candesartan in men and women with chronic heart failure: data from CHARM.

AIMS: Angiotensin receptor blockers have been shown to reduce heart failure hospitalization and cardiovascular mortality in men and women with heart failure with reduced ejection fraction (HFrEF). It is unknown whether there are differences between men and women in achieved dose and treatment discontinuation due to adverse events of candesartan. METHODS AND RESULTS: We conducted a post hoc analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. A total of 3172 men and 1106 women with HFrEF [left ventricular ejection fraction (LVEF) ≤ 40%] in New York Heart Association class II-IV were randomized to candesartan or placebo. Every 2 weeks, patients were up-titrated from 4 or 8, to16, to 32 mg once daily, unless a higher dose was contraindicated or not tolerated. Women were older (66 vs. 64 years), had a higher LVEF (29.9% vs. 28.6%), and had more hypertension (54% vs. 47%) than men. The mean achieved dose of candesartan was 21.5 ± 12.6 mg in men and 20.7 ± 12.9 mg in women (P = 0.19). In both the candesartan and placebo groups, cardiovascular death and heart failure hospitalizations were higher in men and women who achieved lower dose levels. Event rates for achieved dose levels of 0, 4 or 8, 16, and 32 mg candesartan were 20.8, 17.2, 14.0, and 10.1 per 100 person-years in men, respectively, and 23.6, 13.7, 14.0, and 9.1 per 100 person-years in women, respectively. In each of the achieved dose levels, there was no sex difference in the proportion of patients with an event, neither in the candesartan group nor in the placebo group (P-value for all > 0.05). There was no significant interaction between sex and treatment-related discontinuation for hypotension (P = 0.520), an increase in creatinine (P = 0.102), and hyperkalaemia (P = 0.905). CONCLUSIONS: In a randomized clinical trial in patients with HFrEF, men and women achieved similar doses of candesartan. Primary event rates and treatment-related discontinuation due to adverse events were also similar between men and women.

Self-efficacy and healthcare costs in patients with chronic heart failure or chronic obstructive pulmonary disease.

AIMS: This study aims to explore possible associations between self-efficacy and healthcare and drug expenditures (i.e. direct costs) in patients with chronic heart failure (CHF) or chronic obstructive pulmonary disease (COPD) in a study investigating the effects of person-centred care delivered by telephone. METHODS AND RESULTS: This exploratory analysis uses data from an open randomized controlled trial conducted between January 2015 and November 2016, providing remote person-centred care by phone to patients with CHF, COPD, or both. Patients hospitalized due to worsening of CHF or COPD were eligible for the study. Randomization was based on a computer-generated list, stratified for age ≥ 75 and diagnosis. At a 6 month follow-up, 118 persons remained in a control group and 103 in an intervention group. The intervention group received person-centred care by phone as an addition to usual care. Trial data were linked to register data on healthcare and drug use. Group-based trajectory modelling was applied to identify trajectories for general self-efficacy and direct costs. Next, associations between self-efficacy trajectories and costs were assessed using regression analysis. Five trajectories were identified for general self-efficacy, of which three indicated different levels of increasing or stable self-efficacy, while two showed a decrease over time in self-efficacy. Three trajectories were identified for costs, indicating a gradient from lower to higher accumulated costs. Increasing or stable self-efficacy was associated with lower direct costs (P = 0.0013). CONCLUSIONS: The findings show that an increased or sustained self-efficacy is associated with lower direct costs in patients with CHF or COPD. Person-centred phone contacts used as an add-on to usual care could result in lower direct costs for those with stable or increasing self-efficacy.

Independent prognostic importance of blood urea nitrogen to creatinine ratio in heart failure.

AIM: Blood urea nitrogen (BUN) to creatinine ratio is associated with worse outcomes in acute heart failure (HF) but little is known about its importance in chronic HF. METHODS AND RESULTS: We combined individual patient data from clinical trials (HF with reduced ejection fraction [HFrEF]: PARADIGM-HF, ATMOSPHERE and DAPA-HF, and HF with preserved ejection fraction [HFpEF]: PARAGON-HF and I-PRESERVE). The primary outcome examined was a composite time to first HF hospitalization or cardiovascular death; its components and all-cause death were also examined. Each HF phenotype was categorized according to median BUN/creatinine ratio, generating four groups that is, HFpEF ≤ and >median BUN/creatinine ratio and HFrEF ≤ and >median BUN/creatinine ratio. The association between BUN/creatinine ratio and outcomes was evaluated using the Kaplan-Meier estimator and Cox proportional hazard models. Overall, 28 820 patients were analysed. The median (IQR) BUN/creatinine ratio was 20.1 (Q1-Q3 16.7-24.7) in HFpEF and 18.7 (15.2-22.8) in HFrEF. In both HFpEF and HFrEF, higher BUN/creatinine ratio was associated with older age, female sex, and diabetes, but similar estimated glomerular filtration rate (eGFR). The risk of each outcome examined was significantly higher in patients with BUN/creatinine ratio ≥median, compared to

Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. METHODS: In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models. RESULTS: The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; Pinteraction = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration. CONCLUSIONS: Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180).

Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial).

AIMS: Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. METHODS AND RESULTS: The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74-1.08 vs. HR 0.80, 95% CI 0.72-0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72-1.01 vs. HR 0.80, 95% CI 0.71-0.90, P interaction = 0.53), and NYHA III-IV and II (HR 0.83, 95% CI 0.74-0.94 vs. HR 0.81, 95% CI 0.69-0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68-0.85 vs. HR 0.97, 95% CI 0.81-0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. CONCLUSIONS: Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern.

Prevalent and Incident Anemia in PARADIGM-HF and the Effect of Sacubitril/Valsartan.

BACKGROUND: Anemia is common in patients with heart failure with reduced ejection fraction and is associated with poor clinical outcomes. Renin-angiotensin system blockers lower hemoglobin and may induce anemia. OBJECTIVES: The authors investigated whether concomitant neprilysin inhibition might ameliorate this effect of renin-angiotensin system blockers in PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure). METHODS: Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men at screening. The authors investigated the effect of randomized treatment on clinical outcomes according to anemia status, change in hemoglobin from baseline, and the incidence of anemia. RESULTS: Of 8,239 participants with a baseline hemoglobin measurement, 1,677 (20.4%) were anemic. Patients with anemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement, and worse clinical outcomes. Sacubitril/valsartan, compared with enalapril, decreased the risk of cardiovascular death or heart failure hospitalization similarly in patients with (HR: 0.84; 95% CI: 0.71-1.00) and without anemia (HR: 0.78 [95% CI: 0.71-0.87]; P value for interaction = 0.478). Between baseline and 12 months, hemoglobin decreased by 1.5 g/L (95% CI: 1.2-1.7 g/L) with sacubitril/valsartan compared with 2.3 g/L (95% CI: 2.0-2.6 g/L) with enalapril: mean difference 0.8 g/L (95% CI: 0.5-1.2 g/L; P < 0.001). Patients assigned to sacubitril/valsartan were less likely to develop anemia at 12 months (321 of 2,806 [11.4%]) compared with patients randomized to enalapril (440 of 2,824 [15.6%]) (OR: 0.70 [95% CI: 0.60-0.81]; P < 0.001). These findings were similar in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) (sacubitril/valsartan vs valsartan). There was biomarker evidence of increased iron utilization with sacubitril/valsartan. CONCLUSIONS: Irrespective of anemia status, sacubitril/valsartan compared with enalapril, decreased mortality and hospitalization. Hemoglobin decreased less with sacubitril/valsartan and the incidence of new anemia was lower with sacubitril/valsartan. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure [PARADIGM-HF] trial; NCT01035255).

Stroke in patients with heart failure and reduced or preserved ejection fraction.

AIMS: Stroke is an important problem in patients with heart failure (HF), but the intersection between the two conditions is poorly studied across the range of ejection fraction. The prevalence of history of stroke and related outcomes were investigated in patients with HF. METHODS AND RESULTS: Individual patient meta-analysis of seven clinical trials enrolling patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Of the 20 159 patients with HFrEF, 1683 (8.3%) had a history of stroke, and of the 13 252 patients with HFpEF, 1287 (9.7%) had a history of stroke. Regardless of ejection fraction, patients with a history of stroke had more vascular comorbidity and worse HF. Among those with HFrEF, the incidence of the composite of cardiovascular death, HF hospitalization, stroke, or myocardial infarction was 18.23 (16.81-19.77) per 100 person-years in those with prior stroke vs. 13.12 (12.77-13.48) in those without [hazard ratio 1.37 (1.26-1.49), P < 0.001]. The corresponding rates in patients with HFpEF were 14.16 (12.96-15.48) and 9.37 (9.06-9.70) [hazard ratio 1.49 (1.36-1.64), P < 0.001]. Each component of the composite was more frequent in patients with stroke history, and the risk of future stroke was doubled in patients with prior stroke. Among patients with prior stroke, 30% with concomitant atrial fibrillation were not anticoagulated, and 29% with arterial disease were not taking statins; 17% with HFrEF and 38% with HFpEF had uncontrolled systolic blood pressure (≥140 mmHg). CONCLUSION: Heart failure patients with a history of stroke are at high risk of subsequent cardiovascular events, and targeting underutilization of guideline-recommended treatments might be a way to improve outcomes in this high-risk population.

Time to clinical benefit of eplerenone among patients with heart failure and reduced ejection fraction: A subgroups analysis from the EMPHASIS-HF trial.

AIM: Eplerenone reduces the risk of cardiovascular death or first hospitalization for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF), but it is still frequently underused in routine practice. We evaluated the time course of benefits of eplerenone after its initiation in HFrEF patients from the EMPHASIS-HF trial. METHODS AND RESULTS: The EMPHASIS-HF trial was a double-blind randomized clinical trial assessing the effect of eplerenone in patients (n = 2737, mean age 68.6 ± 7.6 years, 22.3% women) with HFrEF and mild symptoms. The time trajectories for the effect of eplerenone versus placebo on the primary composite endpoint (cardiovascular death or first hospitalization for HF) were investigated using Cox proportional hazards models with truncated data at each day post-randomization. A significant reduction in the primary composite endpoint was observed 26 days after randomization (hazard ratio 0.58; 95% confidence interval, 0.34-1.00, p = 0.049). Eplerenone was first associated with a significant reduction in the primary endpoint in 35 days or less in most subgroups, including patients with HF history ≥18 months (day 24), estimated glomerular filtration rate <60 ml/min (day 12), ischaemic HF aetiology (day 28), age ≥65 years (day 28), narrow QRS (day 30), higher MAGGIC score (day 35), lower potassium (day 30), left ventricular ejection fraction ≥30% (day 28) or already treated with beta-blockers (day 25). CONCLUSIONS: Eplerenone provides statistically significant and clinically meaningful benefits shortly after treatment initiation in most patients, irrespective of clinical profile. This result reinforces the need for an early initiation of eplerenone in HFrEF, as part of rapidly instituting guideline-directed medical therapy.

Incremental prognostic value of biomarkers in PARADIGM-HF.

AIMS: It is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure. METHODS AND RESULTS: Aldosterone, cystatin C, high-sensitivity troponin T (hs-TnT), galectin-3, growth differentiation factor-15 (GDF-15), kidney injury molecule-1, matrix metalloproteinase-2 and -9, soluble suppression of tumourigenicity-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and urinary albumin to creatinine ratio were measured in 1559 of PARADIGM-HF participants. We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT-HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all-cause mortality. The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were in New York Heart Association class II. During a mean follow-up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only four biomarkers were independently associated with all outcomes: hs-TnT, GDF-15, cystatin C and TIMP-1. When all biomarkers were added simultaneously to the PREDICT-HF models, only hs-TnT remained an independent predictor of all three endpoints. GDF-15 also remained predictive of the primary endpoint; TIMP-1 was the only other predictor of both cardiovascular and all-cause mortality. Individually or in combination, these biomarkers did not lead to significant improvements in discrimination or reclassification. CONCLUSIONS: None of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables.

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

AIMS: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. METHODS AND RESULTS: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. CONCLUSION: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Impact of multimorbidity on mortality in heart failure with reduced ejection fraction: which comorbidities matter most? An analysis of PARADIGM-HF and ATMOSPHERE.

AIMS: Multimorbidity, the coexistence of two or more chronic conditions, is synonymous with heart failure (HF). How risk related to comorbidities compares at individual and population levels is unknown. The aim of this study is to examine the risk related to comorbidities, alone and in combination, both at individual and population levels. METHODS AND RESULTS: Using two clinical trials in HF - the Prospective comparison of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) with ACEI (Angiotensin-Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and morbidity in HF trial (PARADIGM-HF) and the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure trials (ATMOSPHERE) - we identified the 10 most common comorbidities and examined 45 possible pairs. We calculated population attributable fractions (PAF) for all-cause death and relative excess risk due to interaction with Cox proportional hazard models. Of 15 066 patients in the study, 14 133 (93.7%) had at least one and 11 867 (78.8%) had at least two of the 10 most prevalent comorbidities. The greatest individual risk among pairs was associated with peripheral artery disease (PAD) in combination with stroke (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.28-2.33) and anaemia (HR 1.71; 95% CI 1.39-2.11). The combination of chronic kidney disease (CKD) and hypertension had the highest PAF (5.65%; 95% CI 3.66-7.61). Two pairs demonstrated significant synergistic interaction (atrial fibrillation with CKD and coronary artery disease, respectively) and one an antagonistic interaction (anaemia and obesity). CONCLUSIONS: In HF, the impact of multimorbidity differed at the individual patient and population level, depending on the prevalence of and the risk related to each comorbidity, and the interaction between individual comorbidities. Patients with coexistent PAD and stroke were at greatest individual risk whereas, from a population perspective, coexistent CKD and hypertension mattered most.

Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial.

AIMS: The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation. METHODS AND RESULTS: CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (>-10 and <10 mL/min/1.73 m2), and Group 3 (>10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was -0.7 (-6.4-4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C. CONCLUSION: The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.

Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox.

AIMS: Although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio, better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful. METHODS AND RESULTS: The prognostic value of several newer anthropometric indices was compared with that of BMI in patients with heart failure (HF) and reduced ejection fraction (HFrEF) enrolled in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. The primary outcome was HF hospitalization or cardiovascular death. The association between anthropometric indices and outcomes were comprehensively adjusted for other prognostic variables, including natriuretic peptides. An 'obesity-survival paradox' related to lower mortality risk in those with BMI ≥25 kg/m2 (compared with normal weight) was identified but this was eliminated by adjustment for other prognostic variables. This paradox was less evident for waist-to-height ratio (as an exemplar of indices not incorporating weight) and eliminated by adjustment: the adjusted hazard ratio (aHR) for all-cause mortality, for quintile 5 vs. quintile 1, was 1.10 [95% confidence interval (CI) 0.87-1.39]. However, both BMI and waist-to-height ratio showed that greater adiposity was associated with a higher risk of the primary outcome and HF hospitalization; this was more evident for waist-to-height ratio and persisted after adjustment e.g. the aHR for HF hospitalization for quintile 5 vs. quintile 1 of waist-to-height ratio was 1.39 (95% CI 1.06-1.81). CONCLUSION: In patients with HFrEF, alternative anthropometric measurements showed no evidence for an 'obesity-survival paradox'. Newer indices that do not incorporate weight showed that greater adiposity was clearly associated with a higher risk of HF hospitalization.

Integrating health promotion with and for older people - eHealth (IHOPe) - evaluating remote integrated person-centred care : Protocol of a randomised controlled trial with effectiveness, health economic, and process evaluation.

BACKGROUND: Healthcare and welfare systems worldwide are unprepared to accommodate the growing population of older people. Simultaneously, the cost of reactive care for older people is increasing. However, healthcare systems in many countries are reforming towards integrated and person-centred care with a focus on health promotion and proactive actions. The Integrating Health Promotion with and for Older People - eHealth (IHOPe) project aims to describe and evaluate a person-centred e-support intervention that promotes a sustainable partnership between community-dwelling frail older people and health and social care professionals. METHODS: The IHOPe project is designed as a randomised controlled trial comparing a control group receiving standard care with an intervention group receiving standard care and add-on person-centred care through telephone support and a digital platform. The primary outcome measure is a composite score of changes in general self-efficacy and the need for unscheduled hospital care. The project is conducted in Gothenburg, Sweden. At least 220 participants aged ≥ 75 years will be included after being screened using a frailty instrument. The study design, intervention components, digital platform, and questionnaires were developed in close collaboration with an advisory group of inter-professional researchers, stakeholders, clinicians, and older representatives. Data will mainly be collected through questionnaires at baseline and 3, 6, and 12 months after inclusion in the study. Recruitment is ongoing and should be completed during 2023. Data will be analysed using quantitative and qualitative methods. The evaluation will include effectiveness, process, and health economics. The study was approved by the Regional Ethical Review Board in Gothenburg, Sweden (Dnr 2019-05364, Dnr 2020-03550, Dnr 2021-03255). DISCUSSION: The findings will expand our knowledge of remotely integrated person-centred care for frail older people. Thereby, the IHOPe project is expected to fill highlighted knowledge gaps on intervention evaluations including the triad of person-centred, digital, and integrated care elements, as well as economic evaluations of remote health services for frail older people. The study is ongoing, and the results are not completed but if they turn out to be positive, implementation is not limited to time or location. TRIAL REGISTRATION: ClinicalTrial.gov: NCT04416815. Registered 07/06/2021.

Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.

Importance: Heart failure (HF) treatment recommendations are centered on New York Heart Association (NYHA) classification, such that most apparently asymptomatic patients are not eligible for disease-modifying therapies. Objectives: To assess within-patient variation in NYHA classification over time, the association between NYHA class and an objective measure of HF severity (N-terminal pro-B-type natriuretic peptide [NT-proBNP] level), and their association with long-term prognosis in the PARADIGM-HF trial. Design, Setting, and Participants: All patients in PARADIGM-HF were in NYHA class II or higher at baseline and were treated with sacubitril-valsartan during a 6- to 10-week run-in period before randomization. Patients classified as NYHA class I, II, and III in PARADIGM-HF were compared at randomization. Exposures: NYHA class at randomization after 6 to 10 weeks of the run-in period. Main Outcomes and Measures: Primary outcome was cardiovascular death or first HF hospitalization. Logistic regression models, areas under the receiver operating characteristic curve (AUC), kernel density estimation overlaps, and Cox proportional hazards models were used. Results: The analysis included 8326 patients with known NYHA classification at randomization. Of 389 patients in NYHA class I, 228 (58%) changed functional class during the first year after randomization. Level of NT-proBNP was a poor discriminator of NYHA classification: for NYHA class I vs II, the AUC was 0.51 (95% CI, 0.48-0.54). For NT-proBNP level, estimated kernel density overlap was 93% between NYHA class I vs II, 79% between NYHA I vs III, and 83% between NYHA II vs III. Patients classified as NYHA III displayed a distinctively higher rate of cardiovascular events (NYHA III vs I, hazard ratio [HR], 1.84; 95% CI, 1.44-2.37; NYHA III vs II, HR, 1.49; 95% CI, 1.35-1.64). Patients in NYHA class I and II revealed lower event rates (NYHA II vs I, HR, 1.24; 95% CI, 0.97-1.58). Stratification by NT-proBNP level (<1600 pg/mL or ≥1600 pg/mL) identified subgroups with distinctive risk, such that NYHA class I patients with high NT-proBNP levels (n = 175) had a numerically higher event rate than patients with low NT-proBNP levels from any NYHA class (vs I, HR, 3.43; 95% CI, 2.03-5.87; vs II, HR, 2.12; 95% CI, 1.58-2.86; vs III, HR, 1.37; 95% CI, 1.00-1.88). Conclusions and Relevance: In this study, patients in NYHA class I and II overlapped substantially in objective measures and long-term prognosis. Physician-defined "asymptomatic" functional class concealed patients who were at substantial risk for adverse outcomes. NYHA classification might be limited to differentiate mild forms of HF. Trial Registration: ClinicalTrials.gov Identifier: NCT01035255.

Predicting stroke in heart failure and reduced ejection fraction without atrial fibrillation.

AIMS: Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. METHODS AND RESULTS: In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60-3.45]; fifth quintile HR 3.73 (95% CI 2.58-5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75-0.91). CONCLUSION: It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively.

Clinical Outcomes Related to Background Diuretic Use and New Diuretic Initiation in Patients With HFrEF.

BACKGROUND: Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them. OBJECTIVES: The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started. METHODS: Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined. RESULTS: At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P < 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P < 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002). CONCLUSIONS: Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.

Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials.

BACKGROUND: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. METHODS: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. RESULTS: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: - 0.24%, 95% CI - 0.33 to - 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62-1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05-2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63-0.89, P = 0.001), compared with enalapril or valsartan. CONCLUSIONS: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711.

Effects of a Person-Centered eHealth Intervention for Patients on Sick Leave Due to Common Mental Disorders (PROMISE Study): Open Randomized Controlled Trial.

BACKGROUND: Sick leave due to common mental disorders (CMDs) is a public health problem in several countries, including Sweden. Given that symptom relief does not necessarily correspond to return to work, health care interventions focusing on factors that have proven important to influence the return to work process, such as self-efficacy, are warranted. Self-efficacy is also a central concept in person-centered care. OBJECTIVE: The aim of this study is to evaluate the effects of a person-centered eHealth intervention for patients on sick leave due to CMDs. METHODS: A randomized controlled trial of 209 patients allocated to either a control group (107/209, 51.2%) or an intervention group (102/209, 48.8%) was conducted. The control group received usual care, whereas the intervention group received usual care with the addition of a person-centered eHealth intervention. The intervention was built on person-centered care principles and consisted of telephone support and a web-based platform. The primary outcome was a composite score of changes in general self-efficacy (GSE) and level of sick leave at the 6-month follow-up. An intention-to-treat analysis included all participants, and a per-protocol analysis consisted of those using both the telephone support and the web-based platform. RESULTS: At the 3-month follow-up, in the intention-to-treat analysis, more patients in the intervention group improved on the composite score than those in the control group (20/102, 19.6%, vs 10/107, 9.3%; odds ratio [OR] 2.37, 95% CI 1.05-5.34; P=.04). At the 6-month follow-up, the difference was no longer significant between the groups (31/100, 31%, vs 25/107, 23.4%; OR 1.47, 95% CI 0.80-2.73; P=.22). In the per-protocol analysis, a significant difference was observed between the intervention and control groups at the 3-month follow-up (18/85, 21.2%, vs 10/107, 9.3%; OR 2.6, 95% CI 1.13-6.00; P=.02) but not at 6 months (30/84, 35.7%, vs 25/107, 23.4%; OR 1.8, 95% CI 0.97-3.43; P=.06). Changes in GSE drove the effects in the composite score, but the intervention did not affect the level of sick leave. CONCLUSIONS: A person-centered eHealth intervention for patients on sick leave due to CMDs improved GSE but did not affect the level of sick leave. TRIAL REGISTRATION: ClinicalTrials.gov NCT03404583; https://clinicaltrials.gov/ct2/show/NCT03404583.