Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

AIMS: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. METHODS AND RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

ANZACS-QI Heart Failure Registry: a new approach using age-stratified sampling of hospital discharges to guide quality improvement (ANZACS-QI 79).

Heart failure is a major healthcare problem in New Zealand. The Acute Decompensated Heart Failure (ADHF) Registry was introduced in 2015, and has identified the need for quality improvement strategies to improve care of patients hospitalised with heart failure. In this paper, we describe the implementation of the revised ANZACS-QI Heart Failure Registry, which has a primary aim to support evidence-based management of and quality improvement measures for patients who are hospitalised with heart failure in New Zealand. Taking the learnings from the initial experience with the ADHF Registry, the revised ANZACS-QI Heart Failure Registry i) utilises age-stratified sampling of hospital discharge coding to identify a representative heart failure cohort, ii) utilises existing ANZACS-QI infrastructure for data-linkage to reduce the burden of manual data entry, iii) receives governance from the Heart Failure Working Group, and iv) focusses on established quality improvement indicators for heart failure management.

Longitudinal NT-proBNP: Associations With Echocardiographic Changes and Outcomes in Heart Failure.

BACKGROUND: The relationship of serial NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements with changes in cardiac features and outcomes in heart failure (HF) remains incompletely understood. We determined whether common clinical covariates impact these relationships. METHODS AND RESULTS: In 2 nationwide observational populations with HF, the relationship of serial NT-proBNP measurements with serial echocardiographic parameters and outcomes was analyzed, further stratified by HF with reduced versus preserved left ventricular ejection fraction, inpatient versus outpatient enrollment, age, obesity, chronic kidney disease, atrial fibrillation, and attainment of ≥50% guideline-recommended doses of renin-angiotensin system inhibitors and ß-blockers. Among 1911 patients (mean±SD age, 65.1±13.4 years; 26.6% women; 62% inpatient and 38% outpatient), NT-proBNP declined overall, with more rapid declines among inpatients, those with obesity, those with atrial fibrillation, and those attaining ≥50% guideline-recommended doses. Each doubling of NT-proBNP was associated with increases in left ventricular volume (by 6.1 mL), E/e' (transmitral to mitral annular early diastolic velocity ratio) (by 1.4 points), left atrial volume (by 3.6 mL), and reduced left ventricular ejection fraction (by -2.1%). The effect sizes of these associations were lower among patients with HF with preserved ejection fraction, atrial fibrillation, or advanced age (Pinteraction<0.001). A landmark analysis identified that an SD increase in NT-proBNP over 6 months was associated with a 27% increase in the risk of the composite event of HF hospitalization or all-cause death between 6 months and 2 years (adjusted hazard ratio, 1.27 [95% CI, 1.15-1.40]; P<0.001). CONCLUSIONS: The relationships between NT-proBNP and structural/functional remodeling differed by age, presence of atrial fibrillation, and HF phenotypes. The association of increased NT-proBNP with increased risk of adverse outcomes was consistent in all subgroups.

2023 position statement on improving management for patients with heart failure in Aotearoa New Zealand.

Heart failure affects 1-3% of the population and remains a major public health problem, with high rates of hospitalisation and mortality. Health inequities in the incidence of heart failure have widened over the last 13 years in Aotearoa New Zealand. Urgent action is required to address the inequitable burden of heart failure among Maori and Pasifika. Regional and international heart failure guidelines now provide clear and consistent guidance on the contemporary approach to management for patients with heart failure. The purpose of this position statement is to ensure that all people in Aotearoa New Zealand have access to optimal healthcare delivery and pharmacotherapy for contemporary management of heart failure. Three main areas are addressed, including: 1) access to evidence-based pharmacotherapy for patients with heart failure, 2) the importance of early initiation and titration of pharmacotherapy, and 3) the workforce required to ensure timely delivery of heart failure therapies. Implementation of evidence-based healthcare will ensure all patients with heart failure in Aotearoa New Zealand have opportunity for substantial improvement in health.

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

Widening ethnic inequities in heart failure incidence in New Zealand.

OBJECTIVE: Ethnic inequities in heart failure (HF) have been documented in several countries. This study describes New Zealand (NZ) trends in incident HF hospitalisation by ethnicity between 2006 and 2018. METHODS: Incident HF hospitalisations in ≥20-year-old subjects were identified through International Classification of Diseases, 10th Revision-coded national hospitalisation records. Incidence was calculated for different ethnic, sex and age groups and were age standardised. Trends were estimated with joinpoint regression. RESULTS: Of 116 113 incident HF hospitalisations, 12.8% were Maori, 5.7% Pacific people, 3.0% Asians and 78.6% Europeans/others. 64% of Maori and Pacific patients were aged <70 years, compared with 37% of Asian and 19% of European/others. In 2018, incidence rate ratios compared with European/others were 6.0 (95% CI 4.9 to 7.3), 7.5 (95% CI 6.0 to 9.4) and 0.5 (95% CI 0.3 to 0.8) for Maori, Pacific people and Asians aged 20-49 years; 3.7 (95% CI 3.4 to 4.0), 3.6 (95% CI 3.2 to 4.1) and 0.5 (95% CI 0.4 to 0.6) for Maori, Pacific people and Asians aged 50-69 years; and 1.5 (95% CI 1.4 to 1.6), 1.5 (95% CI 1.3 to 1.7) and 0.5 (95% CI 0.5 to 0.6) for Maori, Pacific people and Asians aged ≥70 years. Between 2006 and 2018, ethnicity-specific rates diverged in ≥70-year-old subjects due to a decline in European/others (annual percentage change (APC) -2.0%, 95% CI -2.5% to -1.6%) and Asians (APC -3.3%, 95% CI -4.4% to -2.1%), but rates remained unchanged for Maori and Pacific people. In contrast, regardless of ethnicity, rates either increased or remained unchanged in <70-year-old subjects. CONCLUSION: Ethnic inequities in incident HF hospitalisation have widened in NZ over the past 13 years. Urgent action is required to address the predisposing factors that lead to development of HF in Maori and Pacific people.

Sex Differences in Heart Failure With Reduced Ejection Fraction in the GALACTIC-HF Trial.

BACKGROUND: Women with heart failure with reduced ejection fraction (HFrEF) receive less guideline-recommended therapy and experience worse quality of life than men. OBJECTIVES: The authors sought to assess differences in baseline characteristics, outcomes, efficacy, and safety of omecamtiv mecarbil between men and women enrolled in the GALACTIC-HF (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction) study. METHODS: In GALACTIC-HF, patients with symptomatic heart failure with EF of 35% or less, recent heart failure event, and elevated natriuretic peptides were randomized to omecamtiv mecarbil or placebo. The current analysis investigated differences in baseline characteristics, clinical outcomes, and efficacy and safety of omecamtiv mecarbil between men and women. RESULTS: Of 8,232 patients analyzed, 21.2% were women. Women more likely self-identified as being Black, had worse symptoms (lower Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and were less likely to be treated with angiotensin receptor/neprilysin inhibitor and devices at baseline. Compared with men, women had lower rates of the primary endpoint (adjusted HR: 0.80, 95% CI: 0.73-0.88). Sex did not significantly modify omecamtiv mecarbil's treatment effect (P interaction = 0.68). Women also had 20% less risk of cardiovascular death, heart failure event, and all-cause death. Women participants had lower rates of serious adverse events. CONCLUSIONS: Women participants of the GALACTIC-HF trial had worse quality of life and were less likely to be treated with guideline-based therapies at baseline. Despite KCCQ-TSS being predictive of poor outcomes in this population, women had a 20% lower risk of an HF event or cardiovascular death compared with men. The beneficial effect of omecamtiv mecarbil did not significantly differ by sex. (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).

Regional Handling and Prognostic Performance of Circulating Insulin-Like Growth Factor Binding Protein-7 in Heart Failure.

BACKGROUND: Regional handling and the prognostic performance of insulin-like growth factor binding protein (IGFBP)-7, in contrast or in combination with other candidate biomarkers, in chronic heart failure (CHF) remain uncertain. OBJECTIVES: The authors investigated the regional handling of plasma IGFBP-7 and its association with long-term outcomes in CHF in comparison with selected circulating biomarkers. METHODS: Plasma concentrations of IGFBP-7, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin-T, growth differentiation factor-15, and high-sensitivity C-reactive protein were measured prospectively in a cohort with CHF (n = 863). The primary outcome was the composite of heart failure (HF) hospitalization or all-cause mortality. In a separate non-HF cohort (n = 66) undergoing cardiac catheterization, transorgan gradients of plasma IGFBP-7 concentrations were evaluated. RESULTS: Among 863 patients (age 69 ± 14 years, 30% female, 36% HF with preserved ejection fraction), IGFBP-7 (median: 121 [IQR: 99-156] ng/mL) related inversely to left ventricular volumes but directly to diastolic function. Above the optimal cutoff, IGFBP-7 ≥110 ng/mL was independently associated with 32% increased hazard of the primary outcome: 1.32 (95% CI: 1.06-1.64). Among the 5 markers, IGFBP-7 had the highest hazard for a proportional increment in plasma concentrations independent of HF phenotype in single- and double-biomarker models, and provided incremental prognostic value beyond clinical predictors plus NT-proBNP, high-sensitivity troponin-T, and high-sensitivity C-reactive protein (P < 0.05). Assessment of regional concentrations indicated renal secretion of IGFBP-7 in contrast to renal extraction of NT-proBNP, possible cardiac extraction of IGFBP-7 in contrast to secretion of NT-proBNP, and common hepatic extraction of both peptides. CONCLUSIONS: Transorgan regulation of IGFBP-7 is distinct from NT-proBNP. Circulating IGFBP-7 independently predicts adverse outcomes in CHF with a strong prognostic performance when compared with other well-recognized cardiac-specific or noncardiac prognostic markers.

Titration of medications and outcomes in multi-ethnic heart failure cohorts (with reduced ejection fraction) from Singapore and New Zealand.

AIMS: We investigated titration patterns of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta-blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all-cause mortality/heart failure (HF) hospitalization] in a real-world population with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Participants with HFrEF (left ventricular ejection fraction <40%) from a prospective multi-centre study were examined for use and dose [relative to guideline-recommended maintenance dose (GRD)] of ACEis/ARBs and beta-blockers at baseline and 6 months. 'Stay low' was defined as <50% GRD at both time points, 'stay high' as ≥50% GRD, and 'up-titrate' and 'down-titrate' as dose trajectories. Among 1110 patients (mean age 63 ± 13 years, 16% women, 26% New York Heart Association Class III/IV), 714 (64%) were multi-ethnic Asians from Singapore and 396 were from New Zealand (mainly European ethnicity). Baseline use of either ACEis/ARBs or beta-blockers was high (87%). Loop diuretic was prescribed in >80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta-blockers. At 6 months, a large majority remained in the 'stay low' category, one third remained in 'stay high', whereas 10-16% up-titrated and 4-6% down-titrated. Patients with lower (vs. higher) N-terminal pro-beta-type natriuretic peptide levels were more likely to be up-titrated or be in 'stay high' for ACEis/ARBs and beta-blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of 'staying low' (all P < 0.005) for prescribed doses of ACEis/ARBs and beta-blockers. Adjusted for inverse probability weighting, ≥100% GRD for ACEis/ARBs [hazard ratio (HR) = 0.42; 95% confidence interval (CI) 0.24-0.73] and ≥50% GRD for beta-blockers (HR = 0.58; 95% CI 0.37-0.90) (vs. Nil) were associated with lower hazards for 1 year composite outcome. Country of enrolment did not modify the associations of dose categories with 1 year composite outcome. Higher medication doses were associated with greater improvements in QoL. CONCLUSIONS: Although HF medication use at baseline was high, most patients did not have these medications up-titrated over 6 months. Multiple clinical factors were associated with changes in medication dosages. Further research is urgently needed to investigate the causes of lack of up-titration of HF therapy (and its frequency), which could inform strategies for timely up-titration of HF therapy based on clinical and biochemical parameters.

Cohort profile: methodology and cohort characteristics of the Aotearoa New Zealand Rheumatic Heart Disease Registry.

PURPOSE: To create a cohort with high specificity for moderate and severe rheumatic heart disease (RHD) in New Zealand, not reliant on International Classification of Diseases discharge coding. To describe the demography and cardiac profile of this historical and contemporary cohort. DESIGN AND PARTICIPANTS: Retrospective identification of moderate or severe RHD with disease onset by 2019. Case identification from the following data sources: cardiac surgical databases, RHD case series, percutaneous balloon valvuloplasty databases, echocardiography databases, regional rheumatic fever registers and RHD clinic lists. The setting for this study was a high-income country with continued incidence of acute rheumatic fever (ARF). FINDINGS TO DATE: A Registry cohort of 4959 patients was established. The initial presentation was RHD without recognised prior ARF in 41%, and ARF in 59%. Ethnicity breakdown: Maori 38%, Pacific 33.5%, European 21.9%, other 6.7%. Ethnic disparities have changed significantly over time. Prior to 1960, RHD cases were 64.3% European, 25.3% Maori and 6.7% Pacific. However, in contrast, from 2010 to 2019, RHD cases were 10.7% European, 37.4% Maori and 47.2% Pacific.Follow-up showed 32% had changed region of residence within New Zealand from their initial presentation. At least one cardiac intervention (cardiac surgery, transcatheter balloon valvuloplasty) was undertaken in 64% of the cohort at a mean age of 40 years. 19.8% of the cohort had multiple cardiac interventions. At latest follow-up, 26.9% of the cohort died. Of those alive, the mean follow-up is 20.5+19.4 years. Maori and Pacific led governance groups have been established to provide data governance and oversight for the registry. FUTURE PLANS: Detailed mortality and morbidity of the registry cases will be defined by linkage to New Zealand national health data collections. The contemporary cohort of the registry will be available for future studies to improve clinical management and outcomes for the 3450 individuals living with chronic RHD.

Identification of clinically relevant cohorts of people with heart failure from electronic health data in Aotearoa: potential, pitfalls and a plan.

Heart failure (HF) is associated with high morbidity and mortality and contributes to substantial burden of disease, significant inequities and high healthcare cost globally as well as in Aotearoa. Management of chronic HF is driven by HF phenotype, defined by left ventricular ejection fraction (EF), as only those with reduced ejection fraction (HFrEF) have been shown to experience reduced mortality and morbidity with long-term pharmacotherapy. To ensure appropriate and equitable implementation of HF management we need to be able to identify clinically relevant cohorts of patients with HF, in particular, those with HFrEF. The ideal HF registry would incorporate and link HF diagnoses and phenotype from primary and secondary care with echocardiography and pharmacotherapy data. In this article we consider several options for identifying such cohorts from electronic health data in Aotearoa, as well as the potential and pitfalls of these options. Given the urgent need to identify people with HF according to EF phenotype, the options for identifying them from electronic health data, and the opportunities presented by health system reform, including a focus on digital solutions, we recommend the following four actions, with oversight from a national HF working group: 1) Establish a HF registry based on random and representative sampling of HF admissions; 2) investigate obtaining HF diagnosis and EF-phenotype from primary care-coded data; 3) amalgamate national echocardiography data; and 4) investigate options to enable the systematic collection of HF diagnosis and EF-phenotype from outpatient attendances. Future work will need to consider reliability and concordance of data across sources. The case for urgent action in Aotearoa is compounded by the stark inequities in the burden of HF, the likely contribution of health service factors to these inequities and the legislative requirement under the Pae Ora (Healthy Futures) Act 2022 that "the health sector should be equitable, which includes ensuring Maori and other population groups - (i) have access to services in proportion to their health needs; and (ii) receive equitable levels of service; and (iii) achieve equitable health outcomes".

Medical Treatment for Rheumatic Heart Disease: A Narrative Review.

BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are rare in high-income countries; however, in Aotearoa New Zealand ARF and RHD disproportionately affect Indigenous Maori and Pacific Peoples. This narrative review explores the evidence regarding non-surgical management of patients with clinically significant valve disease or heart failure due to RHD. METHODS: Medline, EMBASE and Scopus databases were searched, and additional publications were identified through cross-referencing. Included were 28 publications from 1980 onwards. RESULTS: Of the available interventions, improved anticoagulation management and a national RHD register could improve RHD outcomes in New Zealand. Where community pharmacy anticoagulant management services (CPAMS) are available good anticoagulation control can be achieved with a time in the therapeutic range (TTR) of more than 70%, which is above the internationally recommended level of 60%. The use of pharmacists in anticoagulation control is cost-effective, acceptable to patients, pharmacists, and primary care practitioners. There is a lack of local data available to fully assess other interventions; including optimal therapy for heart failure, equitable access to specialist RHD care, prevention, and management of endocarditis. CONCLUSION: As RHD continues to disproportionately affect Indigenous and minority groups, pro-equity tertiary prevention interventions should be fully evaluated to ensure they are reducing disease burden and improving outcomes in patients with RHD.

Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial.

BACKGROUND: Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. METHODS: SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2-3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 100 mmol (ie, <1500 mg/day). The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual. FINDINGS: Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58-74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group and from 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63-1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73-2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54-1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60-2·41]; p=0·60). No safety events related to the study treatment were reported in either group. INTERPRETATION: In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events. FUNDING: Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Relationship Between Soluble Transferrin Receptor and Clinical Outcomes in Patients With Heart Failure According to Ejection Fraction Phenotype: The New Zealand PEOPLE Study.

BACKGROUND: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) but its impact on prognosis in HF with preserved ejection fraction (HFpEF) remains unclear. We assessed whether ID defined by soluble transferrin receptor (sTfR) criteria is independently associated with all-cause mortality in patients with HFpEF, and evaluated its comparative prognostic performance to ID definitions in common clinical use. METHODS AND RESULTS: Data were analyzed from 788 patients (36% HFpEF) in a prospective multicenter HF cohort study. Baseline plasma samples were analyzed with respect to 4 definitions of ID: sTfR of ≥1.59 mg/L (IDsTfR1), sTfR of ≥1.76 mg/L (IDsTfR2), ferritin of <100 µg/L, or ferritin of 100-300 µg/L + transferrin saturation of <20% (IDFerritin), and transferrin saturation of <20% (IDTsat). In multivariable Cox models IDsTfR2 (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.23-2.75) and IDTsat (HR, 1.69, 95% CI 1.10-2.59) were both independently associated with all-cause mortality in patients with HFpEF, whereas IDsTfR1 (HR 1.41, 95% CI 0.92-2.16) and IDFerritin (HR 1.19, 95% CI 0.77-1.85) were not. On inclusion of patients with HF with reduced EF, IDsTfR1 (HR 1.45, 95% CI 1.13-1.86) gained significance, but IDFerritin (HR 1.21, 95% CI 0.95-1.54) did not. For each pair of definitions intra-patient concordance was approximately 65%. CONCLUSION: ID defined by sTfR criteria is independently associated with all-cause mortality in patients with HFpEF. Poor concordance between ID definitions suggests that iron biomarkers do not reflect the same pathological process in the complex relationship between iron and HF. Therefore, which definition should guide iron replacement needs further evaluation.

Contrasting trends in heart failure incidence in younger and older New Zealanders, 2006-2018.

OBJECTIVE: Studies indicate that age-standardised heart failure (HF) incidence has been decreasing internationally; however, contrasting trends in different age groups have been reported, with rates increasing in younger people and decreasing in the elderly. We aimed to describe age-specific trends in HF incidence in New Zealand (NZ). METHODS: In this nationwide data linkage study, we used routinely collected hospitalisation data to identify incident HF hospitalisations in NZ residents aged ≥20 years between 2006 and 2018. Age-specific and age-standardised incidence rates were calculated for each calendar year. Joinpoint regression was used to compare incidence trends. RESULTS: 116 113 incident HF hospitalisations were identified over the 13-year study period. Between 2006 and 2013, age-standardised incidence decreased from 403 to 323 per 100 000 (annual percentage change (APC) -2.6%, 95% CI -3.6 to -1.6%). This reduction then plateaued between 2013 and 2018 (APC 0.8%, 95% CI -0.8 to 2.5%). Between 2006 and 2018, rates in individuals aged 20-49 years old increased by 1.5% per year (95% CI 0.3 to 2.7%) and decreased in those aged ≥80 years old by 1.2% per year (95% CI -1.7 to -0.7%). Rates in individuals aged 50-79 years old initially declined from 2006 to 2013, and then remained stable or increased from 2013 to 2018. The proportion of HF hospitalisations associated with ischaemic heart disease decreased from 35.1% in 2006 to 28.0% in 2018. CONCLUSION: HF remains an important problem in NZ. The decline in overall incidence has plateaued since 2013 due to increasing rates of HF in younger age groups despite an ongoing decline in the elderly.

Impact of change in iron status over time on clinical outcomes in heart failure according to ejection fraction phenotype.

AIMS: The importance of iron deficiency (ID) in heart failure with preserved ejection fraction (HFpEF) is unknown. In HF with reduced ejection fraction (HFrEF), ID is reported as an independent predictor of mortality in HF although not all published studies agree. Different definitions of ID have been assessed, and the natural history of untreated ID not established, which may explain the conflicting results. This study aimed to assess the relationship between ID and mortality in HFpEF, clarify which definition of ID correlates best with outcomes in HFrEF, and determine the prognostic importance of change in ID status over time. METHODS AND RESULTS: Analyses were conducted on data from 1563 patients participating in a prospective international cohort study comparing HFpEF with HFrEF. Plasma samples from baseline and 6 month visits were analysed for the presence of ID. Two ID definitions were evaluated: IDFerritin  = 'ferritin < 100 mcg/L or ferritin 100-300 mcg/L + transferrin saturation < 20%' and IDTsat  = 'transferrin saturation < 20%'. The risk of all-cause mortality and death/HF hospitalization associated with baseline ID (IDFerritin or IDTsat ) and change in ID status at 6 months (persistent, resolving, developing, or never present) was estimated in multivariable Cox proportional hazards models. Of 1563 patients, 1115 (71%) had HFrEF and 448 (29%) HFpEF. Prevalence of ID was similar in HFpEF and HFrEF (58%). Patients with ID were more likely to be female, diabetic, and have a higher co-morbid burden than patients without ID. ID by either definition did not confer independent risk for either all-cause mortality or death/HF hospitalization for patients with HFpEF [IDFerritin hazard ratio (HR) 0.65 (95% confidence interval 0.40-1.05), P = 0.08; IDTsat HR 1.16 (0.72-1.87), P = 0.55]. In the overall study cohort (HFrEF + HFpEF) and HFrEF subgroup, IDFerritin was inferior to IDTsat in prediction of all-cause mortality [overall cohort: HR 1.21 (0.95-1.53), P = 0.12 vs. HR 1.95 (1.52-2.51), P < 0.01; HFrEF: HR 1.12 (0.85-1.48), P = 0.43 vs. HR 1.57 (1.15-2.14), P < 0.01]. Persistence of IDTsat at 6 months was strongly associated with poor outcomes compared with never having IDTsat [HR 2.22 (1.42-3.46), P < 0.01] or having IDTsat at baseline self-resolve by 6 months [HR 1.40 (1.06-1.86), P = 0.02]. CONCLUSIONS: Iron deficiency is equally prevalent in HFpEF and HFrEF but is negatively prognostic only in HFrEF. The natural history of ID is important; persistent ID is strongly associated with mortality whereas resolution is not. IDTsat is the superior definition of ID and should inform future trials investigating the efficacy of intravenous iron replacement in patients with HFrEF.

An NP-led pilot telehealth programme to facilitate guideline-directed medical therapy for heart failure with reduced ejection fraction during the COVID-19 pandemic.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is associated with poor outcomes. While several medications are beneficial, achieving optimal guideline-directed medical therapy (GDMT) is challenging. COVID-19 created a need to explore new ways to deliver care. METHODS: Fifty consecutive patients were taught to identify fluid congestion and monitor their vital signs using BP monitors and electronic scales with NP-led telephone support. Quantitative data were collected and a patient experience interview was performed. RESULTS: The majority (76%) of the cohort (male, 76%; Maori/Pacific, 58%) had a new diagnosis of HFrEF, with 90% having severe left ventricular (LV) dysfunction. There were 216 contacts (129 (60%) by telephone), which eliminated travelling, (time saved, 2.12 hours per patient), petrol costs ($58.17 per patient), traffic pollution (607 Kg of CO2) and time off work. Most (75%) received contact within two weeks and 75% were optimally titrated within two months. Improvements in systolic BP (SBP) (124mmHg to 116mmHg), pulse (78 bpm to 70 bpm) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (292 to 65) were identified. Of the 43 patients who had a follow-up transthoracic echocardiogram (TTE), 33 (77%) showed important improvement in left ventricular ejection fraction (LVEF). CONCLUSIONS: Patients found the process acceptable and experienced rapid titration with less need for clinic review with titration rates comparable with most real-world reports.

NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories.

OBJECTIVES: The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories. BACKGROUND: Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain. METHODS: Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), and mildly (BMI 30-34.9 kg/m2), moderately (BMI 35-39.9 kg/m2), or severely (BMI ≥40 kg/m2) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death. RESULTS: The study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (ß = -0.174 for 1 kg/m2; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men. CONCLUSIONS: NT-proBNP maintains its independent prognostic value up to 40 kg/m2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.