Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

Distinguishing heart failure with reduced ejection fraction from heart failure with preserved ejection fraction: A phenomics approach.

AIM: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. METHODS AND RESULTS: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age- and sex-matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi-block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross-referenced with small-molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60-71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)-8 and IL-6 were possible targets related to lower EF and worsening renal function. CONCLUSION: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF.

Expert recommendations for the management of iron deficiency in patients with heart failure in Asia.

BACKGROUND: Iron deficiency is a common comorbidity in heart failure (HF) and is independently associated with a worse quality-of-life and exercise capacity, as well as increased risk of hospitalization, regardless of anemia status. Although international guidelines have provided recommendations for the management of iron deficiency in patients with HF, guidelines in Asia are less established, and practical use of guidelines for management of iron deficiency is limited in the region. METHODS: A panel comprising cardiologists from China, Hong Kong, India, Japan, Malaysia, Pakistan, Philippines, Singapore, South Korea, Taiwan, and Thailand convened to share insights and provide guidance for the optimal management of iron deficiency in patients with HF, tailored for the Asian community. RESULTS: Expert opinions were provided for the screening, diagnosis, treatment and monitoring of iron deficiency in patients with HF. It was recommended that all patients with HF with reduced ejection fraction should be screened for iron deficiency, and iron-deficient patients should be treated with intravenous iron. Monitoring of iron levels in patients with HF should be carried out once or twice yearly. Barriers to the management of iron deficiency in patients with HF in the region include low awareness of iron deficiency amongst general physicians, lack of reimbursement for screening and treatment, and lack of proper facilities for administration of intravenous iron. CONCLUSIONS: These recommendations provide a structured approach to the management of iron deficiency in patients with HF in Asia.

Angiotensin Receptor-Neprilysin Inhibition in Patients With STEMI vs NSTEMI.

BACKGROUND: Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. OBJECTIVES: The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. METHODS: The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. RESULTS: Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). CONCLUSIONS: Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727).

Differential Associations of A-/B-Type Natriuretic Peptides With Cardiac Structure, Function, and Prognosis in Heart Failure.

BACKGROUND: Natriuretic peptide (NP) elevations are prognostic in heart failure (HF), but relative atrial NP deficiency in acute HF has been suggested. OBJECTIVES: The authors compared plasma concentrations and relative strength of associations of A- and B-type NPs with cardiac structure/function and clinical outcomes in HF. METHODS: Midregional pro-atrial natriuretic peptide (MR-proANP), B-type natriuretic peptide (BNP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured in patients with compensated HF in a prospective, multicenter study. The primary outcome was a composite of HF-hospitalization or all-cause mortality. Secondary outcomes included individual primary outcome components and cardiovascular admission. RESULTS: Among 1,278 patients (age 60.1 ± 12.1 years, 82% men, left ventricular ejection fraction [LVEF] 34% ± 14%), median concentrations of MR-proANP were 990 pg/mL (Q1-Q3: 557-1,563 pg/mL), NT-proBNP 1,648 pg/mL (Q1-Q3: 652-3,960 pg/mL), and BNP 291 pg/mL (Q1-Q3: 103-777 pg/mL). No subpopulation with inappropriately low MR-proANP (relative to BNP/NT-proBNP) was observed. Clinical event rates were similar for biomarker tertiles. Increments in MR-proANP exhibited steeper associations with concurrent shifts in left ventricular size, diastolic indexes and LVEF than BNP/NT-proBNP at baseline and serially (P < 0.05), and lower odds of beneficial left ventricular reverse remodeling: OR: 0.35 (95% CI: 0.18-0.70). In single-biomarker models, MR-proANP(log10) was associated with the highest hazard (4 to 6 times) for each outcome. In multimarker models, independent associations were observed for the primary outcome (MR-proANP and NT-proBNP), HF-hospitalization and cardiovascular admission (MR-proANP only), and all-cause mortality (NT-proBNP only) (P < 0.05). The discriminative value of MR-proANP was superior to BNP/NT-proBNP (HF-hospitalization) and BNP (primary outcome) (P < 0.05). CONCLUSIONS: MR-proANP was not inappropriately low relative to concurrent BNP/NT-proBNP values. Proportional increments in MR-proANP were more pronounced than for B-peptides for given decrements in cardiac structure/function. MR-proANP offered greater independent predictive power overall.

Weak grip strength predicts higher unplanned healthcare utilization among patients with heart failure.

AIMS: Frailty increases healthcare utilization and costs for patients with heart failure but is challenging to assess in clinical settings. Hand grip strength (GS) is a single-item measure of frailty yet lacks evidence as a potential screening tool to identify patients at risk of higher unplanned events and related healthcare costs. We examined the association of baseline and longitudinal GS measurements with healthcare utilization and costs among patients with advanced heart failure. METHODS AND RESULTS: Between July 2017 and April 2019, we enrolled 251 patients with symptoms of advanced heart failure (New York Heart Association class III or IV) in a prospective cohort study in Singapore. We measured GS at baseline and every 4 months for 2 years and linked patients' survey data with their medical and billing records. We categorized patients as having weak GS if their GS measurement was below the 5th percentile of the age- and gender-specific normative GS values in Singapore. We assessed the association between baseline GS and healthcare utilization (unplanned and planned events and healthcare costs, total costs, and length of inpatient stay) over the next 2 years using regression models. We investigated the association between longitudinal 4-monthly GS assessments and the ensuing 4 months of healthcare utilization and costs using mixed-effects logistic and two-part regression models. At baseline, 22.5% of patients had weak GS. Baseline and longitudinal GS measurements were significantly associated with longer length of inpatient stay, greater likelihood of unplanned events, and higher related costs. Patients with weak GS had higher odds of an unplanned event occurring by 8 percentage points [95% confidence interval (CI) (0.01, 0.14), P = 0.026], incurred longer inpatient stays by 4 days [95% CI (1.97, 6.79), P = 0.003], and additional SG$ 4792 [US$ ~ 3594, 95% CI (1894, 7689), P = 0.014] in unplanned healthcare costs over the next 4 months. CONCLUSIONS: GS is a simple tool to identify and monitor heart failure patients at risk of unplanned events, longer inpatient stays, and higher related healthcare costs. Findings support its routine use in clinical settings.

Comparable outcomes of reverse shoulder arthroplasty for proximal humerus fractures and for rotator cuff arthropathy in a predominantly asian population.

Background: Reverse shoulder arthroplasty (RSA) was initially developed for rotator cuff arthropathy but has been expanded to treat comminuted proximal humerus fractures. Few studies have compared RSA for traumatic and degenerative indications. We present the first report of mid-term outcomes of RSA comparing both indications in an Asian population. Methods: 113 degenerative and 20 fracture patients underwent RSA from 2010 to 2019. Patients with degenerative indications were 4:1 propensity-score matched to fractures and adjusted for age and sex. Patients were assessed for range of motion (ROM), strength, pain, Constant-Murley score (CMS), University of California Los Angeles Shoulder Score (UCLA) and Oxford shoulder score (OSS) preoperatively, at 6-months and 1-year. Patients' satisfaction, expectation fulfilment and minimal clinically important difference (MCID) were analysed. Results: Degenerative patients had better ROM, isometric strength and CMS at 6-months, although at 1-year only abduction was superior (104.8 ± 17.3° vs 86.7 ± 19.8°). No significant differences in pain, UCLA and OSS were observed. Most improvements occurred within 6 months. Similar proportions of patients were satisfied (83.3% vs 73.3%, p = 0.460) and attained MCID (85.0% vs 86.7%, p = 1.000) at 1-year. Discussion: Although initially exhibiting slower recovery, patients with proximal humerus fractures can expect similar functional recovery and satisfaction at 1-year compared to those who received RSA for degenerative indications.

Examining predictors for 6-month mortality and healthcare utilization for patients admitted for heart failure in the acute care setting.

BACKGROUND: Acute heart failure (AHF) is a leading cause of mortality and hospitalization. Past studies reported increased healthcare spending in the last year of life in high-income countries, and this has been characterized as inappropriate healthcare resource utilization. The study aimed to examine potentially (in)appropriate healthcare utilization by comparing healthcare utilization patterns across predicted and observed 6-month mortality among patients admitted for HF. METHODS: We conducted a retrospective cohort study among patients presenting at the emergency department (ED) of a tertiary hospital with HF as primary diagnosis and admitted after their ED discharge. We used LASSO Cox proportional hazards models to predict 6-month mortality, and estimated healthcare utilization patterns of predicted and observed mortality across inpatient healthcare services. RESULTS: 3946 patients were admitted into the emergency department with a primary diagnosis of HF. From 57 candidate variables, 17 were retained in the final 6- month mortality model (C-statistic 0.66). Patients who died within 6-months of ED admission had longer length of stay (LOS) and less inpatient surgeries than those who survived. Patients with a greater predicted mortality risk were admitted to the ICU more often and had a longer LOS than those with a lower predicted mortality risk. CONCLUSIONS: There were significant differences in healthcare resource utilization in patients admitted for AHF across predicted versus actual mortality. Lack of information on patients' preferences prevents the estimation of (in)appropriateness. Future studies should account for these considerations to estimate inappropriate healthcare utilization among these patients.

Clinical characteristics and outcomes in Asian patients with heart failure with mildly reduced ejection fraction.

Introduction: Data on heart failure (HF) with mildly reduced ejection fraction (HFmrEF) is still emerging, especially in Asian populations. This study aims to compare the clinical characteristics and outcomes of Asian HFmrEF patients with those of HF patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Methods: Patients admitted nationally for HF between 2008 and 2014 were included in the study. They were categorised according to ejection fraction (EF). Patients with EF <40%, EF 40%-49% and EF ≥50% were categorised into the following groups: HFrEF, HFmrEF and HFpEF, respectively. All patients were followed up till December 2016. Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death and/or HF rehospitalisations. Results: A total of 16,493 patients were included in the study - HFrEF, n = 7,341 (44.5%); HFmrEF, n = 2,272 (13.8%); and HFpEF n = 6,880 (41.7%). HFmrEF patients were more likely to be gender neutral, of mid-range age and have concomitant diabetes mellitus, hyperlipidaemia, peripheral vascular disease and coronary artery disease (P < 0.001). The two-year overall mortality rates for HFrEF, HFmrEF and HFpEF were 32.9%, 31.8% and 29.1%, respectively. HFmrEF patients had a significantly lower overall mortality rate compared to HFrEF patients (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.83-0.95; P < 0.001) and a significantly higher overall mortality rate (adjusted HR 1.25, 95% CI 1.17-1.33; P < 0.001) compared to HFpEF patients. This was similarly seen with cardiovascular mortality and HF hospitalisations, with the exception of similar HF hospitalisations between HFmrEF and HFpEF patients. Conclusion: HFmrEF patients account for a significant burden of patients with HF. HFmrEF represents a distinct HF phenotype with high atherosclerotic burden and clinical outcomes saddled in between those of HFrEF and HFpEF. Further therapeutic studies to guide management of this challenging group of patients are warranted.

Single-Level Endoscopic TLIF Has Decreased Surgery Duration, Blood Loss, and Length of Hospital Stay While Achieving Similar 1-Year Clinical and Radiological Outcomes Compared With Conventional Minimally Invasive TLIF.

BACKGROUND: This study presents a single surgeon's experience comparing 1-year outcomes of endoscopic transforaminal lumbar interbody fusion (E-TLIF) vs minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) in an Asian population. METHODS: Retrospective review of consecutive patients who underwent single-level E-TLIF or MIS-TLIF by a single surgeon in a tertiary spine institution from 2018 to 2021 with 1-year follow-up. Inclusion criteria for both procedures were degenerative disc disease with grade I or II spondylolisthesis and mild to moderate central canal stenosis. Clinical outcomes assessed included surgery duration, blood loss, and length of stay. Patient-reported outcomes assessed included the visual analog score for back pain and lower limb pain, Oswestry Disability Index, and North American Spine Society Neurogenic Symptom Score. Radiographic parameters assessed included segmental lordosis, posterior disc height, listhesis, and the presence of cage migration or subsidence. RESULTS: Twelve E-TLIF and 34 MIS-TLIF patients were identified. E-TLIF had shorter surgery duration (165 ± 15 vs 259 ± 43 min for E-TLIF and MIS-TLIF groups, respectively; P < 0.001), reduced blood loss (83 ± 75 vs 181 ± 225 mL; P = 0.033), and decreased length of stay (1.8 ± 0.9 vs 4.7 ± 2.9 days; P < 0.001) compared with MIS-TLIF. E-TLIF and MIS-TLIF patients had significant improvements (P < 0.05) at 1 year in all patient-reported outcomes scores and radiographic parameters assessed. Both E-TLIF and MIS-TLIF patient groups also had similar postoperative patient-reported outcomes scores and radiographic parameters. No complications were recorded for E-TLIF, while MIS-TLIF had a case of dura tear and another case of meralgia paresthetica. There were no instances of cage subsidence, cage migration, or implant loosening in either group at 1 year. CONCLUSIONS: Although the study size was limited because E-TLIF is a relatively new technique in our institution, 1-year results demonstrate that E-TLIF can be a safe and efficacious option that achieves clinical and radiological results similar to MIS-TLIF with the additional benefits of decreased surgical duration, blood loss, and length of hospital stay. CLINICAL RELEVANCE: The results of this study support the effectiveness and potential advantages of endoscopic TLIF compared with MIS-TLIF.

Geographic differences in patients with acute myocardial infarction in the PARADISE-MI trial.

AIM: The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE-MI. METHODS AND RESULTS: Overall, 23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South-East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of atrial fibrillation), type of myocardial infarction (more often ST-elevation myocardial infarction), and treatment (low rate of primary percutaneous coronary intervention). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (34.8%) and beta-blockers (65.5%) was low in SA, whereas mineralocorticoid receptor antagonist use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident heart failure varied two-fold among regions, with the lowest rate in SA (4.6/100 person-years) and the highest in LA (9.2/100 person-years). Rates of incident heart failure varied almost six-fold among regions, with the lowest rate in SA (1.0/100 person-years) and the highest in Northern Europe (5.9/100 person-years). The effect of sacubitril/valsartan was not modified by region. CONCLUSION: In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a 'real-world' unselected population may be limited, these findings underscore the importance of considering both regional and within-region differences when designing global clinical trials.

Biplanar Expandable Cages for Transforaminal Lumbar Interbody Fusion Are Safe and Achieve Good 1-Year Clinical and Radiological Outcomes in an Asian Population.

BACKGROUND: This study investigated 1-year clinical and radiological outcomes of biplanar expandable (BE) cages following transforaminal lumbar interbody fusion (TLIF) in an Asian population. METHODS: A retrospective review was conducted of all consecutive patients who underwent TLIF with BE cages performed by 2 fellowship-trained spine surgeons from 2020 to 2021. Inclusion criteria included open or minimally invasive (MIS) TLIF, of up to 3 spinal segments, performed for treatment of degenerative disc disease, spondylolisthesis, or spinal stenosis. Patient-reported outcomes, including visual analog score (VAS) for back and lower limb pain, Oswestry Disability Index (ODI) and North American Spine Society neurogenic symptom score (NSS), and various radiographic parameters, were evaluated. RESULTS: A total of 23 patients underwent TLIF with BE cages with a follow-up duration of 1.25 years. Of those patients, 7 (30%) underwent 1-level TLIF, 12 (52%) underwent 2-level TLIF, and 4 (18%) underwent 3-level TLIF, with a total of 43 spinal segments fused. Four patients (17%) underwent MIS TLIF while 19 patients (83%) underwent open TLIF. VAS for back pain scores improved by 4.8 ± 3.4 (P < 0.001) from 6.5 ± 2.6 to 1.7 ± 2.2; VAS for lower limb pain scores improved by 5.2 ± 3.8 (P < 0.001) from 5.7 ± 3.4 to 0.5 ± 1.6; ODI scores improved by 29.0 ± 18.1 (P < 0.001) from 49.4 ± 15.1 to 20.4 ± 14.2; and NSS scores improved by 36.8 ± 22.1 (P < 0.001) from 53.3 ± 21.1 to 16.5 ± 19.8. Significant improvements in radiological parameters included increase in anterior disc height, posterior disc height, foraminal height, segmental lordosis, and lumbar lordosis. There were no implant-related complications, cage subsidence, cage migration, or revision surgery at 1 year. CONCLUSIONS: TLIF performed with BE cages led to significantly improved patient-reported outcomes and radiographic parameters at 1 year and is safe for use in Asians. CLINICAL RELEVANCE: The results of this study support the effectiveness and safety of TLIF with biplanar expandable cages.

Elements of Potentially Inappropriate Interventions and Patient Prognostic Profiles at the End of Life in Cardiology: A Qualitative Analysis.

Background: The determination of what makes a medical treatment inappropriate is unclear with a small likelihood of consensus. Objectives: This study aimed to explore how clinicians in cardiology perceive "inappropriate treatment" and to collate the common profiles of cardiology patients receiving likely "inappropriate treatment" as perceived by clinicians in a multiethnic Asian context. Methods: A qualitative study was conducted using semistructured in-depth interviews with 32 clinicians involved in the care for cardiology patients at a large national cardiology center in Singapore. Results: Clinicians' accounts indicated that elements of potentially inappropriate treatment encompass patient-related treatment elements as well as quantitative and probability-based elements such as resource use and probability of treatment benefit. Patient prognostic profiles, characterized as likely to have received inappropriate treatment by clinicians, were organized into six categories according to demographic, clinical, and functional factors. Conclusions: The perception of inappropriateness of treatments among clinicians in cardiology was primarily focused on patient-related outcomes. Collated patient profiles may serve as meaningful indicators of patient cases receiving potentially inappropriate treatment for further research and intervention.

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.

Cost-Effectiveness of Empagliflozin on Top of Standard of Care for Heart Failure With Reduced Ejection Fraction in Singapore.

OBJECTIVES: The prevalence of heart failure (HF) and its risk factors are high in Singapore. The EMPEROR-Reduced trial demonstrated that add-on empagliflozin resulted in a reduction in the risk of cardiovascular death or hospitalization for HF compared with standard of care (SoC). This study aimed to estimate the cost-effectiveness of empagliflozin+SoC versus SoC in patients with HF with reduced ejection fraction from a Singaporean healthcare perspective. METHODS: A Markov cohort model simulated progression through health states based on New York Heart Association classes over a lifetime horizon using a cycle length of 1 month. Transition probabilities, and the risk of transient events (hospitalization for HF and cardiovascular/all-cause death) were modeled based on the EMPEROR-Reduced trial. Costs for HF-related events, adverse events, and for monitoring were estimated from a combination of published literature and publicly available fees for public hospitals/polyclinics. RESULTS: Empagliflozin+SoC was estimated to be very cost-effective versus SoC alone with an incremental cost-effectiveness ratio of<8000 Singapore Dollars/quality-adjusted life-year gained. The base-case results were robust as evidenced from the consistency of various scenario and sensitivity analyses performed. When using Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score quartiles as the health states, the incremental cost-effectiveness ratio reduced significantly to 4625 Singapore Dollars/quality-adjusted life-year. CONCLUSION: The use of empagliflozin on top of SoC represents a highly cost-effective solution for the treatment of patients with HF with reduced ejection fraction in Singapore when considering its efficacy, relative affordability, and the growing economic burden of HF in Singapore.

Validity and Reliability of the Integrated Palliative Care Outcome Scale in Asian Heart Failure Patients.

Background: The Integrated Palliative Care Outcome Scale (IPOS) was developed in the United Kingdom for health assessment in advanced illness. Objectives: To evaluate the validity and reliability of a culturally adapted IPOS (both patient and staff versions) for heart failure (HF). Design/Setting: We recruited HF patients and staff from a tertiary hospital in Singapore. We collected patient IPOS, New York Heart Association (NYHA) status, Edmonton Symptom Assessment System (ESAS) and Minnesota Living with Heart Failure (MLHF) scores at baseline, and patient IPOS at follow-up. Each baseline patient IPOS was matched with a staff IPOS. Measurements: Pearson correlation coefficient (r) between ESAS, MLHF, and patient IPOS was calculated to assess construct validity. The two-sample T-test assessed difference in patient and staff IPOS scores across NYHA status and care settings for known-group validity. Internal consistency of patient and staff IPOS was assessed using Cronbach's alpha (α). Intraclass correlation coefficient (ICC) was used to assess test-retest reliability of patient IPOS and inter-rater reliability between patient and staff IPOS. Results: Ninety-one patients and 12 staff participated. There was strong convergent validity of total patient IPOS with MLHF (r = 0.78) and ESAS (r = 0.81). There were statistically significant differences in total IPOS across care settings (patient-IPOS: 8.05, staff-IPOS 13.61) and NYHA (patient-IPOS: 7.52, staff-IPOS 12.71).There was high internal consistency of total patient (α = 0.83) and staff IPOS (α = 0.88) and high test-retest reliability of patient IPOS (ICC 0.81). Inter-rater reliability (ICC) ranged between 0.82 and 0.91. Conclusion: The IPOS was valid and reliable for HF patients in Singapore.

Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved.

The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.

Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Frailty is an increasingly common problem, and frail patients are less likely to receive new pharmacologic therapies because the risk-benefit profile is perceived to be less favorable than in nonfrail patients. OBJECTIVES: This study investigated the efficacy of sacubitril/valsartan according to frailty status in 4,796 patients with heart failure with preserved ejection fraction randomized in the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. METHODS: Frailty was measured by using the Rockwood cumulative deficit approach. The primary endpoint was total heart failure hospitalizations or cardiovascular death. RESULTS: A frailty index (FI) was calculable in 4,795 patients. In total, 45.2% had class 1 frailty (FI ≤0.210, not frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 11.4% had class 3 frailty (FI ≥0.311, most frail). There was a graded relationship between FI class and the primary endpoint, with a significantly higher risk associated with greater frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). The effect of sacubitril/valsartan vs valsartan on the primary endpoint from lowest to highest FI class (as a rate ratio) was: 0.98 [95% CI: 0.76-1.27], 0.92 [95% CI: 0.76-1.12], and 0.69 [95% CI: 0.51-0.95]), respectively (Pinteraction = 0.23). When FI was examined as a continuous variable, the interaction with treatment was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction < 0.001), with those most frail deriving greater benefit. CONCLUSIONS: Frailty was common in heart failure with preserved ejection fraction and associated with worse outcomes. Compared with valsartan, sacubitril/valsartan seemed to show a greater reduction in the primary endpoint with increasing frailty, although this was not significant when FI was examined as a categorical variable. (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).