Characterization of serum phosphate levels over time with intravenous ferric carboxymaltose versus placebo as treatment for heart failure with reduced ejection fraction and iron deficiency: An exploratory prospective substudy from HEART-FID.

AIMS: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. METHODS AND RESULTS: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. CONCLUSIONS: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF.

Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Sodium-Glucose Cotransporter 2 Inhibitors in South Australia: The Magic Before the Fame.

BACKGROUND: Recent clinical trials have demonstrated that sodium-glucose cotransporter 2 inhibitors (SGLT2i), which were previously only indicated in treatment of type 2 diabetes mellitus (T2DM), can markedly reduce heart failure hospitalisation (HFH), with less striking potential reductions in acute coronary syndromes and cardiac arrhythmias. To evaluate the impact of SGLT2i on cardiovascular outcomes in real-world practice, we performed a retrospective cohort analysis on South Australian (SA) data. METHODS: A total of 842 individuals with T2DM receiving SGLT2i were identified from SA public hospitals between 2011 and 2019. Episodes of care were temporally matched with those of 3,128 individuals with T2DM not receiving SGLT2i (control). Baseline characteristics were adjusted using inverse probability treatment weighting. The incidence of cardiovascular events at 12 and 24 months was evaluated using coded (International Classification of Diseases, Tenth Revision, Australian Modification [ICD-10-AM]) data. RESULTS: The primary outcome of HFH was lower with SGLT2i use at 12 months (adjusted hazard ratio [HRadj] 0.44; 95% confidence interval [CI] 0.29-0.68; p<0.001) and 24 months. There were also lower hospitalisations due to acute myocardial infarction (HRadj 0.42; 95% CI 0.21-0.85; p=0.015) and atrial or ventricular arrhythmias (HRadj 0.29; 95% CI 0.14-0.59; p=0.001), with no difference observed in hospitalisation due to ischaemic cerebrovascular events. There was no difference in all-cause mortality at 12 months but interestingly a higher rate at 24 months (HRadj 2.08; 95% CI 1.59-2.72; p<0.001). Despite this, similar reductions in cardiovascular outcomes were observed at 24 months. CONCLUSION: Use of SGLT2i in patients with T2DM in SA was associated with reductions in cardiovascular events even before their recent Pharmaceutical Benefits Scheme (PBS) listing for heart failure. Furthermore, this analysis supports that SGLT2i play a role not only in HFH reduction but also in reducing coronary and tachyarrhythmic events. This real-world evidence supports the use of SGLT2i as broadly protective cardiovascular drugs.

Ferric Carboxymaltose in Heart Failure with Iron Deficiency.

BACKGROUND: Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed. METHODS: In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01. RESULTS: We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon-Mann-Whitney P = 0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group). CONCLUSIONS: Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.).

Baseline characteristics of patients in the randomized study to investigate the efficacy and safety of ferric carboxymaltose as treatment for heart failure with iron deficiency: HEART-FID trial.

BACKGROUND: Prior clinical trials have investigated intravenous iron in patients with heart failure (HF) and iron deficiency, but the safety and efficacy of this therapy remains unclear. METHODS: We report the baseline demographics and clinical characteristics of patients enrolled in the HEART-FID study and compare HEART-FID participants with patients within other contemporary clinical trials of patients with HF with reduced ejection fraction (HFrEF), including other intravenous iron trials. RESULTS: In the 3,065 participants randomized in HEART-FID, median (IQR) age was 69.7 (62.0-76.5) years, 1,037 (33.8%) were female, 322 (10.5%) were Black, median ejection fraction was 32% (25%-37%), 1,837 (60.0%) had ischemic etiology, and baseline median NT-proBNP was 1,462 (721-2,966) pg/mL. Median baseline hemoglobin was 12.6 (11.6-13.6) g/dL, and median 6-minute walk test distance was 272 (196-350) m, similar to prior intravenous iron HFrEF trials. Common comorbidities included atrial fibrillation/flutter (43.7%), and type 2 diabetes (45.2%). Compared with several recent HFrEF trials, patients enrolled in HEART-FID had similar baseline demographics and clinical characteristics, though a greater proportion of women and Black participants were recruited in HEART-FID. In HEART-FID, HFrEF therapy included a beta-blocker in 92.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (ARNI) in 86.1% (with 29.7% ARNI), and a mineralocorticoid antagonist (MRA) in 55.6%. CONCLUSIONS: Patients enrolled in HEART-FID were similar to those enrolled in other contemporary HFrEF trials and registries, including trials of intravenous iron in HFrEF. However, the HEART-FID cohort is substantially larger and more racially diverse than prior trials of intravenous iron in HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03037931).

Contrasting the potential benefits of early invasive coronary angiography in acute and chronic myocardial injury patterns.

BACKGROUND: In cases of evolving myocardial injury not definitively attributed to coronary ischaemia precipitated by plaque rupture, referral for invasive coronary angiography (ICA) may be influenced by observed troponin profiles. We sought to explore association between early ICA and elevated high-sensitivity troponin T (hs-cTnT) concentrations with and without dynamic changes, to examine if there may be a hs-cTnT threshold associated with benefit from an initial ICA strategy. METHODS: Using published studies (hs-cTnT study n = 1937, RAPID-TnT study n = 3270) and the Fourth Universal Definition of Myocardial Infarction (MI), index presentations of patients with hs-cTnT concentrations 5-14ng/L were classified as 'non-elevated' (NE). Hs-cTnT greater than upper reference limit (14ng/L) were classified as 'elevated hs-cTnT with dynamic change' (encompassing acute myocardial injury, Type 1 MI, and Type 2 MI), or 'non-dynamic hs-cTnT elevation' (chronic myocardial injury). Patients with hs-cTnT <5ng/L and/or eGFR<15mmol/L/1.73m2 were excluded. ICA was performed within 30 days of admission. Primary outcome was defined as composite endpoint of death, MI, or unstable angina at 12 months. RESULTS: Altogether, 3620 patients comprising 837 (23.1%) with non-dynamic hs-cTnT elevations and 332 (9.2%) with dynamic hs-cTnT elevations were included. Primary outcome was significantly higher with dynamic and non-dynamic hs-cTnT elevations (Dynamic: HR: 4.13 95%CI:2.92-5.82; p<0.001 Non-dynamic: HR: 2.39 95% confidence interval [CI]:1.74-3.28, p<0.001). Hs-cTnT thresholds where benefit from initial ICA strategy appeared to emerge was observed at 110ng/L and 50ng/L in dynamic and non-dynamic elevations, respectively. CONCLUSION: Early ICA appears to portend benefit in hs-cTnT elevations with and without dynamic changes, and at lower hs-cTnT threshold in non-dynamic hs-cTnT elevation. Differences compel further investigation.

Monocyte chemotactic protein (MCP)-1 (CCL2) and its receptor (CCR2) are elevated in chronic heart failure facilitating lung monocyte infiltration and differentiation which may contribute to lung fibrosis.

BACKGROUND: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung. METHODS: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls. RESULTS: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-ß. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF. CONCLUSION: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea.

The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial.

BACKGROUND: In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI. METHODS: We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization. RESULTS: Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P=0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different. CONCLUSIONS: In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Sacubitril/valsartan versus ramipril for patients with acute myocardial infarction: win-ratio analysis of the PARADISE-MI trial.

AIM: The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analysing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE-MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction. METHODS AND RESULTS: We conducted a post-hoc analysis of the PARADISE-MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline-recommended therapy. The principal composite outcome was analysed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical events classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analysed by the unmatched win-ratio method. A win ratio that exceeds 1.00 reflects a better outcome. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril/valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins (1 265 767 [15.7%]) than losses (1 079 502 [13.4%]) in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI] 1.03-1.33; p = 0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI 0.96-1.30; p = 0.16). CONCLUSION: In this post-hoc analysis of the PARADISE-MI trial using the win ratio and including investigator-identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high-risk survivors of acute myocardial infarction.

Consensus statement on the current pharmacological prevention and management of heart failure.

INTRODUCTION: This consensus statement of Australian clinicians provides new recommendations for the pharmacological management of heart failure based on studies reported since the publication of the 2018 Australian heart failure guidelines. MAIN RECOMMENDATIONS: ▪Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors to prevent hospitalisation for heart failure in type 2 diabetes mellitus can be extended to patients with multiple cardiovascular risk factors, albuminuric chronic kidney disease, or atherosclerotic cardiovascular disease. ▪New evidence supports the use of a mineralocorticoid receptor antagonist (finerenone) to prevent heart failure in type 2 diabetes mellitus associated with albuminuric chronic kidney disease. ▪In addition to renin angiotensin system inhibitors (angiotensin receptor neprilysin inhibitor preferred), beta blockers and mineralocorticoid receptor antagonists, an SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in all patients with heart failure with reduced left ventricular ejection fraction (LVEF ≤ 40%) (HFrEF). Lower quality evidence supports these therapies in patients with heart failure with mildly reduced LVEF (41-49%) (HFmrEF). ▪A soluble guanylate cyclase stimulator (vericiguat), selective cardiac myosin activator (omecamtiv mecarbil) and, if iron deficient, intravenous iron (ferric carboxymaltose) provide additional benefits in persistent HFrEF. ▪An SGLT2 inhibitor (empagliflozin) should be considered in patients with heart failure with preserved LVEF (≥ 50%) (HFpEF). Key changes in management from this statement: This document broadens the scope of angiotensin receptor neprilysin inhibitor use in patients with HFrEF and HFmrEF. SGLT2 inhibitor use expands to become a cornerstone therapy in HFrEF, with increasing evidence to support its use in HFmrEF and HFpEF.

Impact of Surgical and Transcatheter Aortic Valve Replacement on Frailty Score.

OBJECTIVE: Frailty is common in the aortic stenosis (AS) population and impacts outcomes after both transcatheter and surgical aortic valve replacement (TAVR and sAVR, respectively). Frailty can significantly impact the decision regarding the suitability of a patient for aortic valve intervention, with frail patients often excluded. Since many frailty tools use indicators which may be influenced by AS itself, some of which are subjectively symptom driven, we sought to determine the impact of intervention on frailty scores. METHODS: A prospective, observational cohort study included patients being assessed for aortic valve (AV) intervention with either TAVR or sAVR due to severe aortic stenosis. Patients were assessed for symptoms at baseline, and 1- and 6-months post intervention subjectively, using the New York Heart Association (NYHA) class and the Kansas City Cardiomyopathy Questionnaire (KCCQ), and objectively, using a 6-minute walk test (6MWT). These were compared with frailty at baseline and final review using the Fried Frailty Scale (FFS). RESULTS AND CONCLUSIONS: Sixty-six (66) patients completed pre- and post-intervention reviews. The mean FFS score was significantly lower, indicating less frailty, at 6 months relative to pre procedure (1.18 vs 1.73, p=0.002). This correlated with the change in symptoms (p<0.001). Between intervention groups, the final mean FFS of both groups decreased significantly, with TAVR to 1.33 (p=0.030) and sAVR to 0.8 (p=0.015). There was no difference in the degree of improvement between interventions (p=0.517). Aortic valve intervention improves frailty scores in both TAVR and sAVR treated patients.

Accuracy of Highly Limited Echocardiographic Screening Images for Determining a Structurally Normal Heart: The Quick-Six Study.

INTRODUCTION: Experienced echocardiographers can quickly glean diagnostic information from limited echocardiographic views. The use of limited cardiac ultrasound, particularly as a screening tool, is increasing. During the COVID-19 pandemic, limited cardiac ultrasound has the major advantage of reducing exposure time between sonographer and patient. The sensitivity and negative predictive value of a "screening" echocardiogram with highly limited views is uncertain. AIM/METHOD: We examined the accuracy of limited echocardiography in 203 consecutive, de novo studies. We used six images: parasternal long axis, with colour Doppler over the mitral valve, and aortic valve, and apical four-chamber with colour Doppler over the mitral valve, and tricuspid valve. We compared the interpretation of 12 subjects with the final echocardiogram report, (gold standard). The subjects comprised four experienced echocardiography-specialised cardiologists, four experienced cardiologists with non-imaging subspecialty interests, and four senior cardiac sonographers. Studies were graded as: (1) normal or (2) needs full study (due to inadequate images or abnormality detected). Sensitivity, specificity, negative predictive value, positive predictive value and accuracy are reported. RESULTS: Forty-one per cent (41%) of studies were normal by the gold standard report. Overall, a screening echocardiogram had a sensitivity of 71.2%, specificity of 57.1% to detect an abnormal echocardiogram, negative predictive value 58.4%, positive predictive value of 70.2%, and accuracy of 65.4%. When inadequate images were excluded, overall accuracy was nearly identical at 64.6%. The overall accuracy between the three groups of interpreters was similar: 66.5% (95% CI 63.1-69.7) for echocardiography-specialised cardiologists, 65.3% (95% CI 61.9-68.5) for non-echocardiography specialised cardiologists, and 64.4% (95% CI 61.0-67.7) for sonographers. These groups are all highly experienced practitioners. There was no difference in sensitivity or specificity comparing echocardiography-specialised cardiologists with cardiologists of other subspecialty experience. Comparing cardiologists to sonographers, cardiologists had lower sensitivity (echocardiography specialists 67.6%, 95% CI 63.2-71.8, non-echocardiography specialists 62.0%, 95% CI 57.4-66.4) compared to sonographers (84.0% [95% CI 80.4-87.2, p<0.05]), but cardiologists had higher specificities (64.9% [95% CI 59.5-70.0] for the echocardiography specialists, and 69.9% [95% CI 64.7-74.8] for non echocardiography specialists), compared to 36.6% (95% CI 31.4-42.0, p<0.05) for the sonographer group. When looking at only the studies considered to be interpretable, cardiologists had higher positive predictive value (echocardiography specialists 73.7%, 95% CI 69.0-78.1, non echocardiography specialists 74.1%, 95% CI 68.8-79.9), as compared to sonographers (64.3%, 95% CI 59.8-68.5%). CONCLUSIONS: Limited cardiac ultrasound as a screening tool for a normal heart had a sensitivity of only 71%, when performed and interpreted by experienced personnel, raising questions regarding the safety of this practice. Caution is especially recommended in extrapolating its use to non-specialised settings.

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Acute pleiotropic effects of dapagliflozin in type 2 diabetic patients with heart failure with reduced ejection fraction: a crossover trial.

AIMS: This study aimed to explore the rapid effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We studied the functional, echocardiographic, electrophysiological, lung ultrasound, ambulatory blood pressure (BP), microvascular and macrovascular function, and biochemical effects of 2 week treatment with dapagliflozin in 19 type 2 diabetic HFrEF patients in a double-blind, crossover, placebo-controlled trial. Dapagliflozin had no significant effect on clinical, functional, or quality of life parameters. Dapagliflozin reduced systolic BP [114 (105, 131) vs. 106 (98, 113) mmHg, P < 0.01] and diastolic BP [71 (61, 78) vs. 62 (55, 70) mmHg, P < 0.01]. There was no effect on cardiac chamber size, ventricular systolic function, lung ultrasound, or arterial wave reflection. Dapagliflozin increased creatinine [117 (92, 129) vs. 122 (107, 135) µmol/L, P < 0.05] and haemoglobin [135 (118, 138) vs. 136 (123, 144) g/L, P < 0.05]. There was a reduction in ventricular ectopy [1.4 (0.1, 2.9) vs. 0.2 (0.1, 1.4) %, P < 0.05] and an increase in standard deviation of normal heart beat intervals [70 (58, 90) vs. 74 (62, 103), P < 0.05]. Unexpectedly, dapagliflozin increased high-sensitivity troponin T [25 (19, 37) vs. 28 (20, 42) ng/L, P < 0.01] and reduced reactive hyperaemia index [1.29 (1.21, 1.56) vs. 1.40 (1.23, 1.84), P < 0.05]. CONCLUSIONS: After 2 weeks, while multiple parameters supported BP reduction and haemoconcentration with dapagliflozin, reduction in cardiac filling pressure, lung water, and functional improvement was not shown. Reduced ventricular ectopic burden suggests an early antiarrhythmic benefit. The small increase in troponin T and the reduction in the reactive hyperaemia index warrant further mechanistic exploration in this treatment of proven mortality benefit in HFrEF.

Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

BACKGROUND: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited. METHODS: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance. CONCLUSIONS: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Right ventricular myocardial deoxygenation in patients with pulmonary artery hypertension.

BACKGROUND: In pulmonary arterial hypertension (PAH), progressive right ventricular (RV) dysfunction is believed to be largely secondary to RV ischaemia. A recent pilot study has demonstrated the feasibility of Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) to detect in-vivo RV myocardial oxygenation. The aims of the present study therefore, were to assess the prevalence of RV myocardial ischaemia and relationship with RV myocardial interstitial changes in PAH patients with non-obstructive coronaries, and corelate with functional and haemodynamic parameters. METHODS: We prospectively recruited 42 patients with right heart catheter (RHC) proven PAH and 11 healthy age matched controls. The CMR examination involved standard functional imaging, OS-CMR imaging and native T1 mapping. An ΔOS-CMR signal intensity (SI) index (stress/rest signal intensity) was acquired at RV anterior, RV free-wall and RV inferior segments. T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at the inferior RV segment. RESULTS: The inferior RV ΔOS-CMR SI index was significantly lower in PAH patients compared with healthy controls (9.5 (- 7.4-42.8) vs 12.5 (9-24.6)%, p = 0.02). The inferior RV ΔOS-CMR SI had a significant correlation to RV inferior wall thickness (r = - 0.7, p < 0.001) and RHC mean pulmonary artery pressure (mPAP) (r = - 0.4, p = 0.02). Compared to healthy controls, patients with PAH had higher native T1 in the inferior RV wall: 1303 (1107-1612) vs 1232 (1159-1288)ms, p = 0.049. In addition, there was a significant difference in the inferior RV T1 values between the idiopathic PAH and systemic sclerosis associated PAH patients: 1242 (1107-1612) vs 1386 (1219-1552)ms, p = 0.007. CONCLUSION: Blunted OS-CMR SI suggests the presence of in-vivo microvascular RV dysfunction in PAH patients. The native T1 in the inferior RV segments is significantly increased in the PAH patients, particularly among the systemic sclerosis associated PAH group.

Impact of increased augmentation index and valvuloarterial impedance on symptom recovery after aortic valve replacement for severe aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is a common valvular disorder with a large symptomatic burden resulting from increased myocardial workload due to valvular obstruction. The contribution of increased afterload from arterial stiffness on symptoms is uncertain. The purpose of this analysis was to determine the symptomatic impact of arterial stiffness as determined by Applanation Tonometry. METHODS: Eighty-eight patients with severe AS undergoing intervention with transcatheter aortic valve replacement (TAVR) (n = 65) or surgical aortic valve replacement (SAVR) (n = 23) were prospectively enrolled. Symptoms were recorded using the NYHA Class, Kansas City Cardiomyopathy Questionnaire (KCCQ) and a 6 min walk test (6MWT) at baseline, and 1- and 6-months post intervention. Pulse Wave Analysis (PWA) using Applanation Tonometry was performed at all reviews, including the augmentation index (AIx). RESULTS: Patients undergoing TAVR were older, with worse renal function and lower aortic valve areas, but were otherwise similar. There was no significant difference between the augmentation index of our AS population compared with an age matched reference population (p = 0.89).Symptoms significantly improved after intervention according to NYHA Class, KCCQ and 6MWT. Additionally, with adjustment, the initial augmentation index correlated with the final KCCQ (Coeff. = -0.383, p = 0.02) and NYHA Class (Coeff. = 0.012, p = 0.03) and a baseline AIx value in the top quartile resulted in a significantly worse final KCCQ (95.1 v 85.2, p = 0.048) relative to the bottom 3 quartiles. CONCLUSIONS: According to our analysis, an elevated baseline AIx is associated with a poorer symptomatic recovery after aortic valve intervention and so is worthy of consideration when assessing potential symptomatic benefit.

Systemic Markers of Monocyte Activation in Acute Pulmonary Oedema.

BACKGROUND: Hydrostatic lung injury followed by pulmonary remodelling variably complicates cardiogenic acute pulmonary oedema (APO). Pulmonary remodelling may be regulated by the balance between distinct phenotypes of pulmonary macrophages; activated/inflammatory (M1), and reparative/anti-inflammatory (M2), derived from circulating monocyte populations. The aim of this study was to identify biomarkers in peripheral blood that are consistent with hydrostatic lung injury and pulmonary remodelling in APO and which follow the variable clinical course. METHODS: To examine peripheral markers of lung inflammation, resolution and remodelling, 18 patients, admitted to the intensive care unit (ICU) with a clinical diagnosis of APO, were enrolled. Admission, 12- and 24-hour post-admission bloods were assayed for cytokines by ELISA (R&D Systems, Minneapolis, MN, USA) and leukocyte surface markers by flow cytometry. RESULTS: Admission PaO2 to FiO2 ratio was positively correlated with Mon 2 (intermediate) monocyte prevalence, through increasing ratio of CD16+ monocytes to CD11b+ and CD40+ monocytes, and negatively correlated with Mon 1 (classical) monocyte prevalence, through decreasing ratio of CD16+ monocytes to CD62L+. Secondary cohort analysis compared 10 APO patients with established chronic heart failure (CHF) to eight without CHF. An increase in monocyte chemotactic peptide (MCP)-1, monocyte prevalence, and CD16-CD62L+ monocytes with CHF, all characteristic of monocyte activation to a Mon 1 phenotype, were found in the CHF APO patients. CONCLUSIONS: Increased systemic monocyte prevalence and expression of cell surface markers suggest a Mon 1 profile in CHF patients during episodes of APO. Future studies should define the role of systemic monocyte prevalence and activation in decompensated CHF.