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Objectives: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials., Background: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF)., Methods: Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo., Results: A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m 2 ; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF., Conclusions: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213])., Competing Interests: Funding Support and Author Disclosures The DELIVER study was funded by AstraZeneca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr De Boer’s institution, the UMCG, has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). Dr DeMets has received consulting fees from Frontier Science, Actelion, Bristol Myers Squibb, Medtronic, Boston Scientific, GlaxoSmithKline, and Merck; and has received consulting fees and is the owner of DL DeMets Consulting. Dr Hernandez has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Myokardia, Merck, Novartis, and Vifor. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and non-executive director of Us2.ai. Dr Martinez has received personal fees from AstraZeneca. Drs Shah and Belohjavek have received either personal or institutional research support for DELIVER from AstraZeneca. Dr Chiang has received honoraria and consultation fees from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. Dr Borleffs has received speaker fees and institutional research support from AstraZeneca; has received speaker fees from Novartis; and has received institutional research support from Boehringer Ingelheim. Dr Comin-Comet has received personal and institutional financial support for the DELIVER study from AstraZeneca; outside this work, he has received fees for speaking and fees for consultancy from Boehringer Ingelheim, Novartis, Orion Pharma, and Vifor Pharma; and he has received research grants from Novartis, Orion Pharma, and Vifor Pharma. Dr Dobreanu has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Drozdz has received personal and institutional research support for DELIVER from AstraZeneca. Dr Fang has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Gamba has received personal fees from Sanfer, Roche, Amgen, Asofarma, Sanofi, AstraZeneca, Eli Lilly, Boehringer, Bristol Myers Squibb, Bayer, Pfizer, Merck, Abbott, Silanes, Servier, Jansen Cilag, Medtronic, and Boston Scientific. Drs Al Habeeb, Han, Cabrera, Janssens, Vardeny, and Nguyen have received either personal or institutional research support for DELIVER from AstraZeneca. Dr Katova has received fees for serving as national coordinator from Novartis and AstraZeneca. Dr Kitakaze has received support for the present manuscript (funding, provision of study materials, medical writing, article processing charges, etc) from AstraZeneca, has received grants or contracts from the Japanese government through the Japan Agency for Medical Research and Development Japan Heart Foundation, and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Ono, Novartis, Tanabe-Mitsubishi, Japan Medical Data Center, Takeda, Pfizer, Daiichi-Sankyo, Otsuka, Sanofi, Boehringer Ingelheim, Amgen, Kowa, Toyama-Kagaku, Kureha, Viatris, and Mochida. Dr Merkely has received personal fees from AstraZeneca and Servier. Dr O’Meara has served as a consultant and speaker for AstraZeneca, Bayer, Boehringer Ingelheim, and Novartis; has served as a steering committee member or a national lead investigator with contracts between her institution (Montreal Heart Institute Research Center) and American Regent, AstraZeneca, Cytokinetics, Merck, and Novartis; and has ongoing clinical trial participation with Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi. Dr Kerr Saraiva has received research grant support from Pfizer, Daichii Sankyo, Sanofi, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Janssen, Amgen, and Novartis; and has received honorarium from Boehringer Ingelheim, Novo Nordisk, Astra Zeneca, and Amgen. Dr Tereshchenko has received personal fees from Servier, AstraZeneca, Pfizer, Novartis, and Boehringer Ingelheim. Dr Thierer has received support for lectures and advisory boards from AstraZeneca, Boehringer Ingelheim, and Pfizer. Dr Verma has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Drs Wilderäng, Zaozerska, Lindholm, and Petersson are employees and shareholders of AstraZeneca. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure., Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed., Findings: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group., Interpretation: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death., Funding: Vifor Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Coronary flow reserve (CFR) is impaired in non-ischemic dilated cardiomyopathy (DCM). Mechanisms by which such impairment occurs are still unknown, but cofactors such as diastolic compressive force, left ventricular hypertrophy, and microvascular disease have been implied. In order to characterize the determinants of CFR in non-ischemic DCM, we evaluated 110 non-ischemic DCM patients (58 men; age=61+/-12 years) and 21 age- and gender-matched control patients (14 men; age=59+/-13 years) by transthoracic (n=88) or transesophageal (n=22) dipyridamole (0.84 mg/ kg in 10') stress echocardiography. All patients showed angiographically normal coronary arteries. Non-ischemic DCM patients had an ejection fraction <45% while control patients had normal left ventricular systolic function. CFR was assessed on LAD by pulsed Doppler as the ratio of maximal vasodilation (dipyridamole) to rest peak diastolic coronary flow velocity. Mean CFR value was 2.0+/-0.6 for DCM patients and 3.2+/-0.5 for controls (p<0.01). At individual non-ischemic DCM patient analysis, 46 patients had normal CFR> or =2 (Group 1) and 64 patients had abnormal CFR<2 (Group 2). On univariate analysis, CFR reduction correlated with NYHA functional class (r=-0.33, p=0.001), left ventricular ejection fraction ( r=0.23, p=0.02), end-systolic volume (r=-0.23, p=0.02), systolic pulmonary artery pressure (r=-0.42, p=0.0001), deceleration time (r=0.24, p=0.02). Logistic multiregression analysis showed that only NYHA functional class significantly and negatively correlated with CFR (odds ratio=0.9; 95% confidence intervals: 0.03-.35, p=0.0001). In patients with non-ischemic DCM, CFR is reduced but with substantial individual variability, only partially accounted for by level of systolic and diastolic dysfunction. The clinical functional class is the strongest predictor of CFR reduction in these patients, with lowest flow reserve found in more advanced NYHA class.

Background: The choice of invasive or noninvasive strategy for low risk patients with unstable angina is a challenge., Objectives: To investigate the impact of clinical factors on adverse outcomes in patients receiving successful medical treatment and referred from the hospital without invasive procedures., Methods: The study group consisted of 166 patients (54% men, age 63+/-11 years) who were discharged symptom free after pharmacological treatment of unstable angina. The authors analyzed demographic, clinical, electrocardiographic, echocardiographic and laboratory parameters., Results: During two years of follow-up, the mortality rate was 4.2%. A composite end point (coronary disease hospitalization, recurrent unstable angina, necessity for revascularization or death) occurred in 99 patients (60%). In multivariate logistic regression, the Canadian Cardiovascular Society (CCS) class (P=0.015) and the left ventricular ejection fraction (P=0.01) were independently predictive for the adverse events. A scoring system was proposed for simple risk stratification, with one point assigned to the patient for CCS class III or IV and left ventricular ejection fraction below 40%, thus yielding a score in the range of 0 to 2. The adverse event rates for total scores of 0, 1 and 2 were 37%, 64% and 86%, respectively., Conclusions: Uncomplicated follow-up in medically treated patients with unstable angina is rare. Patients with CCS class III and IV or left ventricular ejection fraction below 40% have particularly high rates of recurrent ischemia.

Objectives: The aim of this study was to assess the relations between the circadian variations of blood pressure (BP) and the pattern of ischemia and autonomic activity in normotensive and hypertensive patients with coronary artery disease (CAD)., Patients and Methods: On the basis of the results of ambulatory BP monitoring, 115 patients with stable CAD were divided into Group 1 (with arterial hypertension) and Group 2 (normotensives). Groups were subdivided into dippers and non-dippers. Holter monitoring was performed to assess the occurrence and circadian pattern of ischemic episodes. Time domain and frequency domain HRV analyses were performed to evaluate the autonomic activity., Results: The total number of ischemic episodes was similar in dippers and non-dippers. Non-dippers had a greater number of silent episodes and a different circadian pattern of ischemia with more night episodes. Among the time-domain HRV parameters, only SDNN was similar in dippers and non-dippers. Non-dippers had lower pNN50 and rMSSD-the parameters expressing parasympathetic activity. Differences between diurnal and nocturnal results of spectral HRV analysis were observed in dipper patients only. They presented an elevation of HF power and a decline of LF power at night. All differences between dippers and non-dippers were of similar significance in both hypertensives and normotensives., Conclusions: A lack of a nocturnal fall in BP is present in normotensive and hypertensive patients with CAD. Non-dippers with CAD had silent and nighttime ischemia more often. They also had an abnormal pattern of autonomic activity with higher sympathetic and lower parasympathetic modulation.

Study Objectives: Dobutamine echocardiography is widely used for the evaluation of myocardial contractile reserve. The purpose of the study was to determine the prognostic value of low-dose dobutamine echocardiography in patients with idiopathic dilated cardiomyopathy (IDCM)., Patients: The study group consisted of 77 consecutive patients with recently diagnosed IDCM (mean [+/- SD] age, 49 +/- 9 years; men, 82%) and left ventricular (LV) ejection fractions of < 40%., Interventions: Two-dimensional and Doppler echocardiographic variables were measured before and after the infusion of dobutamine at the rate of 10 microg/kg/min for 5 min., Measurements and Results: During a mean follow-up period of 63 +/- 7 months (range, 49 to 75 months) 30 patients (39%) died and five patients (6%) underwent successful heart transplantations. Using multivariate regression analysis, the only significant factors related to fatal outcome or the need for cardiac transplantation were the following: (1) LV end-systolic volume of > 150 mL after low-dose dobutamine infusion (odds ratio [OR], 2.2; confidence interval [CI], 1.2 to 4.1; p = 0.011); (2) no decrease of LV end-diastolic volume after dobutamine infusion (OR, 1.9; CI, 1.1 to 3.4; p = 0.031); (3) atrial fibrillation (OR, 2.7; CI, 1.4 to 5.3; p = 0.003); and (4) male gender (OR, 2.6; CI, 1.2 to 5.5; p = 0.017). A scoring system was proposed with one point assigned for each of the above-mentioned factors. The mortality rates for total scores of 0, 1, 2, 3, and 4 were 0%, 19%, 48%, 83%, and 100%, respectively., Conclusion: The response of the LV to low-dose dobutamine infusion adds clinically valuable prognostic information to the evaluation of the patient with IDCM.

The aim of the study was to assess the influence of aortic valve replacement on left ventricular size and muscle hypertrophy according to the type of preexisting valve disease (aortic stenosis, insufficiency or combined disease). The study group consisted of 143 consecutive patients (pts) after aortic valve replacement (109 men, 34 women, mean age 48.1 +/- 10.9 years). Reason for the operation was aortic stenosis in 35 pts, aortic insufficiency in 64 pts and combined disease in 44 pts. Echocardiography was performed before surgery, 1 month and 1 year after operation, and yearly during 5-year follow-up. Transvalvular aortic pressure gradients decreased significantly after valve replacement in all subsets without further changes during follow-up (Pmax (mmHg): from 54.2 +/- 20.7 to 17.9 +/- 9.6 in combined disease pts, from 72.3 +/- 19.9 to 21.6 +/- 14.6 in aortic stenosis and from 34.5 +/- 24.2 to 15.6 +/- 11.3 in aortic insufficiency pts, respectively, P < 0.0005). One year after surgery the diastolic dimension of the left ventricle decreased significantly in all subjects, whereas the systolic dimension only in aortic insufficiency and combined disease pts (from 44 +/- 11.8 to 31.6 +/- 5.4 mm, P < 0.001 and from 41.9 +/- 11.5 to 33 +/- 6.7 mm, P < 0.05, respectively). Further decrease of both diastolic and systolic dimensions was observed only in the aortic insufficiency group. Ejection fraction of left ventricle increased only in combined disease pts (from 51.6 +/- 10% to 56.8 +/- 8.2%, P < 0.05). Wall thickness of the left ventricle decreased 1 year after valve replacement only in the aortic stenosis group and in further follow-up in the aortic stenosis and combined disease group. Normalization of left ventricular size is observed in more than 90% of patients during 5-year follow-up as opposed to left ventricular muscle hypertrophy, regressed only in less than a half of the study population. In patients with aortic valve disease the greatest hemodynamic improvement is observed 1 year after valve replacement. This is expressed by marked reduction of the left ventricular dimensions and wall thickness, without significant improvement of the ejection fraction. Further regression of left ventricle dimensions occurs in patients operated on due to predominant valve insufficiency, whereas regression of left ventricular hypertrophy is observed in patients with preexisting valvular stenosis.