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Routine use of natriuretic peptides: Lessons from a big data analysis.
Goudot, FX, Msadek, S, Boukertouta, T, Schischmanoff, PO, Meune, C
Annals of clinical biochemistry. 2021;(5):481-486
Abstract
BACKGROUND Natriuretic peptides have broad indications during heart failure and the detection of left ventricular dysfunction in high-risk patients. They can also be used for the diagnosis/management of other cardiac diseases. However, very little is known regarding their use in routine practice. METHODS We examined all biological tests performed from February 2010 to August 2015 in two districts from the French Brittany, covering 13,653 km2 and including 22,265 physicians. We report the settings and conditions of N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements (the only locally natriuretic peptide available). RESULTS From a total of 3,606,432 tests requested in 557,650 adult (older than 20 years) patients, only 56,653 (1.6%) included at least one NT-proBNP measurement. NT-proBNP measurements gradually increased, from 9188 in 2011 to 12,938 in 2014 (P < 0.001). Most NT-proBNP tests were measured in urban laboratories (72.7%) and in private (62.9%) non-hospital/clinics laboratories; they were mostly ordered by general practitioners (66% compared with 11% by cardiologists). The number of NT-proBNP measurements increased with age up to 80-90 years, and 70.3% of tests were measured in ≥75 years patients. Creatinine and electrolytes were not associated with NT-proBNP in 15.8% and 19.7% of tests, respectively. CONCLUSION Among a very large cohort, we observed that natriuretic peptides remain largely undermeasured. NT-proBNP is mostly measured in elderly patients, and its interpretation may be hazardous in up to 16% of all individuals because no measurement of creatinine was associated to NT-proBNP.
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Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.
Mentz, RJ, Ambrosy, AP, Ezekowitz, JA, Lewis, GD, Butler, J, Wong, YW, De Pasquale, CG, Troughton, RW, O'Meara, E, Rockhold, FW, et al
Circulation. Heart failure. 2021;(5):e008100
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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.
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Delineating phenotypes of Kawasaki disease and SARS-CoV-2-related inflammatory multisystem syndrome: a French study and literature review.
Cherqaoui, B, Koné-Paut, I, Yager, H, Bourgeois, FL, Piram, M
Rheumatology (Oxford, England). 2021;(10):4530-4537
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OBJECTIVE To better define the clinical distinctions between the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related paediatric inflammatory multisystem syndrome (PIMS) and Kawasaki disease (KD). METHODS We compared three groups of patients: group 1, cases from our national historic KD database (KD-HIS), before the SARS-CoV-2 pandemic; group 2, patients with KD admitted to an intensive care unit (KD-ICU) from both our original cohort and the literature, before the SARS-CoV-2 pandemic; and group 3, patients with PIMS from the literature. RESULTS KD-HIS included 425 patients [male:female ratio 1.3, mean age 2.8 years (s.d. 2.4)], KD-ICU 176 patients [male:female ratio 1.3, mean age 3.5 years (s.d. 3.1)] and PIMS 404 patients [male:female ratio 1.4, mean age 8.8 years (s.d. 3.7)]. As compared with KD-HIS patients, KD-ICU and PIMS patients had a higher proportion of cardiac failure, digestive and neurological signs. KD-ICU and PIMS patients also had a lower frequency of typical KD-mucocutaneous signs, lower platelet count, higher CRP and lower sodium level. As compared with KD-HIS and KD-ICU patients, PIMS patients were older and more frequently had myocarditis; they also had fewer coronary abnormalities and lower sodium levels. Unresponsiveness to IVIG was more frequent in KD-ICU than KD-HIS and PIMS patients. CONCLUSION On clinical grounds, KD-HIS, KD-ICU and PIMS might belong to a common spectrum of non-specific pathogen-triggered hyperinflammatory states. The causes of increasing inflammation severity within the three entities and the different effects on the heart remain to be determined.
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Efficacy of Sacubitril-Valsartan in Patients With Reduced Left Ventricular Ejection Fraction.
Briasoulis, A, Kuno, T, Ueyama, H
The American journal of cardiology. 2021;:150-152
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Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction.
Berg, DD, Jhund, PS, Docherty, KF, Murphy, SA, Verma, S, Inzucchi, SE, Køber, L, Kosiborod, MN, Langkilde, AM, Martinez, FA, et al
JAMA cardiology. 2021;(5):499-507
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IMPORTANCE Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies. OBJECTIVE To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization. DESIGN, SETTING, AND PARTICIPANTS This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment. EXPOSURES None. MAIN OUTCOMES AND MEASURES Composite of cardiovascular death or worsening HF. RESULTS A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, -1.9% to 6.1%), 4.1% (95% CI, -3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend). CONCLUSIONS AND RELEVANCE In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT03036124.
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Comparison of clinical characteristics of patients with heart failure and preserved ejection fraction with atrial fibrillation versus sinus rhythm: Insights from the APOLLON registry.
Özlek, B, Özlek, E, Tekinalp, M, Kahraman, S, Zencirkiran Agus, H, Başaran, Ö, Kaya, BC, Rencüzoğulları, İ, Mert, KU, Çakır, O, et al
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2020;(3):234-245
Abstract
OBJECTIVE The aim of this study was to assess the clinical characteristics of patients with heart failure and preserved ejection fraction (HFpEF) and atrial fibrillation (AF) and compare them with those of HFpEF patients without AF. METHODS This study was a sub-group analysis of a multicenter, observational, and cross-sectional registry conducted in Turkey (ClinicalTrials.gov identifier: NCT03026114). Patients with HFpEF were divided into 2 groups: HFpEF with AF and HFpEF with sinus rhythm (SR), and the clinical characteristics of the groups were compared. RESULTS In a total of 819 HFpEF patients (median age: 67 years; 58% women), 313 (38.2%) had AF. Compared to the patients with SR, those with AF were older (70 years vs 66 years; p<0.001) and more symptomatic, with a higher rate of classification as New York Heart Association functional class III-IV, paroxysmal nocturnal dyspnea, orthopnea, palpitations, fatigue, pulmonary crepitations, and peripheral edema. The hospitalization rate for heart failure was higher (28.4% vs 12.6%; p<0.001) in patients with AF, and participants with AF had higher level of N-terminal pro-B-type natriuretic peptide (887 pg/mL vs 394.8 pg/mL; p<0.001) and higher left atrial volume index level. Patients without AF had a higher burden of diabetes mellitus, obstructive sleep apnea, and coronary artery disease. The prescription rate of nondihydropyridine calcium blockers, digoxin, loop diuretics, and anticoagulant drugs was higher in the AF group. CONCLUSION The results of this study revealed that in a large Turkish cohort with HFpEF, significant clinical differences were present between those with and without AF and. Further prospective studies are needed to clarify the prognostic implications of AF in this growing heart failure population in our country.
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Pregnancy complications in chronic hypertensive patients are linked to pre-pregnancy maternal cardiac function and structure.
Vasapollo, B, Novelli, GP, Gagliardi, G, Farsetti, D, Valensise, H
American journal of obstetrics and gynecology. 2020;(3):425.e1-425.e13
Abstract
BACKGROUND Chronic hypertension complicates around 3% of all pregnancies and is associated with an increased risk for pregnancy complications such as superimposed preeclampsia, fetal growth restriction, preterm delivery, and stillbirth, reaching a rate of complications of up to 25-28%. OBJECTIVE We performed an echocardiographic study to evaluate pre-pregnancy cardiac geometry and function, along with the hemodynamic features of treated chronic hypertension patients, searching for a possible correlation with the development of feto-maternal complications and with pre-pregnancy therapy. MATERIALS AND METHODS This was a prospective observational cohort study of 192 consecutive patients receiving treatment for chronic hypertension (calcium channel blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, α1-adrenoceptor antagonists, and/or diuretics). Patients underwent echocardiography before pregnancy, assessing left ventricular morphology and function, cardiac output, and total vascular resistance. Pre-pregnancy therapy was noted, patients were shifted to α-methyldopa right before pregnancy, and were followed until delivery, noting major early (<34weeks' gestation) and late (≥34 weeks' gestation) complications. Comparisons among the 3 groups (ie, those with no complications, early complications, and late complications) were performed with 1-way analysis of variance with Student-Newman-Keuls correction for multiple comparisons. The Mann-Whitney U test was used for non-normally distributed data. Comparison of proportions was used as appropriate. Receiver operating characteristic curve analysis was used to identify cutoff values of diastolic dysfunction in this population using the E/e' ratio, and separate cutoff of values for total vascular resistance for the prediction of early and late complications of pregnancy. Binary univariate and multivariate logistic regression as well as Cox proportional hazards regression were used to evaluate the possible correlation among angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and/or calcium channel blocker pre-pregnancy therapy, cardiovascular features, and the risk for subsequent early and late complications of pregnancy. RESULTS Of 192 patients, 141 had no complications, and 51 had a complicated pregnancy (24 had early complications and 27 had late complications). Concentric geometry was more frequent in those women with early versus late and no complications (50% vs 13.5% and 11.1%, respectively; P < .05), whereas eccentric hypertrophy was more represented in women with late versus early and no complications (32% versus 12.5% and 1.4%, respectively; P < .05). The receiver operating characteristic curve showed an E/e' ratio value >7.65 (sensitivity, 59.6%; specificity, 68.6%) as a predictor of subsequent complications of pregnancy, whereas total vascular resistance <1048 (sensitivity, 83.7%; specificity, 55.6%) was predictive for late complications and total vascular resistance >1498 (sensitivity, 87.5%; specificity, 78.0%) for the early complications of pregnancy. Univariate analysis showed that the following parameters were predictive for complications of pregnancy: altered geometry of the left ventricle (odds ratio, 5.94; 95% confidence interval, 2.90-12.19), diastolic dysfunction (odds ratio, 3.22; 95% confidence interval, 1.63-6.37), altered total vascular resistance (odds ratio, 3.52; 95% confidence interval, 1.78-6.97), and pre-pregnancy therapy without calcium channel blockers/angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (odds ratio, 2.73; 95% confidence interval, 1.37-5.42). These parameters, except for altered total vascular resistance, were independent predictors in the multivariate analysis corrected for body mass index, heart rate, parity, and mean arterial pressure. CONCLUSION Chronic hypertension patients with pre-pregnancy cardiac remodeling and dysfunction more often develop early and late complications of pregnancy. Pre-pregnancy therapy for chronic hypertension patients with calcium channel blockers and/or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers may positively influence cardiac profiles and the outcome of a future pregnancy with a reduced rate of complications.
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New pharmacotherapy for heart failure with reduced ejection fraction.
Sotirakos, S, Wheen, P, Spiers, J, Armstrong, R
Expert review of cardiovascular therapy. 2020;(7):405-414
Abstract
INTRODUCTION The European Society of Cardiology (ESC), Canadian Cardiovascular Society, and the American College of Cardiology Heart Failure (HF) guidelines all currently recommend the use of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) and Beta Blockers (BB) in the treatment of HF with a reduced ejection fraction (HFrEF). Newer medications targeting combining an ARB with a neprilysin inhibitor (ARNI) sacubitril/valsartan have shown benefits in mortality and can be used in place of an ACE inhibitor or an ARB. Additionally, dapagliflozin, a medication targeting the sodium-glucose cotransporter 2 (SGLT2) can be used in addition to current therapies. AREAS COVERED This review provides a comprehensive analysis of the evidence around the new pharmacotherapies for HFrEF, specifically, sacubitril/valsartan and dapagliflozin. A comprehensive review of the literature using keywords such as heart failure with reduced ejection fraction, angiotensin receptor, neprilysin inhibitor, and sodium glucose transporter was conducted within the National Centre for Biotechnology Information (NCBI) and Google Scholar databases. The reference sections of articles were also examined to find additional articles. EXPERT OPINION Sacubitril/valsartan and dapagliflozin both show marked benefits on mortality in HFrEF patients. More research needs to be conducted on the mechanisms of action on disease modification.
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Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial.
Jensen, J, Omar, M, Kistorp, C, Poulsen, MK, Tuxen, C, Gustafsson, I, Køber, L, Gustafsson, F, Faber, J, Fosbøl, EL, et al
American heart journal. 2020;:47-56
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AIMS: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor empagliflozin on N-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS Empire HF was an investigator-initiated, multi-center, double-blinded, placebo-controlled, randomized trial. Patients with mildly symptomatic HFrEF, mean (standard deviation (SD)) age 64 (11) years, 85% male, and mean left ventricular ejection fraction 29% (8), on recommended HF therapy were assigned to receive either empagliflozin 10 mg once daily or placebo for 12 weeks. The primary endpoint was the between-group difference in the change of NT-proBNP from baseline to 12 weeks. In total, 95 patients were assigned to empagliflozin and 95 to placebo. No significant difference in the change of NT-proBNP with empagliflozin versus placebo was observed [Empagliflozin: baseline, median (interquartile range (IQR)) 582 (304-1020) pg/mL, 12 weeks, 478 (281-961) pg/mL; Placebo: baseline, 605 (322-1070) pg/mL, 12 weeks, 520 (267-1075) pg/mL, adjusted ratio of change empagliflozin/placebo 0.98; 95% confidence interval (CI) 0.82-1.11, P = 0.7]. Further, no significant difference was observed in accelerometer-measured daily activity level [adjusted mean difference of change, empagliflozin versus placebo, -26.0 accelerometer counts; 95% CI -88.0 to 36.0, P = 0.4] or Kansas City Cardiomyopathy Questionnaire Overall Summary Score [adjusted mean difference of change, empagliflozin versus placebo 0.8; 95% CI -2.3 to 3.9, P = 0.6]. CONCLUSION In low-risk patients with HFrEF with mild symptoms and on recommended HF therapy, empagliflozin did not change NT-proBNP after 12 weeks. Further, no change in daily activity level or health status was observed.
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Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.
Nassif, ME, Windsor, SL, Tang, F, Khariton, Y, Husain, M, Inzucchi, SE, McGuire, DK, Pitt, B, Scirica, BM, Austin, B, et al
Circulation. 2019;(18):1463-1476
Abstract
BACKGROUND Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.