Publications by authors named "João Pedro Ferreira"

181 Publications

Hypertension and heart failure with preserved ejection fraction: position paper by the European Society of Hypertension.

J Hypertens 2021 Jun 7. Epub 2021 Jun 7.

First Department of Cardiology, Hippokration Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy Internal Medicine Department, ICMID, Hospital Clínic, University of Barcelona, Barcelona, Spain Cardiology, Geneva University Hospitals, Geneva, Switzerland King's College London British Heart Foundation Centre, London, UK Université de Lorraine, Centre d'Investigations Cliniques Plurithématique Inserm 1433 CHRU de Nancy, Inserm U1116 FCRIN INI-CRCT, Nancy, France University Medical Centre Ljubljana, Hypertension Department, Medical University Ljubljana, Ljubljana, Slovenia Department of Hypertension, National Institute of Cardiology, Warsaw, Poland Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden Cardiology Department, Asklepeion General Hospital, Athens, Greece Cardiology Department, Klinikum Wels-Grieskirchen, Wels, Austria Økern Heart Centre Institute for Surgical Research and Department of Cardiology, Oslo University Hospital, Rikshospitalet, and University of Oslo Department of Cardiology, Oslo University Hospital Institute of Clinical Medicine, Medical Faculty, University of Oslo, and Departments of Cardiology and Nephrology, Oslo University Hospital, Ullevaal, Oslo, Norway Università Milano-Bicocca, Milan; Policlinico di Monza, Monza, Italy Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.

Hypertension constitutes a major risk factor for heart failure with preserved ejection fraction (HFpEF). HFpEF is a prevalent clinical syndrome with increased cardiovascular morbidity and mortality. Specific guideline-directed medical therapy (GDMT) for HFpEF is not established due to lack of positive outcome data from randomized controlled trials (RCTs) and limitations of available studies. Although available evidence is limited, control of blood pressure (BP) is widely regarded as central to the prevention and clinical care in HFpEF. Thus, in current guidelines including the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers provides the backbone of BP-lowering therapy in hypertensive patients. Although superiority of RAS blockers has not been clearly shown in dedicated RCTs designed for HFpEF, we propose that this core drug treatment strategy is also applicable for hypertensive patients with HFpEF with the addition of some modifications. The latter apply to the use of spironolactone apart from the treatment of resistant hypertension and the use of the angiotensin receptor neprilysin inhibitor. In addition, novel agents such as sodium-glucose co-transporter-2 inhibitors, currently already indicated for high-risk patients with diabetes to reduce heart failure hospitalizations, and finerenone represent promising therapies and results from ongoing RCTs are eagerly awaited. The development of an effective and practical classification of HFpEF phenotypes and GDMT through dedicated high-quality RCTs are major unmet needs in hypertension research and calls for action.
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http://dx.doi.org/10.1097/HJH.0000000000002910DOI Listing
June 2021

Concentration-Dependent Clinical and Prognostic Importance of High-Sensitivity Cardiac Troponin T in Heart Failure and a Reduced Ejection Fraction and the Influence of Empagliflozin: the EMPEROR-Reduced Trial.

Eur J Heart Fail 2021 May 30. Epub 2021 May 30.

Université de Lorraine, Inserm INI-CRCT, CHRU, Nancy, France.

Background: Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials.

Methods: In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (> 97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation.

Results: With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend <0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and show the least improvement in health status (as measured by the Kansas City Cardiomyopathy questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analyzed as hazard ratios or absolute risk reductions (Graphical Abstract)..

Conclusions: Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favorable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT.
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http://dx.doi.org/10.1002/ejhf.2256DOI Listing
May 2021

Dosing of losartan in men vs. women with HFrEF: the HEAAL trial.

Eur J Heart Fail 2021 May 29. Epub 2021 May 29.

INSERM, Centre d'Investigations Cliniques Plurithématique 1433, UMR 1116, CHRU de Nancy, F-CRIN INI-CRCT Cardiovascular and Renal Clinical Trialists, Université de Lorraine, France.

Background: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit.

Methods: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and Machine Learning algorithms.

Results: The mean age was 66 years and 30% of the patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses: HR (95%CI) comparing high- vs- low-dose losartan for the composite outcome of all-cause death or all-cause hospitalisation was 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women, interaction P=0.018. Female sex clustered along with older age, ischemic HF, NYHA III/IV, and eGFR<60 ml/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe HF symptoms.

Conclusions: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g., kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.
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http://dx.doi.org/10.1002/ejhf.2255DOI Listing
May 2021

Omecamtiv Mecarbil: a Personalized Treatment for Patients with Severely Impaired Ejection Fraction.

J Am Coll Cardiol 2021 May 4. Epub 2021 May 4.

Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France; Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2021.04.077DOI Listing
May 2021

Circulating levels of procollagen type I carboxy-terminal propeptide reflect myocardial fibrosis.

Eur J Heart Fail 2021 May 9. Epub 2021 May 9.

Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

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http://dx.doi.org/10.1002/ejhf.2216DOI Listing
May 2021

Perceived risk profile and treatment optimization in heart failure: an analysis from BIOlogy Study to TAilored Treatment in chronic heart failure.

Clin Cardiol 2021 May 7. Epub 2021 May 7.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.

Background: Achieving target doses of angiotensin-converting-enzyme inhibitor/angiotensin-receptor blockers (ACEi/ARB) and beta-blockers in heart failure with reduced ejection fraction (HFrEF) is often underperformed. In BIOlogy Study to TAilored Treatment in chronic heart failure (BIOSTAT-CHF) study, many patients were not up-titrated for which no clear reason was reported. Therefore, we hypothesized that perceived-risk profile might influence treatment optimization.

Methods: We studied 2100 patients with HFrEF (LVEF≤40%) to compare the clinical characteristics and adverse events associated with treatment up-titration (after a 3-month titration protocol) between; a) patients not reaching target doses for unclear reason; b) patients not reaching target doses due to symptoms and/or side effects; c) patients reaching target doses.

Results: For ACEi/ARB, (a), (b) and (c) was observed in 51.3%, 25.9% and 22.7% of patients, respectively. For beta-blockers, (a), (b) and (c) was observed in 67.5%, 20.2% and 12.3% of patients, respectively. By multinomial logistic regression analysis for ACEi/ARB, patients in group (a) and (b) had lower blood pressure and poorer renal function, and patients in group (a) were older and had lower ejection fraction. For beta-blockers, patients in group (a) and (b) had more severe congestion and lower heart rate. At 9 months, adverse events (i.e., hypotension, bradycardia, renal impairment, and hyperkalemia) occurred similarly among the three groups.

Conclusions: Patients in whom clinicians did not give a reason why up-titration was missed were older and had more co-morbidities. Patients in whom up-titration was achieved did not have excess adverse events. However, from these observational findings, the pattern of subsequent adverse events among patients in whom up-titration was missed cannot be determined.
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http://dx.doi.org/10.1002/clc.23576DOI Listing
May 2021

Influence of sex, age and race on coronary and heart failure events in patients with diabetes and post-acute coronary syndrome.

Clin Res Cardiol 2021 Apr 30. Epub 2021 Apr 30.

Centre D'Investigation Clinique-Plurithématique Inserm CIC-P 1433, Inserm U1116, CHRU Nancy hopitaux de Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, 4 Rue du Morvan, 54500, Vandoeuvre lès Nancy, France.

Background: Women, older patients and non-White ethnic groups experience a substantial proportion of acute coronary syndromes (ACS), although they have been historically underrepresented in ACS randomized clinical trials (RCTs). To assess the influence of sex, age and race on major adverse cardiovascular events (MACE) and on heart failure events, we studied patients with type 2 diabetes in a large post-ACS trial (EXAMINE).

Methods: Differences in baseline characteristics and the respective composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE) and cardiovascular death or heart failure hospitalization (HF events) were evaluated by subgroups in a cohort of post-ACS patients with diabetes, using unadjusted and adjusted Cox regression modelling.

Results: The EXAMINE trial enrolled 5380 patients with 35% aged > 65, 32% female and 27% non-White. The risk of MACE was higher in non-White compared to White patients after adjustment for potential confounding (HR = 1.35; 95% CI 1.04-1.75), but there were no significant differences by sex and age (HR = 1.03; 95% CI 0.87-1.22 for women; HR = 1.14; 95% CI 0.96-1.35 for patients ≥ 65 years). The risk of HF events was higher in non-White patients (HR = 1.56; 95% CI 1.13-2.14), and in patients aged > 65 (HR = 1.33; 95% CI 1.07-1.66) and nominally so in women (HR = 1.23; 95% CI 0.99-1.52). The additive risk of each demographic factor (women, older age and non-White race) was greater for HF events in comparison with MACE. Moreover, non-White elderly patients consistently had poorer prognosis regardless of sex.

Conclusions: Older adults, women and non-White patients with diabetes who are post-ACS are often underrepresented in RCTs. The risk for HF events was higher in older and non-White patients, with a trend towards significance in women, whereas only non-White patients (and not women and older patients) were at higher risk for MACE. Future trials should enrich enrollment of these persons at risk.
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http://dx.doi.org/10.1007/s00392-021-01859-2DOI Listing
April 2021

Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

Clin Res Cardiol 2021 Apr 23. Epub 2021 Apr 23.

Centre d'Investigation Clinique 1433 module Plurithematique, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, F-CRIN INI-CRCT Network, Universite de Lorraine, Inserm U1116, 4 rue du Morvan, 54500, Vandoeuvre les Nancy, France.

Background: Sodium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). Sodium handling is fine-tuned in the distal nephron, were eplerenone exhibits some of its pleotropic effects. Little is known about the effect of eplerenone on serum sodium and the prognostic relevance of sodium alterations in patients with MI complicated with LVSD and/or HF.

Methods: The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hyponatremia and hypernatremia were defined as sodium < 135 mmol/L or > 145 mmol/L, respectively. Linear mixed models and time updated Cox regression analysis were used to determine the effect of eplerenone on sodium changes and the prognostic importance of sodium changes, respectively. The primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV-hospitalization.

Results: A total of 6221 patients had a post-baseline sodium measurement, 797 patients developed hyponatremia (mean of 0.2 events/per patient) and 1476 developed hypernatremia (mean of 0.4 events/per patient). Patients assigned to eplerenone had a lower mean serum sodium over the follow-up (140 vs 141 mmol/L; p < 0.0001) and more often developed hyponatremia episodes (15 vs 11% p = 0.0001) and less often hypernatremia episodes (22 vs. 26% p = 0.0003). Hyponatremia, but not hypernatremia was associated with adverse outcome for all outcome endpoints in the placebo group but not in the eplerenone group (interaction p value < 0.05 for all). Baseline sodium values did not influence the treatment effect of eplerenone in reducing the various endpoints (interaction p value > 0.05 for all). Development of new-onset hyponatremia following eplerenone initiation did not diminish the beneficial eplerenone treatment effect.

Conclusion: Eplerenone induces minor reductions in serum sodium. The beneficial effect of eplerenone was maintained regardless of the baseline serum sodium or the development of hyponatremia. Sodium alterations should not refrain clinicians from prescribing eplerenone to patients who had an MI complicated with LVSD and/or HF.

Trail Registry: ClinicalTrials.gov identifier: NCT00232180. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.
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http://dx.doi.org/10.1007/s00392-021-01853-8DOI Listing
April 2021

Cognitive function assessment for personalized heart failure disease management programmes.

Eur J Heart Fail 2021 Apr 7. Epub 2021 Apr 7.

Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

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http://dx.doi.org/10.1002/ejhf.2183DOI Listing
April 2021

Blood pressure reduction and anti-hypertensive treatment choice: A post-hoc analysis of the SPRINT trial.

Clin Cardiol 2021 May 6;44(5):665-674. Epub 2021 Apr 6.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Background: Uncontrolled blood pressure (BP) increases the risk of major adverse cardiovascular events. In SPRINT an intensive versus standard BP lowering strategy resulted in a lower rate of cardiovascular events and death. Whether BP reduction only or also the choice of anti-hypertensive drugs is associated with outcomes remains to be elucidated.

Aims: We aim to study the association of BP and different anti-hypertensive drugs with several cardiovascular outcomes.

Methods: Time-updated Cox and mixed-effects models. The primary outcome was a composite of first myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death.

Results: A total of 9361 patients were included. The anti-hypertensive agents most frequently used were ACEi/ARBs, with an almost 20% higher prescription rate in the intensive arm (80% vs. 61%), followed by thiazide-type diuretics (65% vs. 42%), calcium-channel blockers (57% vs. 39%), and beta-blockers (52% vs. 26%). Mineralocorticoid receptor antagonists were rarely used (≤7% of the observations). In multivariate analysis, the use of ACEi/ARBs, especially in combination with thiazides, were independently associated with a lower primary outcome event-rate (HR [95%CI] 0.75 [0.61-0.92], p = .006), whereas a DBP <60 mmHg was independently associated with a higher event-rate (HR [95%CI] 1.36 [1.07-1.71], p = .011). SBP <120 mmHg was associated with lower rate of cardiovascular and all-cause death on intensive treatment but not on the standard arm (interaction p < .05 for both).

Conclusions: In SPRINT, an intensive therapy strategy achieving SBP <120 mmHg with a DBP ≥60 mmHg, and using ACEi/ARBs plus thiazides was associated with a lower event-rate.
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http://dx.doi.org/10.1002/clc.23591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119807PMC
May 2021

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

Eur Heart J Cardiovasc Pharmacother 2021 Apr 2. Epub 2021 Apr 2.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, 1433, U1116, France.

Background: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined.

Aims: To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone`s effect.

Methods: HOMAGE (Heart OMics in Aging) was a prospective multicenter randomized open-label blinded Endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, month 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations were used.

Results: The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5)mmHg and DBP by -3.2 (-4.8 to -1.7)mmHg (p < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP < 130/80 mmHg (36 vs. 26%; p = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionp=0.041).

Conclusion: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.
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http://dx.doi.org/10.1093/ehjcvp/pvab031DOI Listing
April 2021

Sodium-glucose co-transporter inhibitors in insulin-treated diabetes: a meta-analysis.

Eur J Endocrinol 2021 May 4;184(6):783-790. Epub 2021 May 4.

Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.

Background: Patients with insulin-treated type 2 diabetes (T2D) have a high risk of major adverse cardiovascular events. Sodium-glucose cotransporter inhibitors (SGLTi) improve outcomes without hypoglycaemic risk.

Aims: To study the effect of SGLTi in patients with T2D with and without background insulin treatment in outcome-driven RCTs.

Methods: Random effects models.

Results: A total of 54 374 patients with T2D were included in the analysis, of which 26 551 (48.8%) were treated with insulin. For 3P-MACE in patients without insulin treatment, the HR (95% CI) for the effect of SGLTi vs placebo was 0.93 (0.81-1.05), with moderate heterogeneity (I2 = 49.2%, Q statistic P = 0.11). In insulin-treated patients, the HR (95% CI) was 0.88 (0.82-0.95), without evidence of heterogeneity (I2 =0.0%, Q statistic P =0.91). The pooled effect evidenced a 10% reduction of 3P-MACE with SGLTi (HR: 0.90, 95% CI: 0.85-0.96), without SGLTi-by-insulin interaction P = 0.53. For the composite outcome of HF hospitalisation or cardiovascular death in patients without insulin treatment, the HR (95% CI) for the effect of SGLTi vs placebo was 0.77 (0.61-0.92), with marked heterogeneity (I2 = 66.8%, Q statistic P = 0.02). In insulin-treated patients, the HR (95% CI) was 0.77 (0.68-0.86), without significant heterogeneity (I2 = 31.7%, Q statistic P = 0.25). The pooled effect evidenced a 23% reduction of HF hospitalisations or cardiovascular death with SGLTi (HR: 0.77, 95% CI: 0.68-0.85), without SGLTi-by-insulin interaction P = 0.98.

Conclusion: SGLTi reduces cardiovascular events regardless of insulin use. However, the treatment effect is more homogeneous among insulin-treated patients, supporting the use of SGLTi for the treatment of patients with T2D requiring insulin for glycaemic control.
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http://dx.doi.org/10.1530/EJE-20-1484DOI Listing
May 2021

Cardio/Kidney Composite End Points: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

J Am Heart Assoc 2021 Apr 23;10(7):e020053. Epub 2021 Mar 23.

Centre d'Investigation Clinique-Plurithématique INSERM CIC-P 1433, and INSERM U1116 CHRU Nancy Brabois F-CRIN INI-CRCT Université de Lorraine Nancy France.

Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.
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http://dx.doi.org/10.1161/JAHA.120.020053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174365PMC
April 2021

Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced.

J Am Coll Cardiol 2021 Mar;77(11):1397-1407

Baylor University Medical Center, Dallas, Texas, USA; Imperial College, London, United Kingdom.

Background: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.

Objectives: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).

Methods: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.

Results: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.

Conclusions: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).
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http://dx.doi.org/10.1016/j.jacc.2021.01.044DOI Listing
March 2021

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

J Am Coll Cardiol 2021 Mar;77(11):1381-1392

Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, University Hospital, University of Lorraine, Nancy, France.

Background: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.

Objectives: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.

Methods: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.

Results: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.

Conclusions: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).
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http://dx.doi.org/10.1016/j.jacc.2021.01.033DOI Listing
March 2021

Red cell distribution width in patients with diabetes and myocardial infarction: An analysis from the EXAMINE trial.

Diabetes Obes Metab 2021 Mar 9. Epub 2021 Mar 9.

Centre d'Investigations Cliniques Plurithématique Inserm 1433, Université de Lorraine, CHRU de Nancy, Inserm U1116, FCRIN INI-CRCT, Nancy, France.

Aim: To determine the clinical correlates of increased red blood cell distribution width (RDW), its potential mechanistic association with multiple circulating biomarkers, and its prognostic value in patients with type 2 diabetes (T2D) who had a recent acute coronary syndrome.

Methods: We used time-updated Cox models applied to patients enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial.

Results: A total of 5380 patients were included, the median age was 61 years and 32% were women. Patients with higher RDW were older, more frequently women, with a longer diabetes duration and increased co-morbidities. An RDW of more than 16.1% (both baseline and time-updated) was independently associated with the study primary composite outcome of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death (time-updated adjusted HR = 1.36, 95% CI = 1.16-1.61, p < .001), all-cause death (time-updated adjusted HR = 2.01, 95% CI = 1.60-2.53, p < .001), as well as mortality from non-cardiovascular causes (time-updated adjusted HR = 2.67, 95% CI = 1.72-4.15, p < .001). RDW had a weak-to-moderate correlation with haemoglobin and circulating markers that reflected inflammation, apoptosis, fibrosis and congestion. Alogliptin did not alter RDW values.

Conclusions: RDW is a marker of disease severity associated with a multitude of poor outcomes, including both cardiovascular and non-cardiovascular death. RDW correlated modestly with inflammatory, pro-apoptotic, pro-fibrotic and congestion markers, and its levels were not affected by alogliptin during the course of the trial.
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http://dx.doi.org/10.1111/dom.14371DOI Listing
March 2021

Heart failure re-hospitalizations and subsequent fatal events in coronary artery disease: insights from COMMANDER-HF, EPHESUS, and EXAMINE.

Clin Res Cardiol 2021 Mar 8. Epub 2021 Mar 8.

Centre d'investigations Cliniques Plurithématique, Inserm 1433, Université de Lorraine, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, CHRU Nancy-Hopitaux de Brabois, 4 rue du Morvan, 54500, Nancy, Vandoeuvre les Nancy, France.

Background: Patients with coronary artery disease (CAD) are at increased risk of developing and being hospitalised for heart failure (HFH). However, the risk of HFH versus ischemic events may vary among patients with CAD, depending on whether acute myocardial infarction (MI), left ventricular dysfunction or decompensated HF is present at baseline.

Aims: We aim to explore the risk of non-fatal events (HFH, MI, stroke) and subsequent death in 3 landmark trials, COMMANDER-HF, EPHESUS and EXAMINE that, together, included patients with CAD with and without reduced ejection fraction and acute MI.

Methods: Events, person-time metrics and time-updated Cox models.

Results: In COMMANDER-HF the event-rate for the composite of AMI, stroke or all-cause death was 13.5 (12.8-14.3) events/100 py. Rates for AMI and stroke were much lower (2.2 [2.0-2.6] and 1.3 [1.1-1.6] events/100 py, respectively) than the rate of HFH (16.9 [16.1-17.9] events/100 py). In EPHESUS, the rates of MI and stroke were also lower than the rate of HFH: 7.2 (6.7-7.8), 1.9 (1.7-2.3), and 10.6 (9.9-11.3) events/100 py, but this was not true for EXAMINE with 4.4 (4.0-4.9), 0.7 (0.6-0.9), and 2.4 (2.0-2.7) events/100 py, respectively. In all 3 trials, a non-fatal event (HFH, MI or stroke) during follow-up doubled the risk of subsequent mortality. This most commonly followed a HFH.

Conclusions: A first or recurrent HFH is common in patients with CAD and AMI or HFrEF and indicates a poor prognosis. Preventing the development of heart failure after AMI and control of congestion in patients with CAD and HFrEF are key unmet needs and therapeutic targets.

Registration: ClinicalTrials.gov Identifier: NCT01877915. URL: https://clinicaltrials.gov/ct2/show/NCT01877915 .
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http://dx.doi.org/10.1007/s00392-021-01830-1DOI Listing
March 2021

Serum microRNAs and antifibrotic response to eplerenone in acute myocardial infarction complicated by systolic dysfunction.

Int J Cardiol 2021 06 5;332:35-37. Epub 2021 Mar 5.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address:

Background: After myocardial infarction (MI) complicated by heart failure (HF), eplerenone reduced serum concentrations of amino-terminal propeptide of type III collagen (PIIINP) and carboxy-terminal propeptide of type I collagen (PICP). Determining a subgroup who are more prone to decrease their collagen content and to respond better to the antifibrotic effects of mineralocorticoid receptor antagonists (MRA) may be relevant for a personalized treatment approach. Whether circulating microRNAs may identify a subgroup that have experienced a more pronounced antifibrotic effect of eplerenone as measured by a PICP and PIIINP decrease is unclear.

Methods: A set of circulating microRNAs linked to cardiac fibrosis (mir-1, mir-21, mir-29a, mir-29b, mir-101, mir-122, mir-133a) were measured at baseline in 198 patients in the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Associations between baseline microRNA levels and changes in both PIIINP and PICP from baseline to month 9 were studied using multivariable analysis of covariance, adjusting for age, sex, history of hypertension and diabetes mellitus, prescription of ACE-inhibitors or angiotensin receptor blockers, baseline PIIINP or PICP, and eplerenone treatment. Furthermore, a treatment-by-microRNA interaction was studied.

Results: From the selected microRNAs, only mir-133a was associated with a PICP decrease (ß-6.43, 95%CI-12.71 to -0.15,p = 0.045). None of the microRNAs was associated with a PIIINP change. The microRNAs did not predict an effect of eplerenone on PICP and PIIINP changes.

Conclusion: Although serum mir-133a was associated with PICP change, none of the microRNAs previously linked to cardiac fibrosis predicted an antifibrotic response to eplerenone. Further study is needed to identify other suitable targets for a personalized treatment approach.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.088DOI Listing
June 2021

Non-fatal cardiovascular events preceding sudden cardiac death in patients with an acute myocardial infarction complicated by heart failure: insights from the high-risk myocardial infarction database.

Eur Heart J Acute Cardiovasc Care 2021 Apr;10(2):127-131

National Institute of Health and Medical Research Center for Clinical Multidisciplinary Research, INSERM U1116, Université de Lorraine, Inserm, Centre d'Investigations cliniques-plurithématique 1433, Inserm U1116; CHRU Nancy; F-CRIN INI-CRCT network, Nancy, France.

Aims: Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD).

Methods And Results: The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction (<40%) after AMI. We evaluated the temporal association between SCD with preceding non-fatal CV event [HF hospitalization, recurrent myocardial infarction (MI), or stroke]. Median follow-up was 1.9 years. Mean age was 65.0 ± 11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-years and for SCD was 3.1 per patient-years (40% of CV deaths). The incidence of SCD preceded by HF hospitalization was greater than SCD without preceding HF hospitalization (P < 0.05). However, overall, SCD was less likely to be preceded by a non-fatal CV event compared to other causes of death: 9.6% of SCD events were preceded by an MI (vs. 46.6% for non-sudden CV death); 17.0% of SCD events were preceded with an HF hospitalization (vs. 25.4% for non-sudden CV death); and 2.7% of SCD events were preceded by stroke (vs.12.9% for non-sudden CV death).

Conclusion: Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.
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http://dx.doi.org/10.1093/ehjacc/zuaa012DOI Listing
April 2021

Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial.

Eur J Heart Fail 2021 Feb 20. Epub 2021 Feb 20.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.

Methods And Results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.

Conclusions: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.
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http://dx.doi.org/10.1002/ejhf.2134DOI Listing
February 2021

Head-to-head comparison of clustering methods for heterogeneous data: a simulation-driven benchmark.

Sci Rep 2021 Feb 18;11(1):4202. Epub 2021 Feb 18.

Centre d'Investigations Cliniques Plurithématique 1433, INSERM 1116, CHRU de Nancy, Université de Lorraine, Nancy, France.

The choice of the most appropriate unsupervised machine-learning method for "heterogeneous" or "mixed" data, i.e. with both continuous and categorical variables, can be challenging. Our aim was to examine the performance of various clustering strategies for mixed data using both simulated and real-life data. We conducted a benchmark analysis of "ready-to-use" tools in R comparing 4 model-based (Kamila algorithm, Latent Class Analysis, Latent Class Model [LCM] and Clustering by Mixture Modeling) and 5 distance/dissimilarity-based (Gower distance or Unsupervised Extra Trees dissimilarity followed by hierarchical clustering or Partitioning Around Medoids, K-prototypes) clustering methods. Clustering performances were assessed by Adjusted Rand Index (ARI) on 1000 generated virtual populations consisting of mixed variables using 7 scenarios with varying population sizes, number of clusters, number of continuous and categorical variables, proportions of relevant (non-noisy) variables and degree of variable relevance (low, mild, high). Clustering methods were then applied on the EPHESUS randomized clinical trial data (a heart failure trial evaluating the effect of eplerenone) allowing to illustrate the differences between different clustering techniques. The simulations revealed the dominance of K-prototypes, Kamila and LCM models over all other methods. Overall, methods using dissimilarity matrices in classical algorithms such as Partitioning Around Medoids and Hierarchical Clustering had a lower ARI compared to model-based methods in all scenarios. When applying clustering methods to a real-life clinical dataset, LCM showed promising results with regard to differences in (1) clinical profiles across clusters, (2) prognostic performance (highest C-index) and (3) identification of patient subgroups with substantial treatment benefit. The present findings suggest key differences in clustering performance between the tested algorithms (limited to tools readily available in R). In most of the tested scenarios, model-based methods (in particular the Kamila and LCM packages) and K-prototypes typically performed best in the setting of heterogeneous data.
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http://dx.doi.org/10.1038/s41598-021-83340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892576PMC
February 2021

Circulating multimarker approach to identify patients with preclinical left ventricular remodelling and/or diastolic dysfunction.

ESC Heart Fail 2021 Apr 12;8(2):1700-1705. Epub 2021 Feb 12.

Université de Lorraine, Centre d'Investigations Cliniques-Plurithématique, Inserm1433, CHRU Nancy, Inserm DCAC, and F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM CHU de Nancy, Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, 4 Rue du Morvan, 54500 Vandoeuvre lès, Nancy, France.

Aims: Biomarkers reflecting myocardial fibrosis and inflammation have been individually associated with left ventricular hypertrophy (LVH) and diastolic dysfunction (DD). However, the added value of a fibrosis-inflammation multimarker approach in a populational setting is yet to be studied. We evaluated the value of a multimarker approach to detect LVH and DD in a large population-based cohort.

Methods And Results: In a prespecified analysis (BioSe-PreIC study) of the 4th visit of the STANISLAS cohort (1705 subjects, 47 ± 14 years, 47.4% men), we evaluated the ability of brain natriuretic peptide (BNP), Galectin-3 (GAL3), N-terminal propeptide of procollagen type III (P3NP), and soluble ST2 to predict LVH (LV mass > 116/100 g/m for men/women) and DD using discrimination (C-index) and reclassification analysis (NRI). Participants with LVH and/or DD had significantly higher levels of BNP, GAL3, and ST2. Overall, the predictive value of clinical variables for LVH and/or DD was good (C-index ranging from 0.76 to 0.82) and the addition of BNP, Gal3, P3NP, and ST2 moderately but significantly improved predictive value (delta C-index = 0.03, P = 0.03 for LVH and 0.01, P = 0.01 for DD) and reclassification (NRI = 25.3, P = 0.02 for LVH and NRI = 32.7 for DD, P < 0.0001). Gal3, P3NP, and ST2 significantly improved predictive value (delta C-index = 0.01, P = 0.01) and reclassification (NRI = 31.3, P < 0.0001) for DD of top of clinical variables and BNP.

Conclusions: As the measurement of Gal3, P3NP, and ST2 results in marginal (even if significant) increase in the prediction of DD/LVH on top of routine evaluation, their systematic use should not be promoted in unselected healthy individuals to screen for preclinical DD. Further research is needed to determine whether a more personalized medicine approach combing proteomic and clinical scoring can amplify the added value of biomarkers to identify preclinical DD.
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http://dx.doi.org/10.1002/ehf2.13203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006620PMC
April 2021

Impact of anti-hypertensive therapy in the sexual health of men and women: an analysis from the SPRINT trial.

Am J Hypertens 2021 Feb 11. Epub 2021 Feb 11.

Université de Lorraine, Centre d'Investigations Cliniques Plurithématique Inserm 1433, Nancy, France, CHRU de Nancy, Inserm U1116, Nancy, France, FCRIN INI-CRCT, Nancy, France.

Background: Pharmacologic anti-hypertensive (HT) treatment reduces cardiovascular risk. However, many patients are non-adherent due to perceived or real concern about sexual-related side-effects.

Objectives: In a subset of the SPRINT (a randomized trial of intensive versus standard blood-pressure control) trial, we sought to investigate the impact of anti-HT treatment on sexual activities of men and women over time, and whether this impact varied with a more or less intensive anti-HT therapy.

Methods: Random-effects models for panel/longitudinal data.

Results: Among the 1268 men and 613 women included in this sub-study, 862 (68%) men and 178 (29%) women declared to be engaged in sexual activity of any kind. Compared with women and men not engaged in sexual activity, those engaged were younger (64 vs. 69yr for women and 65 vs. 75yr for men). Women had an overall low satisfaction with their sexual life but their sexual health was not affected by anti-HT therapy over time nor modified by an intensive treatment. Men's erections were slightly deteriorated over time (-0.1 to -0.2 points on a scale of 1 (worse) to 5 (best); p<0.05), but were not aggravated by intensive anti-HT therapy (p>0.05 for all).

Conclusions: Self-declared women`s sexual health was not affected by an intensive anti-HT therapy. Men, reported a slight deterioration in the quality of their erections, irrespective of standard or intensive therapy. These findings may help reassuring patients about the sexual safety of intensive anti-HT therapy, therefore, potentially improving adherence to intensive therapy strategy.
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http://dx.doi.org/10.1093/ajh/hpab035DOI Listing
February 2021

Impact of Geographic Region on the COMMANDER-HF Trial.

JACC Heart Fail 2021 Mar 3;9(3):201-211. Epub 2021 Feb 3.

Centre d'Investigations Cliniques Plurithématique, Université de Lorraine, Inserm 1433, Nancy, France, Centre Hospitalier Régional Universitaire (CHRU) de Nancy, Inserm U1116, Nancy, France, French Clinical Research Infrastructure Network Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, Nancy, France.

Objectives: This study sought to compare patient characteristics, outcomes, and treatment effects among regions in the COMMANDER-HF trial.

Background: Globalization of cardiovascular trials increases generalizability. However, regional differences may also introduce heterogeneity in results.

Methods: Incidence rates and interactions with treatment were recorded in pre-specified regions: Eastern Europe, Western Europe and South Africa, North America, Asia-Pacific, and Latin America.

Results: Most patients (n = 3,224; 64.2%) were from Eastern Europe; 458 (9.1%) were from Western Europe and South Africa; 149 (3.0%) were from North America; 733 (14.6%) were from Asia-Pacific; and 458 (9.1%) were from Latin America. Compared with patients from Eastern Europe, patients from Western Europe and South Africa, North America, and Asia-Pacific were older and more likely to have coronary interventions and cardiac devices. Patients from Eastern Europe had the lowest event rates. For the primary outcome of myocardial infarction (MI), stroke, or all-cause death, event rates (100/year) were 11.6 in Eastern Europe (10.8 to 12.5); 19.5 (16.5 to 23.0) in Western Europe and South Africa; 14.2 (10.5 to 19.2) in North America; 17.7 (15.4 to 20.3) in Asia-Pacific; and 18.6 (15.6 to 22.1) in Latin America. There was a lower incidence of bleeding in Eastern Europe. Blood concentrations of rivaroxaban (Xarelto, Titusville, New Jersey) at 4 weeks were undetectable in 21% patients from Eastern Europe (n = 128) compared to 5% in other regions (n = 42). There was no evidence of treatment-by-region heterogeneity for the primary outcome (interaction = 0.14), but a favorable effect on the secondary outcome of MI, stroke, or cardiovascular death was observed in Western Europe and South Africa, North America, and Latin America but not in Eastern Europe and Asia-Pacific (interaction = 0.017).

Conclusions: In the COMMANDER-HF study, patients from Eastern Europe had a lower risk profile and fewer cardiovascular and bleeding events, possibly related to lower treatment adherence. Those differences might have influenced the effect of rivaroxaban therapy. (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure [COMMANDER HF]; NCT01877915).
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http://dx.doi.org/10.1016/j.jchf.2020.11.007DOI Listing
March 2021

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF.

JACC Heart Fail 2021 Apr 3;9(4):268-277. Epub 2021 Feb 3.

Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address:

Objectives: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.

Background: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.

Methods: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis.

Results: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).

Conclusions: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).
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http://dx.doi.org/10.1016/j.jchf.2020.11.010DOI Listing
April 2021

Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial.

Trials 2021 Feb 5;22(1):115. Epub 2021 Feb 5.

Division of Cardiology, McGill University Health Centre, McGill University, 1001 Decarie Blvd, Montreal, Quebec, H4A 3J1, Canada.

Objectives: The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials.

Trial Design: This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy.

Participants: Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis.

Intervention And Comparator: All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7.

Main Outcomes: PRIMARY ENDPOINT: In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts.

Randomization: Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm.

Blinding: This is an open label study with no blinding.

Numbers To Be Randomised (sample Size): The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations.

Trial Status: Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1 2021.

Trial Registration: Trial registration: ClincalTrials.gov : NCT04508985 , date of registration: August 11 , 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05080-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862851PMC
February 2021

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Eur Heart J 2021 02;42(6):671-680

Université de Lorraine, Inserm INI-CRCT, CHRU, Nancy, France.

Aims: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.

Methods And Results: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.

Conclusion: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.
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http://dx.doi.org/10.1093/eurheartj/ehaa968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878011PMC
February 2021

Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.

Eur Heart J 2021 03;42(13):1203-1212

Cardiovascular Science, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall Street, Dallas, TX 75226, USA.

Aims: In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction.

Methods And Results: Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains.

Conclusion: Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.
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http://dx.doi.org/10.1093/eurheartj/ehaa1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014525PMC
March 2021

Challenges of Cardio-Kidney Composite Outcomes in Large-Scale Clinical Trials.

Circulation 2021 Mar 7;143(9):949-958. Epub 2021 Jan 7.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques, INI CRCT, and INSERM U1116, CHRU Nancy, France (J.P.F., P.R., F.Z.).

Patients with chronic cardiovascular or metabolic diseases, including diabetes, hypertension, obesity, and heart failure, often have comorbid kidney disease. Long-term outcomes are worse in the setting of both cardiac and kidney disease compared with either disease in isolation. In addition, the clinical presentations of certain acute cardiovascular events (such as heart failure) and worsening kidney function overlap and may be challenging to distinguish. Recently, certain novel treatments have demonstrated beneficial effects on both cardiac and kidney outcomes. Sodium-glucose cotransporter-2 inhibitors have exhibited concordant risk reduction and clinically important benefits in chronic kidney disease with and without diabetes, diabetes and established cardiovascular disease or multiple atherosclerotic vascular disease risk factors, and heart failure with reduced ejection fraction with and without diabetes. Primary trial results have revealed that sacubitril-valsartan therapy improves cardiovascular outcomes in patients with chronic heart failure with reduced ejection fraction and post hoc analyses suggest favorable kidney effects. A concordant pattern of kidney benefit with sacubitril-valsartan has also been observed in chronic heart failure with preserved ejection fraction. Given the complex interplay between cardiac and kidney disease and the possibility that treatments may show concordant cardio-kidney benefits, there has been recent interest in formally acknowledging, defining, and using composite cardio-kidney outcomes in future cardiovascular trials. This review describes potential challenges in use of such outcomes that should be considered and addressed before their incorporation into such trials.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920916PMC
March 2021

The Future of Meat: Health Impact Assessment with Randomized Evidence.

Am J Med 2021 05 11;134(5):569-575. Epub 2020 Dec 11.

Université de Lorraine, INSERM, Centre d'Investigation Clinique et Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.

Massive animal farming for meat production poses major problems in terms of resource use, environmental impact, and biodiversity. Furthermore, excessive meat consumption has been associated with multiple deleterious health consequences. However, more and better-designed randomized trials are needed to increase the level of evidence on the health impacts of meat. Novel meat alternatives, such as plant- and cell-based meat, are much less impactful to the environment and might replace traditional animal meat in the future, but, despite promising early data, the health consequences of these novel products need further study. This manuscript focuses on the health impacts of meat over 3 main sections: 1) overview of the evidence highlighting the association of meat consumption with health; 2) novel alternatives to meat, including plant-based and cell-based alternatives; and 3) examine the rationale for randomized studies to evaluate the effects of the novel meat alternatives compared with the standard animal meat.
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http://dx.doi.org/10.1016/j.amjmed.2020.11.007DOI Listing
May 2021