Publications by Garret Cotter


Association of left ventricular ejection fraction with worsening renal function in patients with acute heart failure: insights from the RELAX-AHF-2 study.

European journal of heart failure (2020)

S Feng, S Janwanishstaporn, JR Teerlink, M Metra, G Cotter, B Davison, GM Felker, G Filippatos, P Pang, P Ponikowski, IE Sama, AA Voors, B Greenberg

AIMS:Whether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in-hospital WRF and post-discharge outcomes vary according to left ventricular ejection fraction (LVEF) is uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post-discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX-AHF-2. METHODS AND RESULTS:A total of 6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as a rise in serum creatinine ≥0.3 mg/dL from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (P < 0.001). After baseline adjustment, WRF risk in Q4 (LVEF >50%) remained significantly greater than in Q1 (LVEF ≤29%; hazard ratio 1.2, 95% confidence interval 1-1.43; P = 0.050). Age and comorbidity burden including chronic kidney disease increased as LVEF increased. Neither admission haemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post-discharge events. CONCLUSIONS:Worsening renal function incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than haemodynamic or treatment effects. WRF is associated with increased risk of post-discharge events except in patients in the lowest LVEF quartile.


Search for dark matter signals towards a selection of recently detected DES dwarf galaxy satellites of the Milky Way with HESS

PHYSICAL REVIEW D 102 (2020) ARTN 062001

H Abdallah, R Adam, F Aharonian, FA Benkhali, EO Anguner, M Arakawa, C Arcaro, C Armand, T Armstrong, H Ashkar, M Backes, V Baghmanyan, VB Martins, A Barnacka, M Barnard, Y Becherini, D Berge, K Bernloehr, M Bottcher, C Boisson, J Bolmont, S Bonnefoy, M Breuhaus, J Bregeon, F Brun, P Brun, M Bryan, M Buechele, T Bulik, T Bylund, S Caroff, A Carosi, S Casanova, T Chand, S Chandra, A Chen, G Cotter, M Curylo, ID Davids, J Davies, C Deil, J Devin, P deWilt, L Dirson, A Djannati-Atai, A Dmytriiev, A Donath, V Doroshenko, J Dyks, K Egberts, F Eichhorn, G Emery, J-P Ernenwein, S Eschbach, K Feijen, S Fegan, A Fiasson, G Fontaine, S Funk, M Fuessling, S Gabici, YA Gallant, G Giavitto, L Giunti, D Glawion, JF Glicenstein, D Gottschall, M-H Grondin, J Hahn, M Haupt, G Hermann, JA Hinton, W Hofmann, C Hoischen, TL Holch, M Holler, M Horbe, D Horns, D Huber, H Iwasaki, M Jamrozy, D Jankowsky, F Jankowsky, A Jardin-Blicq, V Joshi, I Jung-Richardt, MA Kastendieck, K Katarzynski, M Katsuragawa, U Katz, D Khangulyan, B Khelifi, S Klepser, W Kluzniak, N Komin, R Konno, K Kosack, D Kostunin, M Kreter, G Lamanna, A Lemiere, M Lemoine-Goumard, J-P Lenain, E Leser, C Levy, T Lohse, I Lypova, J Mackey, J Majumdar, D Malyshev, V Marandon, P Marchegiani, A Marcowith, A Mares, G Marti-Devesa, R Marx, G Maurin, PJ Meintjes, R Moderski, M Mohamed, L Mohrmann, C Moore, P Morris, E Moulin, J Muller, T Murach, K Nakashima, S Nakashima, M de Naurois, H Ndiyavala, F Niederwanger, J Niemiec, L Oakes, P O'Brien, H Odaka, S Ohm, EDO Wilhelmi, M Ostrowski, M Panter, RD Parsons, B Peyaud, Q Piel, S Pita, V Poireau, AP Noel, DA Prokhorov, H Prokoph, G Puehlhofer, M Punch, A Quirrenbach, S Raab, R Rauth, A Reimer, O Reimer, Q Remy, M Renaud, F Rieger, L Rinchiuso, C Romoli, G Rowell, B Rudak, E Ruiz-Velasco, V Sahakian, S Sailer, S Saito, DA Sanchez, A Santangelo, M Sasaki, M Scalici, F Schussler, HM Schutter, U Schwanke, S Schwemmer, M Seglar-Arroyo, M Senniappan, AS Seyffert, N Shafi, K Shiningayamwe, R Simoni, A Sinha, H Sol, A Specovius, S Spencer, M Spir-Jacob, L Stawarz, R Steenkamp, C Stegmann, C Steppa, T Takahashi, T Tavernier, AM Taylor, R Terrier, D Tiziani, M Tluczykont, L Tomankova, C Trichard, M Tsirou, N Tsuji, R Tuffs, Y Uchiyama, DJ van der Walt, C van Eldik, C van Rensburg, B van Soelen, G Vasileiadis, J Veh, C Venter, A Viana, P Vincent, J Vink, HJ Voelk, T Vuillaume, Z Wadiasingh, SJ Wagner, J Watson, F Werner, R White, A Wierzcholska, R Yang, H Yoneda, M Zacharias, R Zanin, D Zargaryan, AA Zdziarski, A Zech, S Zhu, J Zorn, N Zywucka, HESS Collaboration


Mega-trials in heart failure: effects of dilution in examination of new therapies.

European journal of heart failure 22 (2020) 1698-1707

BA Davison, K Takagi, S Senger, G Koch, M Metra, A Kimmoun, A Mebazaa, AA Voors, OW Nielsen, O Chioncel, PS Pang, BH Greenberg, AP Maggioni, A Cohen-Solal, G Ertl, N Sato, JR Teerlink, G Filippatos, P Ponikowski, E Gayat, C Edwards, G Cotter

AIMS:Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power. METHODS AND RESULTS:Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients. CONCLUSIONS:The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.


Improved cardiac and venous pressures during hospital stay in patients with acute heart failure: an echocardiography and biomarkers study.

ESC heart failure 7 (2020) 996-1006

E Akiyama, R Cinotti, K Čerlinskaitė, LNL Van Aelst, M Arrigo, R Placido, T Chouihed, N Girerd, F Zannad, P Rossignol, M Badoz, J-M Launay, E Gayat, A Cohen-Solal, CSP Lam, J Testani, W Mullens, G Cotter, M-F Seronde, A Mebazaa

AIMS:Changes in echocardiographic parameters and biomarkers of cardiac and venous pressures or estimated plasma volume during hospitalization associated with decongestive treatments in acute heart failure (AHF) patients with either preserved left ventricular ejection fraction (LVEF) (HFPEF) or reduced LVEF (HFREF) are poorly assessed. METHODS AND RESULTS:From the metabolic road to diastolic heart failure: diastolic heart failure (MEDIA-DHF) study, 111 patients were included in this substudy: 77 AHF (43 HFPEF and 34 HFREF) and 34 non-cardiac dyspnea patients. Echocardiographic measurements and blood samples were obtained within 4 h of presentation at the emergency department and before hospital discharge. In AHF patients, echocardiographic indices of cardiac and venous pressures, including inferior vena cava diameter [from 22 (16-24) mm to 13 (11-18) mm, P = 0.009], its respiratory variability [from 32 (8-44) % to 43 (29-70) %, P = 0.04], medial E/e' [from 21.1 (15.8-29.6) to 16.6 (11.7-24.3), P = 0.004], and E wave deceleration time [from 129 (105-156) ms to 166 (128-203) ms, P = 0.003], improved during hospitalization, similarly in HFPEF and HFREF patients. By contrast, no changes were seen in non-cardiac dyspnea patients. In AHF patients, all plasma biomarkers of cardiac and venous pressures, namely B-type natriuretic peptide [from 935 (514-2037) pg/mL to 308 (183-609) pg/mL, P < 0.001], mid-regional pro-atrial natriuretic peptide [from 449 (274-653) pmol/L to 366 (242-549) pmol/L, P < 0.001], and soluble CD-146 levels [from 528 (406-654) ng/mL to 450 (374-529) ng/mL, P = 0.003], significantly decreased during hospitalization, similarly in HFPEF and HFREF patients. Echocardiographic parameters of cardiac chamber dimensions [left ventricular end-diastolic volume: from 120 (76-140) mL to 118 (95-176) mL, P = 0.23] and cardiac index [from 2.1 (1.6-2.6) mL/min/m2 to 1.9 (1.4-2.4) mL/min/m2 , P = 0.55] were unchanged in AHF patients, except tricuspid annular plane systolic excursion (TAPSE) that improved during hospitalization [from 16 (15-19) mm to 19 (17-21) mm, P = 0.04]. Estimated plasma volume increased in both AHF [from 4.8 (4.2-5.6) to 5.1 (4.4-5.8), P = 0.03] and non-cardiac dyspnea patients (P = 0.01). Serum creatinine [from 1.18 (0.90-1.53) to 1.19 (0.86-1.70) mg/dL, P = 0.89] and creatinine-based estimated glomerular filtration rate [from 59 (40-75) mL/min/1.73m2 to 56 (38-73) mL/min/1.73m2 , P = 0.09] were similar, while plasma cystatin C [from 1.50 (1.20-2.27) mg/L to 1.78 (1.33-2.59) mg/L, P < 0.001] and neutrophil gelatinase associated lipocalin (NGAL) [from 127 (95-260) ng/mL to 167 (104-263) ng/mL, P = 0.004] increased during hospitalization in AHF. CONCLUSIONS:Echocardiographic parameters and plasma biomarkers of cardiac and venous pressures improved during AHF hospitalization in both acute HFPEF and HFREF patients, while cardiac chamber dimensions, cardiac output, and estimated plasma volume showed minimal changes.


Probing the Magnetic Field in the GW170817 Outflow Using HESS Observations

ASTROPHYSICAL JOURNAL LETTERS 894 (2020) ARTN L16

H Abdalla, R Adam, F Aharonian, FA Benkhali, EO Anguner, M Arakawa, C Arcaro, C Armand, T Armstrong, H Ashkar, M Backes, V Baghmanyan, V Barbosa-Martins, A Barnacka, M Barnard, Y Becherini, D Berge, K Bernloehr, R Blackwell, M Bottcher, C Boisson, J Bolmont, S Bonnefoy, J Bregeon, M Breuhaus, F Brun, P Brun, M Bryan, M Buechele, T Bulik, T Bylund, S Caroff, A Carosi, S Casanova, M Cerruti, T Chand, S Chandra, A Chen, G Cotter, M Curylo, ID Davids, J Davies, C Deil, J Devin, P deWilt, L Dirson, A Djannati-Ata, A Dmytriiev, A Donath, V Doroshenko, J Dyks, K Egberts, F Eichhorn, G Emery, J-P Ernenwein, S Eschbach, K Feijen, S Fegan, A Fiasson, G Fontaine, S Funk, M Fuessling, S Gabici, YA Gallant, G Giavitto, L Giunti, D Glawion, JF Glicenstein, D Gottschall, M-H Grondin, J Hahn, M Haupt, G Heinzelmann, G Hermann, JA Hinton, W Hofmann, C Hoischen, TL Holch, M Holler, M Horbe, D Horns, D Huber, H Iwasaki, M Jamrozy, D Jankowsky, F Jankowsky, A Jardin-Blicq, V Joshi, I Jung-Richardt, MA Kastendieck, K Katarzynski, M Katsuragawa, U Katz, D Khangulyan, B Khelifi, S Klepser, W Kluzniak, N Komin, R Konno, K Kosack, D Kostunin, M Kreter, G Lamanna, A Lemiere, M Lemoine-Goumard, J-P Lenain, E Leser, C Levy, T Lohse, I Lypova, J Mackey, J Majumdar, D Malyshev, V Marandon, P Marchegiani, A Marcowith, A Mares, G Marti-Devesa, R Marx, G Mauring, PJ Meintjes, R Moderski, M Mohamed, L Mohrmann, C Moore, P Morriss, E Moulin, J Muller, T Murach, S Nakashima, K Nakashima, M de Naurois, H Ndiyavala, F Niederwanger, J Niemiec, L Oakes, P O'Brien, HG Odaka, S Ohm, EDO Wilhelmi, M Ostrowski, M Panter, RD Parsons, B Peyaud, Q Piel, S Pita, V Poireau, AP Noel, DA Prokhorov, H Prokoph, G Puehlhofer, M Punch, A Quirrenbach, S Raab, R Rauth, A Reimer, O Reimer, Q Remy, M Renaud, F Rieger, L Rinchiuso, C Romoli, G Rowell, B Rudak, E Ruiz-Velasco, V Sahalcian, S Sailer, S Saito, DA Sanchez, A Santangelo, M Sasaki, M Scalici, R Schlickeiser, F Schuessler, A Schulz, HM Schutte, U Schwanke, S Schwemmer, M Seglar-Arroyo, M Senniappan, AS Seyffert, N Shafi, K Shiningayamwe, R Simoni, A Sinha, H Sol, A Specovius, S Spencer, M Spir-Jacob, L Stawarz, R Steenkamp, C Stegmann, C Steppa, T Takahashi, T Tavernier, AM Taylor, R Terrier, D Tiziani, M Tluczykont, L Tomankova, C Trichard, M Tsirou, N Tsuji, R Tuffs, Y Uchiyama, DJ van der Walt, C van Eldik, C van Rensburg, B van Soelen, G Vasileiadis, J Veh, C Venter, P Vincent, J Vink, HJ Voelk, T Vuillaume, Z Wadiasingh, SJ Wagner, J Watson, F Werner, R White, A Wierzcholska, R Yang, H Yoneda, M Zacharias, R Zanin, AA Zdziarski, A Zech, J Zorn, N Zywucka, X Rodrigues, HESS Collaboration


Acute heart failure: More questions than answers.

Progress in cardiovascular diseases (2020)

D Tomasoni, CM Lombardi, M Sbolli, G Cotter, M Metra

Acute heart failure (AHF) is a life-threatening condition with a dramatic burden in terms of symptoms, morbidity and mortality. It is a specific syndrome requiring urgent, life-saving treatment. Multiple specific pathophysiologic mechanisms may be involved, including congestion, inflammation, and neurohormonal activation. This process eventually leads to symptoms, end-organ damage, and adverse outcomes. Clinical presentation varies, but it almost universally includes worsening of congestion associated with different degrees of hypoperfusion. Due to substantial early symptoms burden and high morbidity and mortality, patients with AHF require intensive monitoring and intravenous treatment. However, beyond variable improvement in congestion, none of the available intravenous therapies for AHF was shown to improve longer term outcomes. Although oral treatment with guideline-directed therapies for stable patients with HF and reduced ejection fraction (HFrEF) before discharge may fully prevent subsequent episodes, proof that this strategy may benefit patients is lacking. First, most patients with AHF have preserved EF (HFpEF) where no therapies have been shown to be effective. Second, all therapies developed for patients with HFrEF were tested for efficacy on outcomes in patients who were stable without recent AHF. Hence, the implementation of these chronic therapies during an AHF episode is untested. Third, the problem to better treat AHF patients in their early phase remains crucial with treatment strategies largely untested, yet. Further studies targeting AHF specific mechanisms, such as inflammation and end-organ damage, and finding effective intravenous drugs remain therefore warranted.


Relationship between left ventricular ejection fraction and cardiovascular outcomes following hospitalization for heart failure: insights from the RELAX-AHF-2 trial.

European journal of heart failure 22 (2020) 726-738

S Janwanishstaporn, S Feng, J Teerlink, M Metra, G Cotter, BA Davison, GM Felker, G Filippatos, P Pang, P Ponikowski, T Severin, C Gimpelewicz, T Holbro, CW Chen, I Sama, AA Voors, BH Greenberg

AIMS:Although left ventricular ejection fraction (LVEF) is routinely used to categorize patients with heart failure (HF), whether it predicts outcomes after hospitalization for acute heart failure (AHF) is uncertain. Consequently, we assessed the relationship between LVEF and cardiovascular (CV) outcomes in a large, well characterized cohort of patients hospitalized for AHF. METHODS AND RESULTS:The 6128 patients from the RELAX-AHF-2 trial who had LVEF measured during AHF hospitalization were separated into LVEF quartiles and the relationship between LVEF and a composite of CV mortality and rehospitalization for HF or renal failure through 180 days was assessed. We found progressively lower risk for this composite outcome as LVEF increased (hazard ratio 0.95, 95% confidence interval 0.93-0.98 per 5% LVEF increase, P < 0.001) that was driven predominantly by decreased risk for rehospitalization. The smoothed spline curve depicting risk remained stable as LVEF decreased until reaching approximately 40%, at which point risk increased progressively with further reductions in LVEF. Significant differences between LVEF quartiles for post-discharge CV risk were seen in patients with an ischaemic aetiology or with a history of HF preceding index hospitalization, but were less robust in patients with non-ischaemic aetiology and absent in those with de novo HF. CONCLUSION:In patients hospitalized with AHF, CV events over 180 days were more frequent in patients with lower LVEF. This was due predominantly to a significant increase in risk for HF/renal failure rehospitalization but not in either CV or all-cause mortality. LVEF had greater prognostic value in patients with ischaemic aetiology or pre-existing HF.


Clinical value of pre-discharge bio-adrenomedullin as a marker of residual congestion and high risk of heart failure hospital readmission.

European journal of heart failure 22 (2020) 683-691

P Pandhi, JM Ter Maaten, JE Emmens, J Struck, A Bergmann, JG Cleland, MM Givertz, M Metra, CM O'Connor, JR Teerlink, P Ponikowski, G Cotter, B Davison, DJ van Veldhuisen, AA Voors

AIMS:Recently, bio-adrenomedullin (bio-ADM) was proposed as a congestion marker in heart failure (HF). In the present study, we aimed to study whether bio-ADM levels at discharge from a hospital admission for worsening HF could provide additional information on (residual) congestion status, diuretic dose titration and clinical outcomes. METHODS AND RESULTS:Plasma bio-ADM was measured in 1236 acute HF patients in the PROTECT trial at day 7 or discharge. Median discharge bio-ADM was 33.7 [21.5-61.5] pg/mL. Patients with higher discharge bio-ADM levels were hospitalised longer, had higher brain natriuretic peptide levels, and poorer diuretic response (all P < 0.001). Bio-ADM was the strongest predictor of discharge residual congestion (clinical congestion score > 3) (odds ratio 4.35, 95% confidence interval 3.37-5.62; P < 0.001). Oedema at discharge was one of the strongest predictors of discharge bio-ADM (β = 0.218; P < 0.001). Higher discharge loop diuretic doses were associated with a poorer diuretic response during hospitalisation (β = 0.187; P < 0.001) and higher bio-ADM levels (β = 0.084; P = 0.020). High discharge bio-ADM levels combined with higher use of loop diuretics were independently associated with a greater risk of 60-day HF rehospitalisation (hazard ratio 4.02, 95% confidence interval 2.23-7.26; P < 0.001). CONCLUSION:In hospitalised HF patients, elevated pre-discharge bio-ADM levels were associated with higher discharge loop diuretic doses and reflected residual congestion. Patients with combined higher bio-ADM levels and higher loop diuretic use at discharge had an increased risk of rehospitalisation. Assessment of discharge bio-ADM levels may be a readily applicable marker to identify patients with residual congestion at higher risk of early hospital readmission.


Detection of very-high-energy gamma-ray emission from the colliding wind binary eta Car with HESS

ASTRONOMY & ASTROPHYSICS 635 (2020)

H Abdalla, R Adam, F Aharonian, FA Benkhali, EO Anguner, M Arakawa, C Arcaro, C Armand, T Armstrong, H Ashkar, M Backes, VB Martins, M Barnard, Y Becherini, D Berge, K Bernloehr, R Blackwell, M Bottcher, C Boisson, J Bolmont, S Bonnefoy, J Bregeon, M Breuhaus, F Brun, P Brun, M Bryan, M Buchele, T Bulik, T Bylund, S Caroff, A Carosi, S Casanova, M Cerruti, T Chand, S Chandra, A Chen, S Colafrancesco, G Cotter, M Curylo, ID Davids, J Davies, C Deil, J Devin, P dewilt, L Dirson, A Djannati-Atai, A Dmytriiev, A Donath, V Doroshenko, J Dyks, K Egberts, F Eichhorn, G Emery, J-P Ernenwein, S Eschbach, K Feijen, S Fegan, A Fiasson, G Fontaine, S Funk, M Fussling, S Gabici, YA Gallant, F Gate, G Giavitto, L Giunti, D Glawion, JF Glicenstein, D Gottschall, M-H Grondin, J Hahn, M Haupt, G Heinzelmann, G Henri, G Hermann, JA Hinton, W Hofmann, C Hoischen, TL Holch, M Holler, M Horbe, D Horns, D Huber, H Iwasaki, M Jamrozy, D Jankowsky, F Jankowsky, A Jardin-Blicq, V Joshi, I Jung-Richardt, MA Kastendieck, KKP Nski, M Katsuragawa, U Katz, D Khangulyan, B Khelifi, J King, S Klepser, W Kluzniak, N Komin, K Kosack, D Kostunin, M Kreter, G Lamanna, A Lemiere, M Lemoine-Goumard, J-P Lenain, E Leser, C Levy, T Lohse, I Lypova, J Mackey, J Majumdar, D Malyshev, D Malyshev, V Marandon, P Marchegiani, A Marcowith, A Mares, G Marti-Devesa, R Marx, G Maurin, PJ Meintjes, R Moderski, M Mohamed, L Mohrmann, C Moore, P Morris, E Moulin, J Muller, T Murach, S Nakashima, K Nakashima, M de Naurois, H Ndiyavala, F Niederwanger, J Niemiec, L Oakes, P O'Brien, H Odaka, S Ohm, EDO Wilhelmi, M Ostrowski, M Panter, RD Parsons, C Perennes, P-O Petrucci, B Peyaud, Q Piel, S Pita, V Poireau, AP Noel, DA Prokhorov, H Prokoph, G Puhlhofer, M Punch, A Quirrenbach, S Raab, R Rauth, A Reimer, O Reimer, Q Remy, M Renaud, F Rieger, L Rinchiuso, C Romoli, G Rowell, B Rudak, E Ruiz-Velasco, V Sahakian, S Sailer, S Saito, DA Sanchez, A Santangelo, M Sasaki, M Scalici, R Schlickeiser, F Schussler, A Schulz, HM Schutte, U Schwanke, S Schwemmer, M Seglar-Arroyo, M Senniappan, AS Seyffert, N Shafi, K Shiningayamwe, R Simoni, A Sinha, H Sol, A Specovius, S Spencer, M Spir-Jacob, L Stawarz, R Steenkamp, C Stegmann, C Steppa, T Takahashi, T Tavernier, AM Taylor, R Terrier, D Tiziani, M Tluczykont, L Tomankova, C Trichard, M Tsirou, N Tsuji, R Tuffs, Y Uchiyama, DJ van der Walt, C van Eldik, C van Rensburg, B van Soelen, G Vasileiadis, J Veh, C Venter, P Vincent, J Vink, HJ Volk, T Vuillaume, Z Wadiasingh, SJ Wagner, J Watson, F Werner, R White, A Wierzcholska, R Yang, H Yoneda, M Zacharias, R Zanin, AA Zdziarski, A Zech, J Zorn, N Zywucka, HESS Collaboration


Effects of serelaxin in patients admitted for acute heart failure: a meta-analysis.

European journal of heart failure 22 (2020) 315-329

JR Teerlink, BA Davison, G Cotter, AP Maggioni, N Sato, O Chioncel, G Ertl, GM Felker, G Filippatos, BH Greenberg, PS Pang, P Ponikowski, C Edwards, S Senger, SL Teichman, OW Nielsen, AA Voors, M Metra

AIMS:The effectiveness and safety of 48 h intravenous 30 μg/kg/day serelaxin infusion in acute heart failure (AHF) has been studied in six randomized, controlled clinical trials. METHODS AND RESULTS:We conducted a fixed-effect meta-analysis including all studies of intravenous serelaxin initiated within the first 16 h of admission for AHF. Endpoints considered were the primary and secondary endpoints examined in the serelaxin phase III studies. In six randomized controlled trials, 6105 total patients were randomized to receive intravenous serelaxin 30 μg/kg/day and 5254 patients to control. Worsening heart failure to day 5 occurred in 6.0% and 8.1% of patients randomized to serelaxin and control, respectively (hazard ratio 0.77, 95% confidence interval 0.67-0.89; P = 0.0002). Serelaxin had no statistically significant effect on length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration resulted in statistically significant improvement in markers of renal function and reductions in both N-terminal pro-B-type natriuretic peptide and troponin. No significant adverse outcomes were noted with serelaxin. Through the last follow-up, which occurred at an average of 4.5 months (1-6 months), serelaxin administration was associated with a reduction in all-cause mortality, with an estimated hazard ratio of 0.87 (95% confidence interval 0.77-0.98; P = 0.0261). CONCLUSIONS:Administration of intravenous serelaxin to patients admitted for AHF was associated with a highly significant reduction in the risk of 5-day worsening heart failure and in changes in renal function markers, but not length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration was safe and associated with a significant reduction in all-cause mortality.


Elevated plasma endothelin-1 is related to low natriuresis, clinical signs of congestion, and poor outcome in acute heart failure

ESC Heart Failure (2020)

R Zymliński, R Sierpiński, M Metra, G Cotter, M Sokolski, P Siwołowski, M Garus, P Gajewski, J Tryba, M Samorek, EA Jankowska, J Biegus, P Ponikowski

© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology Aims: Endothelin-1 (ET-1) is a potent vasoconstrictor, which regulates renal and vascular function. We aimed to relate plasma levels of ET-1 with the clinical picture and outcomes in acute heart failure (AHF). Methods and results: We studied 113 patients with AHF [mean age 65 ± 13 (years), median (upper and lower quartiles) N-terminal pro-B-type natriuretic peptide, 5422 (2689; 8582) (pg/mL)], in whom plasma levels of ET-1 were serially measured at admission (10.8 ± 5.2), Day 1 (9.5 ± 3.4), and Day 2 (8.9 ± 3.8) (pg/mL). The population was divided into tertiles across baseline ET-1 levels. Patients in the highest ET-1 tertile had predominant clinical signs of peripheral congestion; however, no difference was observed in pulmonary congestion and severity of dyspnoea. They also presented lower spot urine sodium at admission (75 ± 35 vs. 99 ± 43 vs. 108 ± 30), 6 h (84 ± 34 vs. 106 ± 43 vs. 106 ± 35), and Day 1 (75 ± 38 vs. 96 ± 36 vs. 100 ± 35) (mmol/L), when compared with the second and first tertile, respectively (all P < 0.05); furthermore, they received higher doses of intravenous furosemide from Day 2 and had longer intravenous diuretics, as median switch to oral furosemide was 4 (3; 4) vs. 3 (2; 4) vs. 2 (2; 3) (days), respectively, P < 0.05. There was no difference in serum creatinine, urea, and renal injury biomarkers (kidney injury molecule-1, serum cystatin C, and urine neutrophil gelatinase-associated lipocalin) between the ET-1 tertiles. Higher values of ET-1 measured at each time point were related with a higher risk of 1 year mortality. Conclusions: Elevation of ET-1 is related to clinical signs of peripheral congestion, low urine sodium excretion, and poor outcome in AHF.


Cardiopoietic stem cell therapy in ischaemic heart failure: long-term clinical outcomes

ESC Heart Failure (2020)

J Bartunek, A Terzic, BA Davison, A Behfar, R Sanz-Ruiz, W Wojakowski, W Sherman, GR Heyndrickx, M Metra, GS Filippatos, SA Waldman, JR Teerlink, TD Henry, BJ Gersh, R Hajjar, M Tendera, S Senger, G Cotter, TJ Povsic, W Wijns

© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology Aims: This study aims to explore long-term clinical outcomes of cardiopoiesis-guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial. Methods and results: CHART-1 is a multinational, randomized, and double-blind trial conducted in 39 centres in heart failure patients (n = 315) on standard-of-care therapy. The ‘active’ group received cardiopoietic stem cells delivered intramyocardially using a retention-enhanced catheter. The ‘control’ group underwent patient-level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann–Whitney estimator 0.52, 95% confidence interval (CI) 0.45–0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow-up, patients with left ventricular end-diastolic volume of 200–370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16–0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09–0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. Conclusions: Longitudinal follow-up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long-term clinical follow-up thus offers guidance for future targeted trials.


Drug development in oncology and devices—lessons for heart failure drug development and approval? a review

Heart Failure Reviews (2020)

BA Davison, G Cotter, GS Filippatos, F Zannad, AA Voors, M Metra, JR Teerlink, S Senger, A Mebazaa, B Greenberg

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Heart failure (HF) and cancer are of the most common diseases globally, both associated with significant adverse outcomes and greatly impaired quality of life. Despite those similarities, over the last 15 years, the United States (USA) and European authorities have approved only 5 and 3 new drugs for HF respectively, none using an accelerated process and none for patients with either acute HF (AHF) or with HF and preserved ejection fraction (HFpEF). During the same period, more than 100 new drugs were approved for treatment of various cancers, several receiving accelerated approval. HF drugs in the last 15 years were mostly approved for reduction in mortality, whereas most approved cancer drugs addressed disease progression and surrogate markers. Consequently, the size of the trials in HF were far greater than those in oncology which was associated with lower probability of success. Given the larger study size and smaller probability of approval, pharma progressively reduces the necessary investments in new HF drugs. We suggest for HF drugs be developed, especially those used to treat patients with HFpEF and AHF, consideration of approval based beyond morbidity and mortality on improvements in symptoms and functional capacity and, like oncology, based on measures of disease progression and end organ damage. At the same time, HF drug development should adopt some approaches used in other diseases (such as oncology) focusing on better defining specific phenotypes and defining specific disease-related targets for new drugs.


Is plasma renin activity associated with worse outcomes in acute heart failure? A secondary analysis from the BLAST-AHF trial.

European journal of heart failure 21 (2019) 1561-1570

RJ Rachwan, J Butler, SP Collins, G Cotter, BA Davison, S Senger, JA Ezekowitz, G Filippatos, PD Levy, M Metra, P Ponikowski, JR Teerlink, AA Voors, RA de Boer, DG Soergel, GM Felker, PS Pang

AIMS:Neurohormonal activation characterizes chronic heart failure (HF) and is a well-established therapeutic target. Neurohormonal activation may also play a key role in acute HF (AHF). We aim to describe the association between plasma renin activity (PRA) and three AHF outcomes: (i) worsening HF or death through day 5 of hospitalization; (ii) HF rehospitalization or death through day 30; and (iii) all-cause death through day 30. METHODS AND RESULTS:A secondary analysis of the BLAST-AHF trial was performed. Eligible patients had a history of HF, elevated natriuretic peptides, signs and symptoms of HF, systolic blood pressure >120 mmHg, and an estimated glomerular filtration rate between 20-75 mL/min/1.73 m2 . The primary trial was neutral, with no differential effect of study drug by PRA levels. Baseline PRA levels were grouped into tertiles. Adjusted Cox proportional hazard model determined the association of PRA levels with outcomes (α set at P < 0.05). Of 618 randomized patients, 578 (93.5%) had a baseline PRA. PRA was modestly, but significantly, associated with each outcome without adjustment [worsening HF or death through day 5: hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.23, P = 0.04; HF rehospitalization or death through day 30: HR 1.13, 95% CI 1.02-1.26, P = 0.02; all-cause death through day 30: HR 1.18, 95% CI 1.02-1.37, P = 0.03]. After multivariable adjustment, PRA was only significantly associated with HF rehospitalization or death through day 30 (HR 1.15, 95% CI 1.01-1.32, P = 0.04). CONCLUSION:Baseline PRA levels are associated with increased risk for the composite of 30-day HF rehospitalization or death in patients with AHF.


Hepatorenal dysfunction identifies high-risk patients with acute heart failure: insights from the RELAX-AHF trial.

ESC heart failure 6 (2019) 1188-1198

J Biegus, B Demissei, D Postmus, G Cotter, BA Davison, GM Felker, G Filippatos, C Gimpelewicz, B Greenberg, M Metra, T Severin, JR Teerlink, AA Voors, P Ponikowski

AIMS:Episodes of acute heart failure (AHF) may lead to end-organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD-XI (Model of End-Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF. METHODS AND RESULTS:On admission, the MELD-XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD-XI score remained constant through a 60 day follow-up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD-XI score on Day 2 and Day 5 (both P < 0.05), but this difference vs. placebo disappeared during longer follow-up. In the multivariable model, an elevated MELD-XI score on admission was associated with higher 180 day mortality: hazard ratios (95% confidence interval) for cardiovascular death were 3.10 (1.22-7.87), and for all-cause death 2.47 (1.19-5.15); both P < 0.05. The addition of the MELD-XI score to a prespecified prognostic model increased the discrimination of the model for all-cause death, but the increment in the C-index was only modest: 0.013 (P = 0.02). CONCLUSIONS:In patients with AHF, hepatorenal dysfunction is prevalent and related to poor outcome. The MELD-XI score is a useful prognosticator in AHF.


Trajectories of Changes in Renal Function in Patients with Acute Heart Failure.

Journal of cardiac failure 25 (2019) 866-874

IE Beldhuis, KW Streng, P van der Meer, JM Ter Maaten, CM O'Connor, M Metra, HC Dittrich, P Ponikowski, G Cotter, JGF Cleland, BA Davison, MM Givertz, JR Teerlink, DM Bloomfield, AA Voors, K Damman

BACKGROUND:Changes in renal function have been associated with differential outcomes in patients with acute heart failure (HF). However, individual trajectories of changes in renal function are unknown, and it is unclear whether they relate to different clinical characteristics and clinical outcomes. Our aim was to investigate the prognostic importance of individual trajectories of change in renal function in acute HF. METHODS:This was a retrospective, observational analysis from the double-blind, randomized, placebo-controlled PROTECT trial in patients with acute HF. We identified and internally validated 8 different renal trajectories among 1897 patients by visual inspection of inhospital serum creatinine changes. The primary outcome measure was all-cause mortality at 180 days. Mean age was 70 ± 12 years; 70% were male, and mean baseline estimated glomerular filtration rate was 49.0 mL/min/1.73m2. RESULTS:A total of 8 different trajectories was established. The most prevalent trajectories were an inhospital bump (19.0%), a sustained increase (17.6%) and a dip (14.5%) in serum creatinine. Overall, the clinical characteristics of patients in different trajectories were remarkably similar. Crude 180-day mortality rates ranged from 12.0% in the trajectory, with no significant changes to 18.3% in the trajectory of sustained increase without significant differences. Overall, after multivariable adjustment, there was no trajectory of changes in renal function that was associated with significantly better or worse outcomes. CONCLUSIONS:Trajectories of changes in renal function in acute HF differ considerably on the patient level. Despite these differences, clinical characteristics and outcomes were similar, therefore, questioning the prognostic importance of changes in renal function in acute HF.


Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies (STRONG-HF): rationale and design for a multicentre, randomized, parallel-group study.

European journal of heart failure 21 (2019) 1459-1467

A Kimmoun, G Cotter, B Davison, K Takagi, F Addad, J Celutkiene, O Chioncel, AC Solal, R Diaz, A Damasceno, H-D Duengen, G Filippatos, E Goncalvesova, I Merai, M Metra, P Ponikowski, D Privalov, K Sliwa, MU Sani, AA Voors, Z Shogenov, A Mebazaa

AIMS:Patients admitted for acute heart failure (HF) are at high risk of readmission and death, especially in the 90 days following discharge. We aimed to assess the safety and efficacy of early optimization of oral HF therapy with beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNi), and mineralocorticoid receptor antagonists (MRA) on 90-day clinical outcomes in patients admitted for acute HF. METHODS:In a multicentre, randomized, open-label, parallel-group study, a total of 900 patients will be randomized in a 1:1 ratio to either 'usual care' or 'high-intensity care'. Patients enrolled in the usual care arm will be discharged and managed according to usual clinical practice at the site. In the high-intensity care arm, doses of oral HF medications - including a BB, ACEi or ARB, and MRA - will be up-titrated to 50% of recommended doses before discharge and to 100% of recommended doses within 2 weeks of discharge. Up-titration will be delayed if the patients develop worsening symptoms and signs of congestion, hyperkalaemia, hypotension, bradycardia, worsening of renal function or significant increase in N-terminal pro-B-type natriuretic peptide between visits. The primary endpoint is 90-day all-cause mortality or HF readmission. CONCLUSIONS:STRONG-HF is the first study to assess whether rapid up-titration of evidence-based guideline-recommended therapies with close follow-up in a large cohort of patients discharged from an acute HF admission is safe and can affect adverse outcomes during the first 90 days after discharge. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT03412201.


Deviations from normal distributions in artificial and real time series: a false positive prescription

Monthly Notices of the Royal Astronomical Society Oxford University Press 489 (2019) 2117-2129

P Morris, N Chakraborty, G Cotter

<jats:title>ABSTRACT</jats:title> <jats:p>Time-series analysis allows for the determination of the Power Spectral Density (PSD) and Probability Density Function (PDF) for astrophysical sources. The former of these illustrates the distribution of power at various time-scales, typically taking a power-law form, while the latter characterizes the distribution of the underlying stochastic physical processes, with Gaussian and lognormal functional forms both physically motivated. In this paper, we use artificial time series generated using the prescription of Timmer &amp; Koenig to investigate connections between the PDF and PSD. PDFs calculated for these artificial light curves are less likely to be well described by a Gaussian functional form for steep (Γ⪆1) PSD indices due to weak non-stationarity. Using the Fermi LAT monthly light curve of the blazar PKS2155-304 as an example, we prescribe and calculate a false positive rate that indicates how likely the PDF is to be attributed an incorrect functional form. Here, we generate large numbers of artificial light curves with intrinsically normally distributed PDFs and with statistical properties consistent with observations. These are used to evaluate the probabilities that either Gaussian or lognormal functional forms better describe the PDF. We use this prescription to show that PKS2155-304 requires a high prior probability of having a normally distributed PDF, $P(\rm {G})~$ ≥ 0.82, for the calculated PDF to prefer a Gaussian functional form over a lognormal. We present possible choices of prior and evaluate the probability that PKS2155-304 has a lognormally distributed PDF for each.</jats:p>


Effects of Serelaxin in Patients with Acute Heart Failure.

The New England journal of medicine 381 (2019) 716-726

M Metra, JR Teerlink, G Cotter, BA Davison, GM Felker, G Filippatos, BH Greenberg, PS Pang, P Ponikowski, AA Voors, KF Adams, SD Anker, A Arias-Mendoza, P Avendaño, F Bacal, M Böhm, G Bortman, JGF Cleland, A Cohen-Solal, MG Crespo-Leiro, M Dorobantu, LE Echeverría, R Ferrari, S Goland, E Goncalvesová, A Goudev, L Køber, J Lema-Osores, PD Levy, K McDonald, P Manga, B Merkely, C Mueller, B Pieske, J Silva-Cardoso, J Špinar, I Squire, J Stępińska, W Van Mieghem, D von Lewinski, G Wikström, MB Yilmaz, N Hagner, T Holbro, TA Hua, SV Sabarwal, T Severin, P Szecsödy, C Gimpelewicz, RELAX-AHF-2 Committees Investigators

BACKGROUND:Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS:In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS:A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS:In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).


The feasibility of magnetic reconnection powered blazar flares from synchrotron self-Compton emission

Monthly Notices of the Royal Astronomical Society Oxford University Press (OUP) 486 (2019) 1548-1562

PJ Morris, WJ Potter, G Cotter

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