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1. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure

Author

Greenberg, B, Butler, J, Felker, GM, Ponikowski, P, Voors, AA, Pogoda, JM, Provost, R, Guerrero, J, Hajjar, RJ, and Zsebo, KM

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Heart Disease, Genetics, Biotechnology, Gene Therapy, Cardiovascular, Animals, Antibodies, Neutralizing, Antibodies, Viral, Dependovirus, Genetic Therapy, Genetic Vectors, Heart Failure, Humans, Models, Animal, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Swine, Swine, Miniature, Biological Sciences, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

Published
2016

2. Diuretic response in patients with acute decompensated heart failure: Characteristics and clinical outcome - An analysis from RELAX-AHF

Author

Teerlink, John, Voors, AA, Davison, BA, Teerlink, JR, Felker, GM, Cotter, G, Filippatos, G, Greenberg, BH, Pang, PS, Levin, B, and Hua, TA

Abstract

© 2014 The Authors European Journal of Heart Failure.Aims We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).Methods and results RELAX-AHF was

Published
2014

3. Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial: VICTORIA Outcomes Model

Author

Mentz, R, Mulder, H, Mosterd, A, Sweitzer, N, Senni, M, Butler, J, Ezekowitz, J, Lam, C, Pieske, B, Ponikowski, P, Voors, A, Anstrom, K, Armstrong, P, O'Connor, C, VICTORIA Study, G, Mentz RJ, Mulder H, Mosterd A, Sweitzer NK, Senni M, Butler J, Ezekowitz JA, Lam CSP, Pieske B, Ponikowski P, Voors AA, Anstrom KJ, Armstrong PW, O'Connor CM, VICTORIA Study Group, Mentz, R, Mulder, H, Mosterd, A, Sweitzer, N, Senni, M, Butler, J, Ezekowitz, J, Lam, C, Pieske, B, Ponikowski, P, Voors, A, Anstrom, K, Armstrong, P, O'Connor, C, VICTORIA Study, G, Mentz RJ, Mulder H, Mosterd A, Sweitzer NK, Senni M, Butler J, Ezekowitz JA, Lam CSP, Pieske B, Ponikowski P, Voors AA, Anstrom KJ, Armstrong PW, O'Connor CM, and VICTORIA Study Group

Abstract

Background: The prediction of outcomes in patients with heart failure (HF) may inform prognosis, clinical decisions regarding treatment selection, and new trial planning. The VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction included high-risk patients with HF with reduced ejection fraction and a recent worsening HF event. The study participants had a high event rate despite the use of contemporary guideline-based therapies. To provide generalizable predictive data for a broad population with a recent worsening HF event, we focused on risk prognostication in the placebo group. Methods and Results: Data from 2524 participants randomized to placebo with chronic HF (New York Heart Association functional class II–IV) and an ejection fraction of less than 45% were studied and backward variable selection was used to create Cox proportional hazards models for clinical end points, selecting from 66 candidate predictors. Final model results were produced, accounting for missing data, and nonlinearities. Optimism-corrected c-indices were calculated using 200 bootstrap samples. Over a median follow-up of 10.4 months, the primary outcome of HF hospitalization or cardiovascular death occurred in 972 patients (38.5%). Independent predictors of increased risk for the primary end point included HF characteristics (longer HF duration and worse New York Heart Association functional class), medical history (prior myocardial infarction), and laboratory values (higher N-terminal pro-hormone B-type natriuretic peptide, bilirubin, urate; lower chloride and albumin). Optimism-corrected c-indices were 0.68 for the HF hospitalization/cardiovascular death model, 0.68 for HF hospitalization/all-cause death, 0.72 for cardiovascular death, and 0.73 for all-cause death. Conclusions: Predictive models developed in a large diverse clinical trial with comprehensive clinical and laboratory baseline data—including novel measures—performed well in high-risk patients

Published
2021

4. A heart failure phenotype stratified model for predicting 1-year mortality in patients admitted with acute heart failure: results from an individual participant data meta-analysis of four prospective European cohorts

Author

Chen, YT, Voors, AA, Jaarsma, T, Lang, CC, Sama, IE, Akkerhuis, Martijn, Boersma, Eric, Hillege, HL, Postmus, D, Chen, YT, Voors, AA, Jaarsma, T, Lang, CC, Sama, IE, Akkerhuis, Martijn, Boersma, Eric, Hillege, HL, and Postmus, D

Abstract

Background: Prognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF. Methods: Four prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration. Results: 3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF < 40%), 588 as having HF with midrange EF (HFmrEF; EF 40–49%), and 621 as having HF with preserved EF (HFpEF; EF ≥ 50%). A total of 11 readily available variables built up the prognostic index. For four of these predictor variables, namely systolic blood pressure, serum creatinine, myocardial infarction, and diabetes, the effect differed across the three HF phenotypes. With a weighted IECV-adjusted AUC of 0.79 (0.74–0.83) for HFrEF, 0.74 (0.70–0.79) for HFmrEF, and 0.74 (0.71–0.77) for HFpEF, the model showed excellent discrimination. Moreover, there was a good agreement between the average observed and predicted 1-year mortality risks, especially after recalibration of the baseline mortality risks. Conclusions: Our HF phenotype stratified model showed excellent generalizability across four European cohorts and may provide a useful tool in HF phenotype-specific clinical decision-making.

Published
2021

5. Clinical Role of CA125 in Worsening Heart Failure A BIOSTAT-CHF Study Subanalysis

Author

Nunez, J, Bayes-Genis, A, Revuelta-Lopez, E, ter Maaten, JM, Minana, G, Barallat, J, Cserkoova, A, Bodi, V, Fernandez-Cisnal, A, Nunez, E, Sanchis, J, Lang, C, Ng, LL, Metra, M, Voors, AA, and Cardiovascular Centre (CVC)

Subjects
CA125, carbohydrate antigen 125, congestion, outcome, worsening heart failure, endocrine system diseases, NATRIURETIC PEPTIDE, HOSPITALIZATION, MORTALITY, ANTIGEN CARBOHYDRATE 125
Abstract

OBJECTIVES The aim of this study was to evaluate the association between antigen carbohydrate 125 (CA125) and the risk of 1-year clinical outcomes in patients with worsening heart failure (HF). BACKGROUND CA125 is a widely available biomarker that is up-regulated in patients with acute HF and has been postulated as a useful marker of congestion and risk stratification. METHODS hi a large multicenter cohort of patients with worsening HF, either in-hospital or in the outpatient setting, the independent associations between CA125 and 1-year death and the composite of death/HF readmission (adjusted for outcome-specific prognostic risk score [BIOSTAT risk score]) were determined by using the Royston-Parmar method (N = 2356). In a sensitivity analysis, the prognostic implications of CA125 were also adjusted for a composite congestion score (CCS). Data were validated in the B1OSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure validation) cohort (N = 1,630). RESULTS Surrogates of congestion, such as N-terminal pro-B-type natriuretic peptide and CCS, emerged as independent predictors of CA125. In muttivariabte survival analyses, higher CA125 was associated with an increased risk of mortality and the composite of death/HF readmission (p < 0.001 for both comparisons), even after adjustment for the CCS (p < 0.010 for both comparisons). The addition of CA125 to the B1OSTAT score led to a significant risk reclassification for both outcomes (category-free net reclassification improvement 0.137 [p < 0.001] and 0.104 [p 0.003] respectively). AR outcomes were confirmed in an independent validation cohort. CONCLUSIONS In patients with worsening HF, higher levels of CA125 were positively associated with parameters of congestion. Furthermore, CA125 remained independently associated with a higher risk of clinical outcomes, even beyond a predefined risk model and clinical surrogates of congestion. (C) 2020 by the American College of Cardiology Foundation.

Published
2020

6. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

Author

Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam CSP, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM, and VICTORIA Study Group

Subjects
animal structures
Abstract

The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear.

Published
2020

7. Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial

Author

Butler, J, Khan, M, Anker, S, Fonarow, G, Kim, R, Nodari, S, O'Connor, C, Pieske, B, Pieske-Kraigher, E, Sabbah, H, Senni, M, Voors, A, Udelson, J, Carr, J, Gheorghiade, M, Filippatos, G, Butler J, Khan MS, Anker SD, Fonarow GC, Kim RJ, Nodari S, O'Connor CM, Pieske B, Pieske-Kraigher E, Sabbah HN, Senni M, Voors AA, Udelson JE, Carr J, Gheorghiade M, Filippatos G, Butler, J, Khan, M, Anker, S, Fonarow, G, Kim, R, Nodari, S, O'Connor, C, Pieske, B, Pieske-Kraigher, E, Sabbah, H, Senni, M, Voors, A, Udelson, J, Carr, J, Gheorghiade, M, Filippatos, G, Butler J, Khan MS, Anker SD, Fonarow GC, Kim RJ, Nodari S, O'Connor CM, Pieske B, Pieske-Kraigher E, Sabbah HN, Senni M, Voors AA, Udelson JE, Carr J, Gheorghiade M, and Filippatos G

Abstract

Background: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging. Methods: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days. Results: The mean age (standard deviation) of the study population was 65 ± 10 years, 24% were females, and the mean EF was 31% ± 7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4 mg (89.4 mL to 85 mL; difference, −4.4 mL) or 40 mg (77.9 mL to 76.6 mL; difference, −1.2 mL) compared with placebo (77.7 mL to 74.6 mL; difference, −3.8 mL) (4 mg vs placebo: difference of means, −0.3; 95% CI, −4.6 to 4.0; P = 0.90; and 40 mg vs placebo: difference of means, 2.3; 95% CI, −1.9 to 6.5; P = 0.28). Also, no significant differences in change in LVESV and LVEF were observed between placebo and either of the elamipretide groups. Rates of any study drug-related adverse events were similar in the 3 groups. Conclusions: Elamipretide was well tolerated but did not improve LVESV at 4 weeks in patients with stable HFrEF compared with placebo.

Published
2020

9. NHG-Standaard Hartfalen

Author

Hoes, AW, primary, Voors, AA, additional, Rutten, FH, additional, Van Lieshout, J, additional, Janssen, PGH, additional, and Walma, EP, additional

Published
2011
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10. Safety and efficacy of the partial adenosine A1 receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced ejection fraction: a phase IIb, randomized, double-blind, placebo-controlled trial

Author

Voors, A, Bax, J, Hernandez, A, Wirtz, A, Pap, A, Ferreira, A, Senni, M, van der Laan, M, Butler, J, Voors AA, Bax JJ, Hernandez AF, Wirtz AB, Pap AF, Ferreira AC, Senni M, van der Laan M, Butler J, Voors, A, Bax, J, Hernandez, A, Wirtz, A, Pap, A, Ferreira, A, Senni, M, van der Laan, M, Butler, J, Voors AA, Bax JJ, Hernandez AF, Wirtz AB, Pap AF, Ferreira AC, Senni M, van der Laan M, and Butler J

Abstract

Aims: Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose–response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods and results: PANTHEON was a dose-finding, phase IIb, randomized, double-blind, placebo-controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo. The primary endpoints were change from baseline to 20 weeks in left ventricular ejection fraction (LVEF) (echocardiography) and in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Mean age of the patients was 67 years, 17% were female, mean LVEF was 28%, mean NT-proBNP was 2085 ng/L. After 20 weeks of treatment, there was no dose–effect of neladenoson bialanate on changes in NT-proBNP or LVEF (primary endpoints). No effect of neladenoson bialanate was found on left ventricular volumes, high-sensitivity troponin T, or cardiovascular mortality, HF hospitalization, and urgent visits for HF (secondary endpoints). There was a dose-dependent increase in creatinine and cystatin C, and a dose-dependent decrease in estimated glomerular filtration rate and heart rate. Conclusions: In patients with chronic HFrEF, treatment with neladenoson bialanate was not associated with dose-dependent favourable effects on cardiac structure and function, cardiac risk markers, or clinical outcome but was associated with a dose-dependent decrease in renal function. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02992288.

Published
2019

11. The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis

Author

Bayes-Genis, A, Núñez, J, Zannad, F, Ferreira, JP, Anker, SD, Cleland, JG, Dickstein, K, Filippatos, G, Lang, CC, Ng, LL, Ponikowski, P, Samani, NJ, Van Veldhuisen, DJ, Zwinderman, AH, Metra, M, Lupón, J, and Voors, AA

Subjects
Heart Failure, Male, Risk, 1102 Cardiovascular Medicine And Haematology, PCSK9, LDLR, low-density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9, Receptors, LDL, 1117 Public Health And Health Services, Cardiovascular System & Hematology, Multivariate Analysis, Humans, Prospective Studies, Proprotein Convertase 9, Aged, Forecasting, Proportional Hazards Models
Abstract

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression. OBJECTIVES: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF). METHODS: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores. RESULTS: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance. CONCLUSIONS: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

Published
2017

13. Eplerenone in patients with systolic heart failure and mild symptoms

Author

Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, Drexler H, McMurray J, Remme WJ, Cornel JH, Hildebrandt P, Hradec J, Mareev V, Reddy KS, Sindone A, Martinez F, Alonso Garcia A, Wilhelmsen L, Dargie HJ, Tavazzi L, Pocock S, Leizorovic A, Collier T, Nul DR, Serra JL, Thierer JM, Cross DB, Sindone AP, Singh BB, Boreux JL, Charlier FP, Dendale P, De Keulenaer G, Marchandise B, Marechal P, Marenne F, Mieghem WV, Van Dorpe AC, Vanhaecke J, Arnold JM, Dion D, Huynh T, Kouz SM, Lepage S, McKelvie RS, O'Meara E, Proulx G, Sauve C, Aschermann M, Brecka D, Filipovsky J, Groch L, Jerabek O, Jokl I, Linkova H, Motovska Z, Munz J, Penicka M, Rucka D, Mid JS, Spacek R, Spinar J, Stipal R, Vojacek J, Attali P, Bonneau A, Bousser JP, Dutoit L, Funck F, Galinier MP, Gibelin P, Hautefeuille BD, Hittinger L, Jobic Y, Jourdain P, Komajda M, Maupas E, Olive T, Philias A, Roul G, Rouleau F, Trochu JN, Boehm M, Bruch L, Engelhardt H, Erbs S, Foerster A, Franz N, Hambrecht R, Heuer H, Krueger U, Landmesser U, Leischik R, Mitrovic V, Moehlenkamp S, Monti J, Mueller Ehmsen J, Oezcelik C, Philipp S, Pieske B, Roehnisch JU, Schunkert H, Schwinger R, Wachter R, Willenbrock R, Winkelmann BR, Winkler R, Wollert KC, Adamopoulos S, Kalikazaros I, Karavidas A, Karvounis H, Kremastinos D, Manolis AJ, Nanas I, Sotirellos K, Vasiliadis K, Zaboulis C, Lee S, Yu CM, Czibok C, Édes I, Forster T, Preda I, Simon K, Takacs J, Zámolyi K, Bhagavatula KS, Chockalingam K, Desai N, Iyengar SS, Jayadev SM, Mullasari AS, Sathe SP, Sinha N, Vadagenalli PS, Wander GS, McDonald KM, Nash P, Vaughan CJ, Agostoni P, Ambrosio GB, Bittolo Bon G, Boffa G, Cacciavillani L, Capucci A, Chiariello M, Cirrincione V, Gensini GF, Masini F, Modena MG, Monte I, Rosano GM, Senni M, Sinagra G, Tamburino C, Terrosu P, Villani GQ, Volterrani M, Chae SC, Ha CW, Ha JW, Shin JH, Bayram Llamas E, Calvillo JC, Cruz Diaz A, Delgado Leal L, Estrada Gomez MM, Kosturakis D, Petersen Aranguren F, Velasco Sanchez RG, Daniëls MC, Dirkali A, Dunselman PH, de Kluiver EP, Kragten JA, Lok DJ, Maas AH, Michels HR, Nicastia DM, Stoel I, de Swart JB, Thijssen HJ, Van Kempen LH, Voors AA, Willems FF, Dluzniewski M, Gaciong Z, Kawecka Jaszcz K, Jozwa R, Korewicki J, Krzeminska Pakula M, Kurowski M, Ogorek M, Pempera M, Rynkiewicz A, Ujda M, Wierzchowiecki M, Abreu Á, Andrade A, Carrageta M, Fonseca C, Franco F, Gil VM, Lousada N, Mendonca C, Moreira I, Padua FP, Providência L, Cardoso JC, Trabulo M, Aroutyunov GP, Gindin K, Karpov YB, Kostenko VA, Nikitin YP, Obraztsova GI, Shilkina NP, Shlyakhto EV, Skvortsov A, Ding ZP, Yeo DP, Ambrovicova V, Gaspar L, Goncalvesova E, Kycina P, Litvinova J, Mikes Z, Murin J, Poliacik P, Uhliar R, Lloyd EA, Marx D, Naidoo DP, Prozesky HW, Sliwa Hahnle K, Theron H, Anguita M, De Teresa E, Galve E, Juanatey JR, Orbe PM, Vida M, Ahremark U, Andersson B, Axelsson U, Berglund S, Boman K, Dahlstrom U, Fu M, Holm Orndahl L, Johansson A, Lindgren M, Nemeczek C, Prantare H, Roussine V, Stehn G, Stenberg A, Vasko P, Bazylevych A, Dyadyk OI, Dzyak GV, Girina OM, Ignatenko GA, Kononenko LG, Kubyshkin VF, Kuryata OV, Parkhomenko AN, Perepelytsya MV, Pertseva TO, Popik GS, Rishko MV, Sakharchuk II, Tseluyko VI, Tykhonova SA, Vizir V, Voronkov LG, Al Khaja N, Almahmeed WA, Bazargani N, Adgey AA, Al Mohammad A, Banerjee P, Barlow M, Bridges AB, Brooks N, Connolly EC, Denvir MA, Egdell RM, Kardos A, Keeling PJ, Khokhar AA, Senior R, Williams SG, Anand IS, Anderson JL, Berk MR, Bertolet BD, Bisognano JD, Blonder RD, Breburda CS, Canaday DB, Capodilupo RC, Choiunard MD, Colucci WS, Dahiya RJ, Dunlap SH, Essandoh LK, Flores AR, Henderson DA, Herzog WR Jr, Katz RJ, Kosinski EJ, Labin IN, Lally FL, Lash JA, McGrew FA 3rd, Mohiuddin SM, Moraes D, Murali SC, Nallasivan M, Philbin E, Prabhu S, Primack DS, Ramani R, Rawitscher D, Sangrigoli R, Schamalfuss CM, Stoletniy L, Strong MH, Thadani U, Treasure CB 2nd, Vicari RM, Vogel CD, Wlsh MN, Wencker D, Wilson SA, Winkel E, Wiseman AH, Zoiopoulos LY, Mancebo JR, Mendoza I, Waich S.T., PERRONE FILARDI, PASQUALE, Zannad, F, Mcmurray, Jj, Krum, H, van Veldhuisen, Dj, Swedberg, K, Shi, H, Vincent, J, Pocock, Sj, Pitt, B, Drexler, H, Mcmurray, J, Remme, Wj, Cornel, Jh, Hildebrandt, P, Hradec, J, Mareev, V, Reddy, K, Sindone, A, Martinez, F, Alonso Garcia, A, Wilhelmsen, L, Dargie, Hj, Tavazzi, L, Pocock, S, Leizorovic, A, Collier, T, Nul, Dr, Serra, Jl, Thierer, Jm, Cross, Db, Sindone, Ap, Singh, Bb, Boreux, Jl, Charlier, Fp, Dendale, P, De Keulenaer, G, Marchandise, B, Marechal, P, Marenne, F, Mieghem, Wv, Van Dorpe, Ac, Vanhaecke, J, Arnold, Jm, Dion, D, Huynh, T, Kouz, Sm, Lepage, S, Mckelvie, R, O'Meara, E, Proulx, G, Sauve, C, Aschermann, M, Brecka, D, Filipovsky, J, Groch, L, Jerabek, O, Jokl, I, Linkova, H, Motovska, Z, Munz, J, Penicka, M, Rucka, D, Mid, J, Spacek, R, Spinar, J, Stipal, R, Vojacek, J, Attali, P, Bonneau, A, Bousser, Jp, Dutoit, L, Funck, F, Galinier, Mp, Gibelin, P, Hautefeuille, Bd, Hittinger, L, Jobic, Y, Jourdain, P, Komajda, M, Maupas, E, Olive, T, Philias, A, Roul, G, Rouleau, F, Trochu, Jn, Boehm, M, Bruch, L, Engelhardt, H, Erbs, S, Foerster, A, Franz, N, Hambrecht, R, Heuer, H, Krueger, U, Landmesser, U, Leischik, R, Mitrovic, V, Moehlenkamp, S, Monti, J, Mueller Ehmsen, J, Oezcelik, C, Philipp, S, Pieske, B, Roehnisch, Ju, Schunkert, H, Schwinger, R, Wachter, R, Willenbrock, R, Winkelmann, Br, Winkler, R, Wollert, Kc, Adamopoulos, S, Kalikazaros, I, Karavidas, A, Karvounis, H, Kremastinos, D, Manolis, Aj, Nanas, I, Sotirellos, K, Vasiliadis, K, Zaboulis, C, Lee, S, Yu, Cm, Czibok, C, Édes, I, Forster, T, Preda, I, Simon, K, Takacs, J, Zámolyi, K, Bhagavatula, K, Chockalingam, K, Desai, N, Iyengar, S, Jayadev, Sm, Mullasari, A, Sathe, Sp, Sinha, N, Vadagenalli, P, Wander, G, Mcdonald, Km, Nash, P, Vaughan, Cj, Agostoni, P, Ambrosio, Gb, Bittolo Bon, G, Boffa, G, Cacciavillani, L, Capucci, A, Chiariello, M, Cirrincione, V, Gensini, Gf, Masini, F, Modena, Mg, Monte, I, PERRONE FILARDI, Pasquale, Rosano, Gm, Senni, M, Sinagra, G, Tamburino, C, Terrosu, P, Villani, Gq, Volterrani, M, Chae, Sc, Ha, Cw, Ha, Jw, Shin, Jh, Bayram Llamas, E, Calvillo, Jc, Cruz Diaz, A, Delgado Leal, L, Estrada Gomez, Mm, Kosturakis, D, Petersen Aranguren, F, Velasco Sanchez, Rg, Daniëls, Mc, Dirkali, A, Dunselman, Ph, de Kluiver, Ep, Kragten, Ja, Lok, Dj, Maas, Ah, Michels, Hr, Nicastia, Dm, Stoel, I, de Swart, Jb, Thijssen, Hj, Van Kempen, Lh, Voors, Aa, Willems, Ff, Dluzniewski, M, Gaciong, Z, Kawecka Jaszcz, K, Jozwa, R, Korewicki, J, Krzeminska Pakula, M, Kurowski, M, Ogorek, M, Pempera, M, Rynkiewicz, A, Ujda, M, Wierzchowiecki, M, Abreu, Á, Andrade, A, Carrageta, M, Fonseca, C, Franco, F, Gil, Vm, Lousada, N, Mendonca, C, Moreira, I, Padua, Fp, Providência, L, Cardoso, Jc, Trabulo, M, Aroutyunov, Gp, Gindin, K, Karpov, Yb, Kostenko, Va, Nikitin, Yp, Obraztsova, Gi, Shilkina, Np, Shlyakhto, Ev, Skvortsov, A, Ding, Zp, Yeo, Dp, Ambrovicova, V, Gaspar, L, Goncalvesova, E, Kycina, P, Litvinova, J, Mikes, Z, Murin, J, Poliacik, P, Uhliar, R, Lloyd, Ea, Marx, D, Naidoo, Dp, Prozesky, Hw, Sliwa Hahnle, K, Theron, H, Anguita, M, De Teresa, E, Galve, E, Juanatey, Jr, Orbe, Pm, Vida, M, Ahremark, U, Andersson, B, Axelsson, U, Berglund, S, Boman, K, Dahlstrom, U, Fu, M, Holm Orndahl, L, Johansson, A, Lindgren, M, Nemeczek, C, Prantare, H, Roussine, V, Stehn, G, Stenberg, A, Vasko, P, Bazylevych, A, Dyadyk, Oi, Dzyak, Gv, Girina, Om, Ignatenko, Ga, Kononenko, Lg, Kubyshkin, Vf, Kuryata, Ov, Parkhomenko, An, Perepelytsya, Mv, Pertseva, To, Popik, G, Rishko, Mv, Sakharchuk, Ii, Tseluyko, Vi, Tykhonova, Sa, Vizir, V, Voronkov, Lg, Al Khaja, N, Almahmeed, Wa, Bazargani, N, Adgey, Aa, Al Mohammad, A, Banerjee, P, Barlow, M, Bridges, Ab, Brooks, N, Connolly, Ec, Denvir, Ma, Egdell, Rm, Kardos, A, Keeling, Pj, Khokhar, Aa, Senior, R, Williams, Sg, Anand, I, Anderson, Jl, Berk, Mr, Bertolet, Bd, Bisognano, Jd, Blonder, Rd, Breburda, C, Canaday, Db, Capodilupo, Rc, Choiunard, Md, Colucci, W, Dahiya, Rj, Dunlap, Sh, Essandoh, Lk, Flores, Ar, Henderson, Da, Herzog WR, Jr, Katz, Rj, Kosinski, Ej, Labin, In, Lally, Fl, Lash, Ja, McGrew FA, 3rd, Mohiuddin, Sm, Moraes, D, Murali, Sc, Nallasivan, M, Philbin, E, Prabhu, S, Primack, D, Ramani, R, Rawitscher, D, Sangrigoli, R, Schamalfuss, Cm, Stoletniy, L, Strong, Mh, Thadani, U, Treasure CB, 2nd, Vicari, Rm, Vogel, Cd, Wlsh, Mn, Wencker, D, Wilson, Sa, Winkel, E, Wiseman, Ah, Zoiopoulos, Ly, Mancebo, Jr, Mendoza, I, and Waich, S. T.

Published
2011

14. Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

Author

Parving, Hh, Brenner, Bm, Mcmurray, Jj, de Zeeuw, D, Haffner, Sm, Solomon, Sd, Chaturvedi, N, Persson, F, Desai, As, Nicolaides, M, Richard, A, Xiang, Z, Brunel, P, Pfeffer, Ma, Viberti, G, Lachin, Jm, Zinman, B, Pedersen, Tr, Villamil, As, Juncos, L, Prager, R, Verpooten, G, Zanella, Mt, Leiter, L, Pan, C, Wang, H, Botero, R, Cifkova, R, Christiansen, Js, Groop, Ph, Marre, M, Haller, H, Nickenig, G, Siamopoulos, K, Gero, L, Maggioni, A, Remuzzi, G, Katayama, Ss, Kim, Sg, Petrulioniene, Z, Lok, D, Kooy, A, Jorde, R, Medina, F, Polonia, J, Wong, Ks, Dukat, A, Rayner, Bl, Ruilope, L, Weiss, L, Wuethrich, R, Sheu, W, Sritara, P, Comlekci, A, Bilous, R, Toto, R, Jamerson, K, Carillo, E, Orias, M, Kuschnir, E, Rusculleda, M, Garcia, S, Farias, E, Lema, L, Hominal, M, Montaña, O, Sala, J, Diaz, M, Piskorz, D, Vita, N, Litwak, L, Sinay, I, Marin, M, Massari, P, Majul, C, Aizemberg, D, Azize, Gm, Bartolacci, I, Reboredo, A, Vico, M, Milesi, R, Sessa, H, Wassermann, A, Margulis, F, Zangroniz, P, Watschinger, B, Toplak, H, Paulweber, B, Drexel, H, Francesconi, C, Foeger, B, Mayer, G, Braun, Rk, Brath, H, Gaal, Lv, Niepen, Pv, Persu, A, Vercammen, C, Vriese, Ad, Coucke, F, Mathieu, C, Fery, F, Treille, S, Meeus, G, Acker, Kv, Scheen, A, Tits, J, Ruige, J, Krzesinski, Jm, Hollanders, G, Liénart, F, Dendale, P, Quinonez, M, Arnouts, P, Vanuytsel, J, Zanella, M, Mion D., Jr, Forti, A, Almeida, F, Cunha, R, de Paula RB, Brandao, A, Rocha, J, Krieger, E, Feitosa, G, Saraiva, J, Martin, J, Hissa, Mn, Schmid, H, Felicio, J, Sgarbi, J, Oigman, W, Bowering, K, Garceau, C, Berlingieri, Jc, Weisnagel, Sj, Hardin, P, Powell, C, Turcot, R, Muirhead, N, Aronson, R, Barima, Yt, Steele, Aw, Pandey, S, Woo, V, Cha, J, Dattani, D, Godin, C, Gupta, M, Saunders, K, Tellier, G, Ting, R, Tobe, S, Chouinard, G, Schlosser, R, Khandwala, H, Ekoe, Jm, Harris, Sb, Pichette, V, Lachance, P, Ooi, Tc, Tildesley, H, Barrett, B, Cournoyer, S, Lu, J, Zhang, H, Liu, X, Yan, S, Qi, X, Li, Q, Li, H, Lv, X, Yang, J, Sun, N, Xia, W, Wang, N, Tong, N, Mei, C, Gu, S, Zhang, J, Chen, X, Li, L, Su, B, Wang, L, Qiu, M, Wu, X, Liu, Z, Jia, W, Xu, G, Dong, J, Zhu, D, Zhang, M, Yan, J, Liu, B, Chen, J, Fu, J, Yan, L, Zhan, X, Zhong, L, Yang, T, Ma, J, Xu, M, Xu, X, Shi, B, Ji, Q, Zhong, H, He, R, Yuan, Z, Zhou, Z, Lin, H, Yang, W, Ke, Y, Hong, T, Franco, C, Casas, L, Triana, A, Jaramillo, C, Hernandez, E, Barrera, C, Blanco, D, Stipal, R, Widimsky, P, Dohnalova, L, Komroskova, M, Kvapil, M, Belobradkova, J, Tesar, V, Vodnansky, P, Kocourkova, B, Lervang, Hh, Perrild, H, Rossing, P, Oestergaard, O, Juhl, H, Thorsteinsson, B, Snorgaard, O, Urhammer, S, Egstrup, K, Tikkanen, T, Helin, K, Rinne, J, Lahtela, J, Strand, J, Valtonen, E, Saari, M, Kananen, K, Savela, K, Blacher, J, Aldigier, Jc, Zaoui, P, Fauvel, Jp, Gouet, D, Valensi, Pe, Charpentier, G, Marechaud, R, Penfornis, A, Ovize, M, Kovalchuck, Aa, Dellanna, F, Schoen, N, Groeschel, W, Eickhoff, F, Hanefeld, M, Merke, J, Rambausek, M, Zimmermann, U, Stuetz, W, Vosskuehler, A, Hevendehl, G, Schax, U, Lehmann, G, Haack, A, Hilgenberg, J, Klausmann, G, Adelberger, V, Gessner, S, Fiesselmann, A, Oerter, E, Hohenstatt, T, Groeschel, A, Behnke, T, Sisting, Rt, Schoch, D, Bieler, T, Schleyer, S, Altes, U, Klepzig, C, Rudofsky, G, Mueller, G, Burkhardt, F, Reschke, K, Senftleber, I, Wiesweg, Ck, Herrmann, Hj, Brandstetter, R, Segner, A, Schmitt, H, Rippert, R, Goebel, R, Schreibmueller, F, Pencz, I, Ott, P, Migdalis, I, Pappas, S, Pagkalos, E, Yalouris, A, Tsapas, A, Maltezos, E, Tentolouris, N, Papadakis, I, Ioannidis, G, Goumenos, D, Corona, V, Gonzalez, R, Haase, F, Monterroso, V, Sánchez, V, Turcios, E, Wyss, F, Arango, Jl, Bako, B, Deak, L, Dömötör, E, Dudas, M, Fulop, T, Kiss, I, Koranyi, L, Lengyel, Z, Nyirati, G, Oroszlan, T, Aniko, S, Vörös, P, Kapocsi, J, Wittmann, I, Paragh, G, Abraham, G, Tandon, N, Thomas, N, Mohan, V, Sahay, R, Sethi, B, Rao, V, Kumar, S, Chowdhury, S, Dharmalingam, M, Seshiah, V, Bantwal, G, Viswanathan, V, Yajnik, C, Adhikari, P, Krishnan, U, Varthakavi, P, Hiremath, J, Bhattacharyya, A, Dani, S, Modi, Kk, Glorioso, N, Morosetti, M, Veglio, Franco, Perticone, F, Dotta, F, Quarello, F, Sesti, G, Aiello, A, D'Ospina, A, Giordano, C, Novo, S, Santoro, A, Ferri, C, Capuano, V, Trimarco, B, Tonolo, G, Villa, G, De Pellegrin, A, Zanette, G, Federici, M, Aucello, G, Piatti, P, Vinciguerra, A, Mannarino, E, Taddei, S, Filetti, S, Grandaliano, G, Marchionni, N, Lambiase, C, Locatelli, F, Scanferla, F, Lembo, G, Leotta, S, Mos, L, Calatola, P, Fogari, R, David, S, Pedrinelli, R, Pignone, Am, Cozzolino, D, Bevilacqua, Mt, Catena, C, Del Prato, S, Cerasola, G, Frontoni, S, Falcone, C, Porta, A, Bonora, E, Cocchi, R, Fucili, A, Frisinghelli, A, Volpe, M, Carugo, S, Gambardella, S, Spagnuolo, V, Maglia, G, D'Angelo, Ar, Corsi, A, Limone, Pp, Guarnieri, A, Ghigo, Ezio, Ronchi, E, Ravera, M, Scioli, Ga, Sekiguchi, M, Aoki, S, Ogawa, Y, Seino, H, Onishi, Y, Tojo, A, Narimiya, M, Iwaita, Y, Takeda, H, Shimizu, H, Yamada, T, Kojima, S, Zushi, S, Kaneko, S, Matsumoto, A, Kajiyama, S, Fujita, H, Shikata, K, Tone, A, Matsubayashi, S, Tanaka, S, Sekigami, T, Tatsukawa, Y, Abe, N, Kawahara, K, Kasahara, H, Maeda, Y, Suzuki, Y, Okamoto, H, Tachi, K, Yamada, K, Uzu, T, Itou, T, Fukui, T, Kim, S, Kim, Y, Cho, W, Kwak, I, Chae, D, Oh, H, Ha, S, Shin, Y, Cha, D, Kang, S, Lim, C, Song, J, Kwon, Y, Badariene, J, Labutiniene, Ip, Zabuliene, L, Poteliuniene, V, Miglinas, M, van den Meiracker AH, Gregoor, Pj, Luik, Aj, van Loon BJ, Feenstra, Hj, Kaasjager, Ha, Viergever, Pp, Woittiez, Aj, van Bemmel, T, Lieverse, Ag, Simsek, S, Gaillard, Ca, van der Zwaan, C, Lok, Dj, Spiering, W, Nierop, Pr, Baggen, Mg, Leendert, Rj, de Jong, A, Leurs, Pb, Vincent, Hh, Wins, Eh, Voors, Aa, Ronner, E, Heeg, Je, van Hal JM, Boermans, T, Feis, Wl, Mostard, G, Bakker, Rc, Dunselman, Ph, Skeie, S, Istad, H, Skjelvan, G, Gronert, J, Tomala, T, Gudnason, S, Torvik, Dt, Risberg, K, Abedini, S, Cabrera, W, Medina, B, Herrada, B, Saavedra, A, Polonia, Dj, Providencia, Dl, Carvalho, D, Vasconcelos, Mp, da Silva GF, Branco, P, Gil, Dv, da Costa AG, da Silva PM, Arez, L, Martins, L, Birne, R, Dzuponova, J, Surovcikova, M, Culak, J, Filipova, S, Andre, I, Stevlik, J, Uhliar, R, Fabryova, L, Benacka, J, Koleny, D, Szentivanyi, M, Spisak, V, Pella, D, Pastrnakova, E, Martinka, E, Chua, T, Lau, T, Ng, Tg, Yeoh, Ly, Bhana, Sa, Rayner, B, Wellmann, H, Amod, A, Ranjith, N, Ahmed, F, Rheeder, P, Makan, H, Naicker, P, Podgorski, G, De Teresa, E, Olivan, J, Fernandez, Vl, Povedano, St, Terns, M, Ricart, W, Gonzalez, Jm, Fernandez, P, Parreño Lde, T, Redon, J, Parra, J, Calvo, C, Lopez, I, Puig, Jg, Calle, A, Garcia, Jc, Lopez, Jm, Jimenez, Ml, Fraile, B, Perez, Js, Nadal, Jj, Guija, E, Calviño, J, Barrios, V, Iglesias, Jn, Armario, P, Garcia, M, Aranda, P, Brotons, C, Gomez, P, Catelao, Am, Cusachs, Ar, Sarro, M, Martinez, V, dell Valle MH, Trias, F, Comas, A, Salvador, N, Martinez, F, Hernandez, F, Martinez, J, Mateos, C, Peral, Jl, Tolosana, J, Sobrino, J, Isart, J, Vizcaino, J, Vega, Ff, Zamorano, Jl, Bacariza, M, Soubriet, A, Fernández Cruz, A, Querejeta, R, Leira, Vm, Iglesias, Fe, Ibrik, O, Martin, D, Nanclares, Ms, Mediavilla, Jd, Galceran, Jm, Lopez, A, Muros, T, Pascual, J, Casalla, F, Tornero, F, Fernandez, G, Pettersson, P, Olsen, H, Franke, F, Stroembom, U, Furuland, H, Larnefelt, H, Allemann, Y, Krapf, R, Gerber, P, Munger, R, Hayoz, D, Graf, Hj, Burnier, M, Petrillo, A, Batt, R, Constam, En, Moccetti, T, Bianda, T, Rickli, H, Bulliard, C, Wu, Kd, Lin, Sh, Wu, Cj, Sheu, Wh, Su, Sl, Chen, Sc, Chou, Cw, Lee, Ct, Yang, Tc, Chen, Hc, Sukonthasarn, A, Sriratanasathavorn, C, Eiam Ong, S, Supasyndh, O, Chanchairujira, T, Kitiyakara, C, Arici, M, Usalan, C, Guneri, S, Koc, M, Kalender, B, Ates, K, Gurgun, C, Araz, M, Demirbas, B, Biernacki, W, Calvert, J, Eavis, P, Kerrane, J, Litchfield, J, Middleton, A, Roberts, J, Simpson, H, Charles, H, Jardine, A, Fisher, M, Banerjee, D, Gallen, I, Gnudi, L, Harvey, J, O'Hare, P, Vora, J, Winocour, P, Soran, H, Browne, D, Darko, D, Mancebo, Jg, de Roa ER, Antepara, N, Carrillo, E, Berrizbeitia, M, Guevara, L, Pernalete, N, Ontiveros, C, Zigrang, W, Blakney, E, Rosenblit, P, Weinstein, R, Klaff, L, Lipetz, R, Busick, E, Tung, P, Cooperman, M, Michael, S, Sun, Ch, Hart, T, Maddux, A, Bowden, R, East, C, Arakaki, R, Villafuerte, B, Mamish, Z, Mendez, R, Connery, L, Nour, K, Wynne, A, Busch, R, Zamora, B, Sachson, R, Prasad, J, Lasala, G, Smith, M, Fitz Patrick, D, Ruiz Rivera, L, Barranco, E, Solomon, R, Woolley, A, Brown, C, Freedman, Z, Schmidt, S, Pollock, J, Ruddy, M, Kopyt, Np, Bazzi, A, Horowitz, B, Feng, W, Wahl, T, Duprez, D, Gilbert, J, Steigerwalt, S, Jacqmein, J, Gorton, S, 3rd, Allison J., Pino, J, Lock, J, Leimbach, W, Anderson, J, Beacom, M, Craig, W, Gorson, D, Kerstein, H, Segal, S, Downey, H, Ledger, G, Mcgill, J, Gabriel, J, Nolen, T, Levinson, L, Williams, T, Levenson, D, Lerman, S, Minehart, C, Agarwal, N, Verma, S, Valitutto, M, Demetry, K, Mersey, J, Koeper, D, Fanti, P, Eng, G, Grimm, R, Fagan, T, Bajaj, M, Katz, L, Portnay, G, Altschuller, A, Desai, V, Bilazarian, S, Ipp, E, Rodelas, R, Burstein, D, Berg, J, Velez, J, Lund, R, Rekhi, A, Martin, E, Robertson, D, Singh, N, Narayan, P, Moustafa, M, Lanier, D, Seidner, M, Phillips, A, Vaughters, B, Sprague, A, Swartz, S, Lopez, R, Kumar, J, Bressler, P, Sadler, L, Wise, J, Kilbane, A., and Groningen Kidney Center (GKC)

Subjects
Male, Hyperkalemia, CARDIOVASCULAR MORTALITY, BLOOD-PRESSURE, Angiotensin-Converting Enzyme Inhibitors, Type 2 diabetes, GLOMERULAR-FILTRATION-RATE, DOUBLE-BLIND, chemistry.chemical_compound, Fumarates, cardiovascular disease, Renin, Treatment Failure, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, 610 Medicine & health, diabetes, Medicine (all), Hazard ratio, aliskiren, diabete, trial clinico, Liter, General Medicine, Middle Aged, hypertension, Cardiovascular Diseases, Combination, HEART-FAILURE, Drug Therapy, Combination, Female, Kidney Diseases, type 2 diabetes, medicine.symptom, Type 2, medicine.medical_specialty, Patient Dropouts, Urology, Hypokalemia, Aliskiren, chronic kidney disease, Placebo, Angiotensin Receptor Antagonists, LEFT-VENTRICULAR DYSFUNCTION, Drug Therapy, Double-Blind Method, Diabetes Mellitus, medicine, Humans, CONVERTING-ENZYME INHIBITORS, Antihypertensive Agents, Aged, Amides, Diabetes Mellitus, Type 2, Follow-Up Studies, business.industry, medicine.disease, Confidence interval, Surgery, Blood pressure, MYOCARDIAL-INFARCTION, chemistry, SYSTOLIC DYSFUNCTION, FOLLOW-UP, business
Abstract

BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, = 6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P CONCLUSIONS The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.)

Published
2012
Full Text
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15. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

Author

Mcmurray, Jj, Adamopoulos, S, Anker, Sd, Auricchio, A, Böhm, M, Dickstein, K, Falk, V, Filippatos, G, Fonseca, C, Gomez Sanchez MA, Jaarsma, T, Køber, L, Lip, Gy, Maggioni, Ap, Parkhomenko, A, Pieske, Bm, Popescu, Ba, Rønnevik, Pk, Rutten, Fh, Schwitter, J, Seferovic, P, Stepinska, J, Trindade, Pt, Voors, Aa, Zannad, F, Zeiher, A, Task Force for the Diagnosis, Treatment of Acute, Chronic Heart Failure 2012 of the European Society of Cardiology, Bax, Jj, Baumgartner, H, Ceconi, Claudio, Dean, V, Deaton, C, Fagard, R, Funck Brentano, C, Hasdai, D, Hoes, A, Kirchhof, P, Knuuti, J, Kolh, P, Mcdonagh, T, Moulin, C, Reiner, Z, Sechtem, U, Sirnes, Pa, Tendera, M, Torbicki, A, Vahanian, A, Windecker, S, Bonet, La, Avraamides, P, Ben Lamin HA, Brignole, M, Coca, A, Cowburn, P, Dargie, H, Elliott, P, Flachskampf, Fa, Guida, Gf, Hardman, S, Iung, B, Merkely, B, Mueller, C, Nanas, Jn, Nielsen, Ow, Orn, S, Parissis, Jt, Ponikowski, P, and ESC Committee for Practice Guidelines

Subjects
Beta-blockers, Ejection fraction, Transplantation, Digitalis, Heart failure, Natriuretic peptides, Reninangiotensin system, NO
Published
2012

16. Effects of the Adenosine A(1) Receptor Antagonist Rolofylline on Renal Function in Patients With Acute Heart Failure an Renal Dysfunction Results From PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine ReceptorAntagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function)

Author

Voors, Aa, Dittrich, Hc, Massie, Bm, Delucca, P, Mansoor, Ga, Metra, Marco, Cotter, G, Weatherley, Bd, Ponikowski, P, Teerlink, Jr, Cleland, Jg, O'Connor, Cm, and Givertz, M. M.

Subjects
renal function, heart failure
Published
2011

22. Risk stratification for sudden cardiac death: current status and challenges for the future

Author

Wellens, HJJ, Schwartz, PJ, Lindemans, FW, Buxton, A E, Goldberger, JJ, Hohnloser, SH, Huikuri, HV, Kaab, S, La Rovere, MT, Malik, M, Myerburg, RJ, Simoons, Maarten, Swedberg, K, Tijssen, J, Voors, AA, Wilde, AA, Wellens, HJJ, Schwartz, PJ, Lindemans, FW, Buxton, A E, Goldberger, JJ, Hohnloser, SH, Huikuri, HV, Kaab, S, La Rovere, MT, Malik, M, Myerburg, RJ, Simoons, Maarten, Swedberg, K, Tijssen, J, Voors, AA, and Wilde, AA

Abstract

Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.

Published
2014

23. Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction

Author

Gori, M, Senni, M, Gupta, D, Charytan, D, Kraigher-Krainer, E, Pieske, B, Claggett, B, Shah, A, Santos, A, Zile, M, Voors, A, Mcmurray, J, Packer, M, Bransford, T, Lefkowitz, M, Solomon, S, Gori M, Senni M, Gupta DK, Charytan DM, Kraigher-Krainer E, Pieske B, Claggett B, Shah AM, Santos ABS, Zile MR, Voors AA, McMurray JJV, Packer M, Bransford T, Lefkowitz M, Solomon SD, Gori, M, Senni, M, Gupta, D, Charytan, D, Kraigher-Krainer, E, Pieske, B, Claggett, B, Shah, A, Santos, A, Zile, M, Voors, A, Mcmurray, J, Packer, M, Bransford, T, Lefkowitz, M, Solomon, S, Gori M, Senni M, Gupta DK, Charytan DM, Kraigher-Krainer E, Pieske B, Claggett B, Shah AM, Santos ABS, Zile MR, Voors AA, McMurray JJV, Packer M, Bransford T, Lefkowitz M, and Solomon SD

Abstract

Aim Renal dysfunction is a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). We sought to determine whether renal dysfunction was associated with measures of cardiovascular structure/function in patients with HFpEF. Methods We studied 217 participants from the PARAMOUNT study with HFpEF who had echocardiography and measures of kidney function. We evaluated the relationships between renal dysfunction [estimated glomerular filtration rate (eGFR) >30 and <60 mL/min/1.73 m2 and/or albuminuria] and cardiovascular structure/function. Results The mean age of the study population was 71 years, 55% were women, 94% hypertensive, and 40% diabetic. Impairment of at least one parameter of kidney function was present in 62% of patients (16% only albuminuria, 23% only low eGFR, 23% both). Renal dysfunction was associated with abnormal LV geometry (defined as concentric hypertrophy, or eccentric hypertrophy, or concentric remodelling) (adjusted P = 0.048), lower midwall fractional shortening (MWFS) (P = 0.009), and higher NT-proBNP (P = 0.006). Compared with patients without renal dysfunction, those with low eGFR and no albuminuria had a higher prevalence of abnormal LV geometry (P = 0.032) and lower MWFS (P < 0.01), as opposed to those with only albuminuria. Conversely, albuminuria alone was associated with greater LV dimensions (P < 0.05). Patients with combined renal impairment had mixed abnormalities (higher LV wall thicknesses, NT-proBNP; lower MWFS). Conclusion Renal dysfunction, as determined by both eGFR and albuminuria, is highly prevalent in HFpEF, and associated with cardiac remodelling and subtle systolic dysfunction. The observed differences in cardiac structure/function between each type of renal damage suggest that both parameters of kidney function might play a distinct role in HFpEF.

Published
2014

26. Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?

Author

van de Wal, RMA, van Veldhuisen, DJ, van Gilst, WH, Voors, AA, and Cardiovascular Centre (CVC)

Subjects
renin angiotensin system, dual blockade, CONGESTIVE-HEART-FAILURE, INTERNAL MAMMARY ARTERIES, RANDOMIZED CONTROLLED-TRIAL, ace-inhibitor, DIABETIC-NEPHROPATHY, RENAL-DISEASE, LEFT-VENTRICULAR DYSFUNCTION, MYOCARDIAL-INFARCTION, cardiovascular disease, angiotensin receptor blockade, CONVERTING ENZYME-INHIBITION, HYPERTENSIVE SUBJECTS
Abstract

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.

Published
2005

29. Functional antagonism of different angiotensin II type I receptor blockers in human arteries

Author

Voors, AA, Buikema, H, van Buiten, A, Lubeck, RH, Boonstra, PW, van Veldhuisen, DJ, van Gilst, WH, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)

Subjects
INHIBITION, angiotensin II, RESISTANCE ARTERIES, CV-11974, FOREARM, angiotensin receptor blockers, arteries, PHARMACOLOGICAL PROFILE, AT(1) RECEPTOR, BINDING, vasoconstriction, human, LOSARTAN, ESSENTIAL-HYPERTENSION, RESPONSES
Abstract

Objectives. To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type I receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries. Methods. Human internal mammary arteries were obtained as excess graft material during coronary bypass surgery. Vessels were prepared as rings and mounted in an organ bath in which vasoconstriction and -dilation can be measured. Concentration-response curves of angiotensin II-mediated vasoconstriction were measured in absence or presence of different concentrations of one of the ARBs. Results. Losartan showed a rightward shift of the angiotensin II-mediated vasoconstriction, whereas addition of its metabolite EXP 3174 caused a decrease of the maximal effect of angiotensin II. Incubation with valsartan and candesartan also resulted in a decrease of the maximal effect. The inhibiting effects on the angiotensin II-mediated vasoconstriction by the highest concentration of EXP 3174, valsartan and candesartan did not differ significantly. Conclusion. In human internal mammary arteries, losartan acts as a surmountable antagonist. On the other hand, EXP 3174, valsartan and candesartan demonstrate an insurmountable type of antagonism. Furthermore, the inhibiting effects of EXP 3174, valsartan and candesartan in our study are equal in the highest concentrations.

Published
2002

30. Approaches to statistical analysis of repeated echocardiographic measurements after myocardial infarction and its relation to heart failure: Application of a random-effects model

Author

de Kam, PJ, Voors, AA, Brouwer, J, van Gilst, WH, Faculteit Medische Wetenschappen/UMCG, and Cardiovascular Centre (CVC)

Subjects
THROMBOLYSIS, DILATION, left ventricular dilatation, heart failure, random-effects model, myocardial infarction, LEFT-VENTRICULAR DYSFUNCTION, VOLUME, SURVIVAL, CATS, CAPTOPRIL, TRIAL, repeated measurements, CONVERTING-ENZYME-INHIBITION
Abstract

Background: Extensive left ventricular (LV) dilatation after myocardial infarction (MI) is associated with increased heart failure risk. Aims: To investigate whether the power to demonstrate the relation between LV dilatation and heart failure depends on the method applied to predict LV dilatation after MI. Methods: A random-effects model and ANOVA model for repeated measurements (MANOVA) were applied to predict LV volume index during I year for 298 post-MI patients. Spearman correlation coefficients (r) were calculated and Cox regression analysis was used to calculate risk ratio's (RR). Results: LV volume indices were more accurately predicted by a random-effects model than by a MANOVA model (systolic/diastolic respectively r=0.93/0.91 vs. r=0.67/0.64). Furthermore, patients with high LV volume index as predicted by the random-effects model, had significantly increased heart failure risk (systolic RR 2.04 (95% CL 1.31 to 3.17; P=0.001), diastolic RR 1.80 (95% Cl: 1.16 to 2.78; P=0.007). Using the same data, MANOVA failed to demonstrate this relation significantly (systolic RR 1.77 (95% CL 0.79 to 3.98; P=0.16), diastolic RR 1.49 (95% Cl: 0.68 to 3.30; P=0.31). Conclusion: When analyzing repeated measurement data, random-effect models are more powerful in detecting clinical relations than are MANOVA models, especially in the presence of missing values. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.

Published
2002

31. Effect of very early angiotensin-converting enzyme inhibition on left ventricular dilation after myocardial infarction in patients receiving thrombolysis - Results of a meta-analysis of 845 patients

Author

de Kam, PJ, Voors, AA, van den Berg, MP, van Veldhuisen, DJ, Brouwer, J, Crijns, HJGM, Borghi, C, Ambrosioni, E, Hochman, JS, LeJemtel, TH, Kingma, JH, van Gilst, WH, and Cardiovascular Centre (CVC)

Subjects
DILATATION, ENALAPRIL, VOLUME, SURVIVAL, CATS, CAPTOPRIL, TRIAL, THERAPY, DYSFUNCTION
Abstract

OBJECTIVES: We sought to investigate the effect of angiotensin-converting enzyme (ACE) inhibition BACKGROUND: The ACE inhibitors reduce mortality after MI. Attenuation of LV dilation has been suggested as an important mechanism. METHODS: The data of 845 patients with three-month echocardiographic follow-up after MI were combined from three randomized, double-blind, placebo-controlled studies. The criteria for these studies included: 1) thrombolytic therapy; 2) ACE inhibition within 6 to 9 h; and 3) evaluation of LV dilation as the primary objective. RESULTS: The ACE inhibitor was started 3.2 +/- 1.7 h after the patients' first (mainly, 85%) anterior MI. After three months, LV dilation was not significantly attenuated by very early treatment with an ACE inhibitor. The diastolic volume index was attenuated by 0.5 ml/m(2) (95% confidence interval [CI] -1.5 to 2.5, p = 0.61), and the systolic volume index by 0.5 ml/m2 (95% CI -1.0 to 1.9, p = 0.50). Subgroup analysis demonstrated that LV dilation was significantly attenuated by ACE inhibitor treatment for patients in whom reperfusion failed. In contrast, LV dilation was almost unaffected by ACE inhibitor treatment in successfully reperfused patients. CONCLUSIONS: We could not demonstrate attenuation of LV dilation in patients receiving thrombolysis by ACE inhibitor treatment within 6 to 9 h after MI. We speculate that very early treatment with an ACE inhibitor has a beneficial effect on LV remodeling only in patients in whom reperfusion failed. Other mechanisms may be responsible for the beneficial effects of ACE inhibitors in successfully reperfused patients after MI. (C) 2000 by the American College of Cardiology.

Published
2000

32. Angiotensin II formation in human vasculature after chronic ACE inhibition: A prospective, randomized, placebo-controlled study

Author

Oosterga, M, Voors, AA, Buikema, H, Pinto, YM, Haber, HE, Ebels, T, Morshuis, WJ, Kingma, JH, Crijns, HJGM, van Gilst, WH, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)

Subjects
vasculature, HYPERTENSION, renin-angiotensin system, ACE inhibition, angiotensin, QUINAPRIL, DYSFUNCTION, HYPERTROPHY, ENDOTHELIUM, BRADYKININ, ARTERIES, HEART-FAILURE, CAPTOPRIL, CONVERTING ENZYME-INHIBITION, endothelial factors
Abstract

The QUO VADIS (the effects of QUinapril On Vascular Ace and Determinants of ISchemia) study was a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of long-term angiotensin-converting enzyme (ACE) inhibition on angiotensin II formation in human vasculature. Patients (n

Published
2000

34. Comparison of the temporal release pattern of copeptin with conventional biomarkers in acute myocardial infarction

Author

Gu, YLL, Voors, AA, Zijlstra, Felix, Hillege, HL, Struck, J, Masson, S, Vago, T, Anker, SD, van den Heuvel, AFM, Veldhuisen, DJ, de Smet, BJGL, Gu, YLL, Voors, AA, Zijlstra, Felix, Hillege, HL, Struck, J, Masson, S, Vago, T, Anker, SD, van den Heuvel, AFM, Veldhuisen, DJ, and de Smet, BJGL

Abstract

Background Early detection of acute myocardial infarction (AMI) using cardiac biomarkers of myocardial necrosis remains limited since these biomarkers do not rise within the first hours from onset of AMI. We aimed to compare the temporal release pattern of the C-terminal portion of provasopressin (copeptin) with conventional cardiac biomarkers, including creatine kinase isoenzyme (CK-MB), cardiac troponin T (cTnT), and high-sensitivity cTnT (hs-cTnT), in patients with ST-elevation AMI. Methods We included 145 patients undergoing successful primary percutaneous coronary intervention (PCI) for a first ST-elevation AMI presenting within 12 h of symptom onset. Blood samples were taken on admission and at four time points within the first 24 h after PCI. Results In contrast to all other markers, copeptin levels were already elevated on admission and were higher with a shorter time from symptom onset to reperfusion and lower systolic blood pressure. Copeptin levels peaked immediately after symptom onset at a maximum of 249 pmol/L and normalized within 10 h. In contrast, CK-MB, cTnT, and hs-cTnT peaked after 14 h from symptom onset at a maximum of 275 U/L, 5.75 mu g/L, and 4.16 mu g/L, respectively, and decreased more gradually. Conclusions Copeptin has a distinct release pattern in patients with ST-elevation AMI, peaking within the first hour after symptom onset before conventional cardiac biomarkers and falling to normal ranges within the first day. Further studies are required to determine the exact role of copeptin in AMI suspects presenting within the first hours after symptom onset.

Published
2011

36. Low recurrence of angina pectoris after coronary artery bypass graft surgery with bilateral internal thoracic and right gastroepiploic arteries

Author

Bergsma, TM, Grandjean, JG, Voors, AA, Boonstra, PW, den Heyer, P, Ebels, T, and Cardiovascular Centre (CVC)

Subjects
angina, arteries, revascularization, FOLLOW-UP, bypass, follow-up studies, DISEASE
Abstract

Background-In the past 10 years, there has been a trend to use more arterial grafts instead of vein grafts for coronary artery bypass graft surgery. Although there are many reports on the short-and mid-term follow-up of patients who underwent arterial revascularization with 1 or 2 arteries, little has been reported on the follow-up of patients with 3-vessel disease who received 3 arteries. Methods and Results-We reviewed a group of 256 patients with 3-vessel disease who received the right gastroepiploic artery together with both internal thoracic arteries (ITAs). Vein grafts were not used in these patients. The patients were monitored for up to 7 years (mean, 51+/-15 months). Seven-year actuarial survival was 91.1%. The cumulative probability of event-free survival for myocardial infarction, reintervention, and angina pectoris at 7 years was 97.3%, 95.4%, and 85.4%, respectively. Conclusions-We conclude that concomitant use of the gastroepiploic artery with both ITAs results in low mortality and a low incidence of myocardial infarction and reintervention at follow-up. Most interestingly, we found 85.4% freedom from angina pectoris after 7 years, which is considerably lower than the results of studies in which vein grafts, single ITA grafts, or double ITA grafts are used. These results strongly support the use of both ITAs and the right gastroepiploic artery for bypass grafting in patients with 3-vessel disease.

Published
1998

37. Plasma angiotensin-converting enzyme activity and left ventricular dilation after myocardial infarction

Author

Oosterga, M, Voors, AA, deKam, PJ, Schunkert, H, Pinto, YM, Kingma, H, vanGilst, WH, and Cardiovascular Centre (CVC)

Subjects
ACTIVATION, myocardial infarction, enzymes, CAPTOPRIL, angiotensin, genes, THERAPY, GENE, remodeling
Abstract

Background Left ventricular dilation after acute myocardial infarction (MI) is mainly determined by infarct size. In addition, this detrimental structural adaptation seems to be augmented in patients with the ACE DD genotype. The ACE DD genotype is associated with increased ACE activity. The aim of the present study was to evaluate whether ACE activity per se may carry prognostic significance far subsequent left ventricular dilation as assessed by echocardiography during 1-year follow-up after acute MI. Methods and Results Left ventricular end-systolic and end-diastolic volume indexes were assessed by two-dimensional echocardiography. In 102 consecutive patients, plasma ACE activity was determined 3.7 +/- 0.1 hours after the onset of MI. In 64 of these patients, left ventricular volume indexes obtained at baseline and 1 year after MI were used for the present analysis. Patients were divided into a group having low ACE activity (less than or equal to 12 IU/L, n = 15) and a group having high ACE activity (>12 IU/L, n = 49). Infarct size was a significant predictor of the increase in left ventricular volume indexes (P = .0001) in these patients. Multivariate regression analysis, after correction for infarct size, demonstrated that elevated plasma ACE activity is a significant predictor of the increase in left ventricular end-diastolic and end-systolic volume indexes (P = .0006 and P = .02, respectively) 1 year after RI. Conclusions Elevated plasma ACE activity determined soon after the onset of MI may be a significant predictor of the development of left ventricular dilation and may identify patients at risk.

Published
1997

42. Inflammation and anaemia in a broad spectrum of patients with heart failure.

Author

Kleijn L, Belonje AM, Voors AA, De Boer RA, Jaarsma T, Ghosh S, Kim J, Hillege HL, Van Gilst WH, J van Veldhuisen D, and van der Meer P

Abstract

AIMS: Anaemia in heart failure (HF) is associated with a poor prognosis. Although inflammation is assumed to be an important cause of anaemia, the association between anaemia and inflammatory markers in patients with HF has not been well established. METHODS: Data from a multicentre randomised clinical trial, in which patients were eligible if they were >18 years of age and admitted for HF (New York Heart Association II-IV), were used. In a subset of 326 patients, haemoglobin (Hb), haematocrit, high sensitivity C-reactive protein (hsCRP), interleukin-(IL) 6, soluble tumour necrosis factor receptor (sTNFR)-1 and erythropoietin (Epo) were measured at discharge and the primary endpoint was all-cause mortality. Follow-up was 18 months. RESULTS: Anaemia (Hb <13 g/dl (men) and <12 g/dl (women)) was present in 40% (130/326) of the study population. Median levels of IL-6, hsCRP and sTNFR-1 were significantly higher in anaemic patients than in non-anaemic patients. Logistic regression demonstrated that each increase in hsCRP values (OR 1.58 per SD log hsCRP; 95% CI 1.09 to 2.29; p=0.016) and each increase in sTNFR-1 values (OR 1.62 per SD log sTNFR-1; 95% CI 1.24 to 2.11; p<0.001) were independently associated with anaemia. Epo (HR 1.31 per log Epo; 95% CI 1.01 to 1.69; p=0.041) and sTNFR-1 (HR 1.47 per log sTNFR-1; 95% CI 1.16 to 1.86; p=0.001) levels were independently associated with outcome. CONCLUSION: Anaemia is present in 40% of patients hospitalised for HF and is independently associated with inflammation. [ABSTRACT FROM AUTHOR]

Published
2012

43. Urinary proteins in heart failure.

Author

Valente MA, Damman K, Dunselman PH, Hillege HL, and Voors AA

Abstract

Renal insufficiency is common in patients with heart failure (HF), with both acute kidney injury and worsening renal function being associated with poor prognosis. The interplay between cardiac and renal failure has been termed the cardiorenal syndrome and is currently the subject of intense investigation. Urinary biochemistry has several advantages over blood or serum analyses, including lower costs, better patient comfort, and higher sensitivity to renal injury. However, urinalysis is currently not part of routine daily practice in cardiology. Recent advances in proteomics have allowed identification of numerous novel urinary biomarkers, many of which show promise in HF populations. In this review, we aim to provide an overview of both traditional and novel urinary biomarkers, examining evidence for diagnostic and prognostic value in HF as well as potential clinical utility. [ABSTRACT FROM AUTHOR]

Published
2012

45. The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.

Author

Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, Miller AB, Piña IL, Thomson S, Varosy PD, Zile MR, Cleland JG, Givertz MM, Metra M, Ponikowski P, Voors AA, Davison BA, Cotter G, Wolko D, and Delucca P

Abstract

Background: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.Objective: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.Methods: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.Results: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.Conclusions: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure. [ABSTRACT FROM AUTHOR]

Published
2012
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46. Current and novel renal biomarkers in heart failure.

Author

Damman K, Voors AA, Navis G, van Veldhuisen DJ, Hillege HL, Damman, Kevin, Voors, Adriaan A, Navis, Gerjan, van Veldhuisen, Dirk J, and Hillege, Hans L

Abstract

Renal function is the most important predictor of clinical outcome in heart failure (HF). It is therefore essential to have accurate and reliable measurement of renal function and early specific markers of renal impairment in patients with HF. Several renal functional entities exist, including glomerular filtration (GFR), glomerular permeability, tubulointerstitial damage, and endocrine function. Different markers have been studied that can be used to determine changes and the effect of treatment in these entities. In the present review, we summarize current and novel markers that give an assessment of renal function and prognosis in the setting of acute and chronic HF. [ABSTRACT FROM AUTHOR]

Published
2012
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47. Advanced glycation end-products, a pathophysiological pathway in the cardiorenal syndrome.

Author

Willemsen S, Hartog JW, Heiner-Fokkema MR, van Veldhuisen DJ, Voors AA, Willemsen, Suzan, Hartog, Jasper W L, Heiner-Fokkema, M Rebecca, van Veldhuisen, Dirk J, and Voors, Adriaan A

Abstract

The prevalence of heart failure (HF) is increasing. A distinction is made between diastolic HF (preserved left ventricular ejection fraction (LVEF)) and systolic HF (reduced LVEF). Advanced glycation end-products (AGEs) are crystallized proteins that accumulate during ageing, but are particularly increased in patients with diabetes mellitus and in patients with renal failure. Through the formation of collagen crosslinks, and by interaction with the AGE-receptor, which impairs calcium handling and increases fibrosis, AGE-accumulation has pathophysiologically been associated with the development of diastolic and renal dysfunction. Interestingly, diastolic dysfunction is a frequent finding in elderly patients, diabetic patients and in patients with renal failure. Taken together, this suggests that AGEs are related to the development and progression of diastolic HF and renal failure. In this review, the role of AGEs as a possible pathophysiological factor that link the development and progression of heart and renal failure, is discussed. Finally, the role of AGE intervention as a possible treatment in HF patients will be discussed. [ABSTRACT FROM AUTHOR]

Published
2012
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