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Original ArticlesMaintenance Dialysis
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Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis

The ARCADIA Multicenter Randomized Controlled Trial

Piero Ruggenenti, Manuel Alfredo Podestà, Matias Trillini, Annalisa Perna, Tobia Peracchi, Nadia Rubis, Davide Villa, Davide Martinetti, Monica Cortinovis, Patrizia Ondei, Carmela Giuseppina Condemi, Carlo Maria Guastoni, Agnese Meterangelis, Antonio Granata, Emanuele Mambelli, Sonia Pasquali, Simonetta Genovesi, Federico Pieruzzi, Silvio Volmer Bertoli, Goffredo Del Rosso, Maurizio Garozzo, Angelo Rigotti, Claudio Pozzi, Salvatore David, Giuseppe Daidone, Giulio Mingardi, Giovanni Mosconi, Andrea Galfré, Giorgio Romei Longhena, Alfonso Pacitti, Antonello Pani, Jorge Hidalgo Godoy, Hans-Joachim Anders, Giuseppe Remuzzi and on behalf of the ARCADIA Study Organization
CJASN April 2021, 16 (4) 575-587; DOI: https://doi.org/10.2215/CJN.12940820
Piero Ruggenenti
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
2Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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Manuel Alfredo Podestà
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
2Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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  • ORCID record for Manuel Alfredo Podestà
Matias Trillini
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Annalisa Perna
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Tobia Peracchi
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Nadia Rubis
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Davide Villa
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Davide Martinetti
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Monica Cortinovis
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Patrizia Ondei
2Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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Carmela Giuseppina Condemi
2Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
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Carlo Maria Guastoni
3Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Ovest Milanese, Ospedali di Legnano e Magenta, Milano, Italy
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Agnese Meterangelis
4Unit of Nephrology and Dialysis, Policlinico San Pietro, Ponte San Pietro, Bergamo, Italy
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Antonio Granata
5Unit of Nephrology and Dialysis, Azienda Ospedaliera per l'Emergenza “Cannizzaro,” Catania, Italy
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Emanuele Mambelli
6Unit of Nephrology, Dialysis and Hypertension, Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi, Bologna, Italy
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Sonia Pasquali
7Unit of Nephrology and Dialysis, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
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Simonetta Genovesi
8Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo, Monza, Italy
9Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy.
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Federico Pieruzzi
8Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo, Monza, Italy
9Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy.
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Silvio Volmer Bertoli
10Unit of Nephrology and Dialysis, Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Sesto San Giovanni, Milano, Italy
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Goffredo Del Rosso
11Unit of Nephrology and Dialysis, Ospedale Giuseppe Mazzini, Teramo, Italy
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Maurizio Garozzo
12Unit of Nephrology and Dialysis, Presidio Ospedaliero S. Marta e S. Venera, Acireale, Catania, Italy
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Angelo Rigotti
13Unit of Nephrology and Dialysis, Ospedale Infermi, Rimini, Italy
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Claudio Pozzi
14Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Nord Milano-Ospedale Bassini, Cinisello Balsamo, Milano, Italy
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Salvatore David
15Department of Nephrology and Dialysis, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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Giuseppe Daidone
16Unit of Nephrology and Dialysis, Ospedale Umberto I, Siracusa, Italy
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Giulio Mingardi
17Unit of Nephrology and Dialysis, Humanitas Gavazzeni, Bergamo, Italy
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Giovanni Mosconi
18Unit of Nephrology and Dialysis, Ospedale “Morgagni-Pierantoni,” Forlì, Italy
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Andrea Galfré
19Unit of Nephrology and Dialysis, Azienda Sanitaria Locale 8, Cagliari, Italy
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Giorgio Romei Longhena
20Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Rhodense-Ospedale Garbagnate Milanese, Milano, Italy
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Alfonso Pacitti
21Unit of Nephrology and Dialysis, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
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Antonello Pani
22Unit of Nephrology and Dialysis, Department of Reproduction, Genitourinary and Kidney Disease and Kidney Transplantation, Azienda Ospedaliera Brotzu, Cagliari, Italy
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Jorge Hidalgo Godoy
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
23Institute of Medicine, Universidad Austral de Chile, Valdivia, Chile
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Hans-Joachim Anders
24Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilians Universität Munich, Munich, Germany
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Giuseppe Remuzzi
1Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Abstract

Background and objectives Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis.

Design, setting, participants, & measurements In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25–10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization.

Results At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: −16.3 g/m2; 95% confidence interval, −29.4 to −3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls.

Conclusions Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis.

Clinical Trial registry name and registration number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008–003529–17.

  • Ramipril
  • hemodialysis
  • ACE inhibitors
  • cardiovascular events
  • renin angiotensin system
  • Received August 7, 2020.
  • Accepted February 15, 2021.
  • Copyright © 2021 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 16 (4)
Clinical Journal of the American Society of Nephrology
Vol. 16, Issue 4
April 07, 2021
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Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis
Piero Ruggenenti, Manuel Alfredo Podestà, Matias Trillini, Annalisa Perna, Tobia Peracchi, Nadia Rubis, Davide Villa, Davide Martinetti, Monica Cortinovis, Patrizia Ondei, Carmela Giuseppina Condemi, Carlo Maria Guastoni, Agnese Meterangelis, Antonio Granata, Emanuele Mambelli, Sonia Pasquali, Simonetta Genovesi, Federico Pieruzzi, Silvio Volmer Bertoli, Goffredo Del Rosso, Maurizio Garozzo, Angelo Rigotti, Claudio Pozzi, Salvatore David, Giuseppe Daidone, Giulio Mingardi, Giovanni Mosconi, Andrea Galfré, Giorgio Romei Longhena, Alfonso Pacitti, Antonello Pani, Jorge Hidalgo Godoy, Hans-Joachim Anders, Giuseppe Remuzzi, on behalf of the ARCADIA Study Organization
CJASN Apr 2021, 16 (4) 575-587; DOI: 10.2215/CJN.12940820

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Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis
Piero Ruggenenti, Manuel Alfredo Podestà, Matias Trillini, Annalisa Perna, Tobia Peracchi, Nadia Rubis, Davide Villa, Davide Martinetti, Monica Cortinovis, Patrizia Ondei, Carmela Giuseppina Condemi, Carlo Maria Guastoni, Agnese Meterangelis, Antonio Granata, Emanuele Mambelli, Sonia Pasquali, Simonetta Genovesi, Federico Pieruzzi, Silvio Volmer Bertoli, Goffredo Del Rosso, Maurizio Garozzo, Angelo Rigotti, Claudio Pozzi, Salvatore David, Giuseppe Daidone, Giulio Mingardi, Giovanni Mosconi, Andrea Galfré, Giorgio Romei Longhena, Alfonso Pacitti, Antonello Pani, Jorge Hidalgo Godoy, Hans-Joachim Anders, Giuseppe Remuzzi, on behalf of the ARCADIA Study Organization
CJASN Apr 2021, 16 (4) 575-587; DOI: 10.2215/CJN.12940820
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  • cardiovascular events
  • renin angiotensin system

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