Piero Ruggenenti1,2, Manuel Alfredo Podestà1,2, Matias Trillini1, Annalisa Perna1, Tobia Peracchi1, Nadia Rubis1, Davide Villa1, Davide Martinetti1, Monica Cortinovis1, Patrizia Ondei2, Carmela Giuseppina Condemi2, Carlo Maria Guastoni3, Agnese Meterangelis4, Antonio Granata5, Emanuele Mambelli6, Sonia Pasquali7, Simonetta Genovesi8,9, Federico Pieruzzi8,9, Silvio Volmer Bertoli10, Goffredo Del Rosso11, Maurizio Garozzo12, Angelo Rigotti13, Claudio Pozzi14, Salvatore David15, Giuseppe Daidone16, Giulio Mingardi17, Giovanni Mosconi18, Andrea Galfré19, Giorgio Romei Longhena20, Alfonso Pacitti21, Antonello Pani22, Jorge Hidalgo Godoy1,23, Hans-Joachim Anders24, Giuseppe Remuzzi25. 1. Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò", Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. 2. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. 3. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Ovest Milanese, Ospedali di Legnano e Magenta, Milano, Italy. 4. Unit of Nephrology and Dialysis, Policlinico San Pietro, Ponte San Pietro, Bergamo, Italy. 5. Unit of Nephrology and Dialysis, Azienda Ospedaliera per l'Emergenza "Cannizzaro," Catania, Italy. 6. Unit of Nephrology, Dialysis and Hypertension, Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi, Bologna, Italy. 7. Unit of Nephrology and Dialysis, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. 8. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo, Monza, Italy. 9. Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy. 10. Unit of Nephrology and Dialysis, Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Sesto San Giovanni, Milano, Italy. 11. Unit of Nephrology and Dialysis, Ospedale Giuseppe Mazzini, Teramo, Italy. 12. Unit of Nephrology and Dialysis, Presidio Ospedaliero S. Marta e S. Venera, Acireale, Catania, Italy. 13. Unit of Nephrology and Dialysis, Ospedale Infermi, Rimini, Italy. 14. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Nord Milano-Ospedale Bassini, Cinisello Balsamo, Milano, Italy. 15. Department of Nephrology and Dialysis, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. 16. Unit of Nephrology and Dialysis, Ospedale Umberto I, Siracusa, Italy. 17. Unit of Nephrology and Dialysis, Humanitas Gavazzeni, Bergamo, Italy. 18. Unit of Nephrology and Dialysis, Ospedale "Morgagni-Pierantoni," Forlì, Italy. 19. Unit of Nephrology and Dialysis, Azienda Sanitaria Locale 8, Cagliari, Italy. 20. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Rhodense-Ospedale Garbagnate Milanese, Milano, Italy. 21. Unit of Nephrology and Dialysis, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy. 22. Unit of Nephrology and Dialysis, Department of Reproduction, Genitourinary and Kidney Disease and Kidney Transplantation, Azienda Ospedaliera Brotzu, Cagliari, Italy. 23. Institute of Medicine, Universidad Austral de Chile, Valdivia, Chile. 24. Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilians Universität Munich, Munich, Germany. 25. Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò", Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy giuseppe.remuzzi@marionegri.it.
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.
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.
Authors: Ralph L Sacco; Scott E Kasner; Joseph P Broderick; Louis R Caplan; J J Buddy Connors; Antonio Culebras; Mitchell S V Elkind; Mary G George; Allen D Hamdan; Randall T Higashida; Brian L Hoh; L Scott Janis; Carlos S Kase; Dawn O Kleindorfer; Jin-Moo Lee; Michael E Moseley; Eric D Peterson; Tanya N Turan; Amy L Valderrama; Harry V Vinters Journal: Stroke Date: 2013-05-07 Impact factor: 7.914
Authors: Peter A McCullough; Keisha R Sandberg; Jerry Yee; Michael P Hudson Journal: J Renin Angiotensin Aldosterone Syst Date: 2002-09 Impact factor: 1.636