Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial.

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.

Erythropoiesis-stimulating agents: dose and mortality risk.

Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality in end-stage renal disease patients. It is not clear if this effect is related to the elevated ESAs dosage for targeting hemoglobin levels or underlying morbid conditions that lead to ESA resistance. We retrospectively evaluated from 2008 to death or December 2011, 28 consecutive incident hemodialysis patients. We identified 2 cohort of patients based on their mean annual ESAs dosage. The correlation between data was evaluated with the Spearman's rho test. Kaplan-Meier curves were generated to assess survival in subjects with high and low ESAs mean dose. Median ESAs dosage, used as a cutoff point between patients at high and low ESAs dose, was at 11.000 IU/week for epoetin alfa and beta, 55 mcg/week for darbopoietin, and 220 mcg/month for cera. Mean hemoglobin (Hb) level was 10.58 ± 0.13 g/dL. Of 28 patients, during follow-up, 6 (21,4%) died of all causes. High-dose ESA therapy was associated with increased all-cause mortality (P = .047). Moreover, there was a negative correlation between ESAs dose and Hb levels (rho = -0.825; P < .001). Higher ESAs dose for the treatment of anemia in incident hemodialysis patients was associated with higher mortality risk. ESAs and Hb serum levels were inversely correlated with mortality. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner or an interactive effect that adversely affects mortality.