Worsening renal function during renin–angiotensin–aldosterone system inhibitor initiation and long‐term outcomes in patients with left ventricular systolic dysfunction

Abstract

AimsImpaired renal function is associated with worse clinical outcomes in patients with LV systolic dysfunction (LVSD) and heart failure. Renin-angiotensin-aldosterone system (RAAS) inhibitors provide clinical benefit in these settings and often worsen renal function. It is not clear whether worsening renal function (WRF) in patients exposed to these agents predicts a worse prognosis or merely reflects the pharmacological action of the drug on the kidney. Methods and resultsWe performed a meta-analysis of all RAAS inhibitor LVSD trials reporting on outcomes according to WRF (as per individual study definition) in both active intervention and placebo groups. Five major studies (SOLVD, SAVE, RALES, Val-HeFT and EPHESUS) contributed, with 20 573 patients. Compared with placebo, RAAS inhibitors reduced allcause mortality overall [n = 20 573, relative risk ratio (RR) 0.91, 95% confidence interval (CI) 0.86-0.95, P = 0.0003], in the group with no WRF (n = 18 209, RR 0.91, 95% CI 0.83-0.99, P = 0.04), and in the WRF group (n = 2364, RR 0.72, 95% CI 0.62-0.84, P < 0.0001). Compared with no WRF, WRF was associated with increased all-cause mortality; however, this was less in the RAAS inhibitor group (n = 8905, RR 1.22, 95% CI 1.10-1.36, P = 0.0003) than in the placebo group (n = 9304, RR 1.52, 95% CI 1.37-1.69, P < 0.00001).

On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin

“…19,20 WRF, evaluated as a time-dependent covariate in Cox proportional hazards models, was defined as a decrease of >20% in CrCl from the screening CrCl measurement at any time during the study period. This definition was recently used in several secondary analyses of randomized, controlled trials in patients with heart failure, [21][22][23] and it may be more accurate than an absolute increase in serum creatinine (ie, ≥0.3 mg/ dL), which could be biased by baseline renal function.…”

Spironolactone Treatment and Effect on Survival in Chronic Heart Failure Patients with Reduced Renal Function: A Propensity-Matched Study

“…In our study, the beneficial effect of spironolactone on survival was observed despite decrease in renal function and increase in serum potassium during follow-up at the outpatient HF clinics. It is well accepted that worsening renal function has a negative impact on survival in HF patients [11,12,23]. However, the prognostic effect of worsening renal function might depend on the HF medication used.…”

“…Caution is necessary in patients with renal dysfunction, as use of spironolactone may cause hyperkalemia and worsening renal function [9,10]. Worsening renal function is a strong predictor of increased mortality in HF patients, and the safety of spironolactone in patients with reduced renal function is still a matter of uncertainty [11,12,13,14]. Yet, spironolactone is used extensively in HF outpatients with renal dysfunction [2].…”

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

“…Despite the fact that RAAS blockers can frequently cause a decrease in GFR in patients with HF, this reduction is usually small and should not lead to treatment discontinuation unless there is a marked decrease, as the treatment benefit in these patients is probably largely maintained. 480 When large increases in serum creatinine occur, care should be taken to evaluate the patient thoroughly and should include assessment of a possible renal artery stenosis, excessive hyper-or hypovolaemia, concomitant medication and hyperkalaemia, which frequently coincides with WRF. Diuretics, especially thiazides, but also loop diuretics, may be less effective in patients with a very low GFR, and if used, should be dosed appropriately (higher doses to achieve similar effects).…”