Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy—A meta-analysis of 11 randomized controlled trials involving 21,295 participants
Graphical abstract
Introduction
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality not only among the general population, but also in patients with chronic kidney disease (CKD) [1]. Several clinical trials have demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD [2], [3], [4]. The role of statins in primary prevention of CVD risk in CKD patients still remains to be clarified. No large randomized clinical trials have provided evidence that statins as a primary prevention strategy reduce CVD in these patients. It has been suggested that these agents are effective and appear safe for secondary prevention of cardiovascular (CV) events in individuals with mild chronic renal insufficiency (especially stages 1–3 of CKD) [5], [6].
There are potential explanations for the putative effects of statins on the rate of CV events in patients with CKD. Statins may exert their protection against kidney disease through a variety of immunomodulatory effects [3], [4], [5], [6]. Statin therapy attenuates endothelial dysfunction, enhances renal perfusion and reduces abnormal permeability to plasma proteins [7]. In experimental models, statins have been shown to inhibit the progression of renal damage, but in humans there are only observational studies, which do not provide definite information [8].
In several animal models, the beneficial effects of statins on renal disease associated with hypertension and vascular injury have been described [8], [9]. Moreover, in a rat model of glomerulonephritis statin treatment prevented macrophage glomerular infiltration and suppressed mesangial cell proliferation and mesangial matrix expansion [10]. In consideration of the anti-inflammatory effects on vascular structure, regardless of cholesterol reduction, statins have experimentally been demonstrated to attenuate tumor necrosis factor-α induced angiogenesis in vitro and reverse myocardial expression of inflammatory and growth factors [11]. The inhibition of inflammatory cytokine-induced vascular endothelial growth factor expression was hypothesized [11]. Some investigators postulate that the benefit of statin therapy in patients with CKD is attributable to better kidney perfusion secondary to improved endothelial and cardiac function and improved protein trafficking in the glomerulus and proximal tubular epithelium [12].
Meta-analyses and post hoc analyses have reported benefits of statins for all-cause and CV mortality in CKD patients [13], [14]. It has been suggested that the absolute benefit of treatment with statins seems to be greater among individuals with non-dialysis-dependent CKD. Studies in end-stage renal disease (ESRD) patients on dialysis yielded conflicting results and such positive effects were not found in the 4D (Die Deutsche Diabetes Dialyse) (expect from the fatal stroke and cardiac events) and AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) studies [15], [16]. Recently, however, the SHARP (Study of Heart and Renal Protection) study, despite its limitations (simvastatin + ezetimibe vs. placebo), showed an insignificant trend toward reducing CV events in dialysis patients [17]. Therefore, we performed a meta-analysis to evaluate the impact of statin therapy on CV events and death from all causes in patients with CKD.
Section snippets
Data sources
We searched PubMed, Web of Science (ISI), Cochrane Library, and Scopus using keywords such as statins, chronic kidney disease, chronic renal failure, hemodialysis, atorvastatin, lovastatin, pravastatin, simvastatin and rosuvastatin. We limited our search to randomized clinical trials written in English. Data were collected for the years 1966 to October 2012. Studies were chosen for the meta-analysis if they met the inclusion criteria including CKD, chronic renal failure, hemodialysis,
Results
The electronic searches yielded 667 items: 293 from PubMed, 63 from Web of Sciences, 300 from Scopus, and 11 from the Cochrane Library. Of these, 32 trials were scrutinized in the full text, of which 21 trials were considered unsuitable while 11 trials [14], [15], [16], [19], [20], [21], [22], [23], [24], [25], [26] were included in the analysis (Fig. 1). Of these 11 studies, 8 [14], [15], [16], [19], [23], [24], [25], [26] obtained a Jadad score of ≥3 and the others [20], [21], [22] gained a
Discussion
This meta-analysis is part of a group of meta-analyses assessing different aspects of the role of statins in patients with hypertension and its complications, including chronic kidney disease [5], [27]. In the present study, we gathered the reliable evidence available to date including 21,295 patients with non-dialysis and dialysis-dependent CKD from 11 randomized trials assessing the specific effect of statins on cardiovascular events and death from all causes [14], [15], [16], [19], [20], [21]
Conflict of interest statement
M.B. (Marcin Barylski), S.N., P.S., J.R., M.A. have no conflict of interest. D.P.M. has given talks, attended conferences and participated in trials and advisory boards sponsored by MSD, Genzyme and Abbott. P.P.T. has given talks for AbbVie, Amarin, Astra-Zeneca, Genzyme, Kowa, Merck and is consultant for Amgen, Atherotech, Genzyme, Kowa, Liposcience, Merck. K.K.R. has received honoraria for lectures or advisory boards from Pfizer, Astra-Zeneca, MSD, Roche, Novartis, Sanofi, Regeneron, Servier,
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