Homocysteine-lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta-analysis of randomised, controlled trials

Abstract

The efficacy of homocysteine (Hcy)-lowering therapy in reducing the risk of CVD among patients with chronic kidney disease (CKD) remains controversial. We performed a meta-analysis to determine whether pooling the data from the few small randomised, controlled trials that address this topic would improve the statistical power of the analysis and resolve some of the inconsistencies in the results. Randomised, controlled clinical trials (RCT) were identified from MEDLINE, EMBASE, www.clinicaltrials.gov, the Cochrane Controlled Clinical Trials Register Database and Nephrology Filters. Independent extraction of articles was performed using predefined data fields. The primary outcome was relative risk (RR) of CVD, CHD, stroke and all-cause mortality for the pooled trials. A stratified analysis was planned, assessing the RR for cardiovascular events between the patients on and not on dialysis. Overall, ten studies met the inclusion criteria. The estimated RR were not significantly different for any outcomes, including CHD (RR 1·00, 95 % CI 0·75, 1·31, P ¼ 0·97), CVD (RR 0·94, 95 % CI 0·84, 1·05, P ¼ 0·30), stroke (RR 0·83, 95 % CI 0·57, 1·19, P ¼ 0·31) and all-cause mortality (RR 1·00, 95 % CI 0·92, 1·09, P ¼ 0·98). In the stratified analysis, the estimated RR were not significantly different for cardiovascular events regardless of dialysis or in combination with vitamin B therapy or the degree of reduction in Hcy levels. Our meta-analysis of RCT supports the conclusion that Hcy-lowering therapy was not associated with a significant decrease in the risk for CVD events, stroke and all-cause mortality among patients with CKD.Key words: CVD: Chronic kidney disease: Folic acid: Homocysteine-lowering therapy: Homocysteine: Meta-analyses CVD is the leading cause of mortality both among the general population and among patients with chronic kidney disease (CKD). The rate of mortality from CVD among patients on haemodialysis (HD) is 20-fold higher than that among the general population (1) , and impaired renal function per se is a very strong cardiovascular prognostic factor (2,3) . Therefore, much attention has been focused on managing risk factors to attempt to reduce the associated CVD risks, especially among patients with CKD. Elevated plasma total homocysteine (Hcy) has been proposed as a risk factor for cardiovascular morbidity and mortality in patients either with normal renal function or with CKD (4,5) . Among patients with CKD, plasma Hcy levels tend to increase with decreasing glomerular filtration rate (6) ; thus, hyperhomocysteinaemia may potentially further increase the risk of CVD in this special population. In the Cardiovascular Risk Extended Evaluation in Dialysis trial, investigators followed-up on 175 patients with kidney failure for 29 months and found that an increase in Hcy of 10 mmol/l was associated with a 20 % increased risk for CVD events (7) . In another study, Hcy was found to be a strong independent predictor of mortality among patients on HD with a 3 % increase in mortality for each 1 mmol...

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“…A meta-analysis of 10 studies concluded that Hcy-lowering therapy is not associated with a significant decrease in the risks for CVD events, stroke, and all-cause mortality among patients with CKD [58]. The deviation from the previous meta-analysis may reflect the enrollment in some RCTs of a high number of DM participants and their performance in grain fortification areas.…”

Superior Predictive Value for NTproBNP Compared with High Sensitivity cTnT in Dialysis Patients: A Pilot Prospective Observational Study

“…Almost 40% of this mortality is attributable to cardiovascular (CV) disease [2]. Unfortunately, there seems to be little hope in sight for improvements since almost all large, randomized controlled trials have persistently shown no survival benefit from several “new” treatment approaches: use of statins [3], ESA's [4], vitamin D or cinacalcet [5,6], antioxidant or homocysteine lowering therapies [7], prolonged or more frequent dialysis sessions [8] or convective therapies [9]. …”

Homocysteine, cysteine, folate and vitamin B12 status in type 2 diabetic patients with chronic kidney disease

“…It has been demonstrated that Hcy could block the Cys transport at the level of the ASC transporter [21]. Sekhar and co-workers [22] showed indeed that Cys levels are diminished in T2D erythrocytes, most probably because of the block of the transporter. In addition, we found high levels of tHcy also in T2D patients at stage 0 of CKD.…”

“…However, clinical studies have shown that folic acid therapy is not very effective in normalizing hyperhomocysteinemia in uremic patients [4]. In a meta-analysis of randomized controlled trials, Pan and collaborators [22] reported that the estimated relative risk of CVD was not significantly different for cardiovascular events regardless of dialysis or in combination with B-vitamin therapy or the degree of reduction of Hcy levels, supporting the conclusion that Hcy-lowering therapy was not associated with a significant decrease in the risk for CVD events, stroke and all-cause mortality among patients with CKD.…”