Two investigators (Yaru Zhang and Dandan He) independently searched and identified relevant studies from MEDLINE (from 1950 to October 2018), EMBASE (from 1970 to October 2018), and the Cochrane Library database. Randomised clinical trials in non-dialysis CKD3-5 patients treated with renin-angiotensin system (RAS) inhibitors were included. We used standard criteria (Cochrane risk of bias tool) to assess the inherent risk of bias of trials. We calculated the odds ratio (OR) and 95% confidence interval (CI) for each outcome by random-effects model. A 2-sided p value < 0.05 was considered statistically significant, and all statistical analyses were performed using STATA, version 15.0. This network meta-analysis was undertaken by the frequency model.
RESULTS: Forty-four randomised clinical trials with 42,319 patients were included in our network meta-analysis. ACEIs monotherapy significantly decreased the odds of kidney events (OR 0.54, 95% CI 0.41-0.73), cardiovascular events (OR 0.73, 95% CI 0.64-0.84), cardiovascular death (OR 0.73, 95% CI 0.63-0.86) and all-cause death (OR 0.77, 95% CI 0.66-0.91) when compared to placebo. According to the cumulative ranking area (SUCRA), ACEI monotherapy had the highest probabilities of their protective effects on outcomes of kidney events (SUCRA 93.3%), cardiovascular events (SUCRA 77.2%), cardiovascular death (SUCRA 86%), and all-cause death (SUCRA 94.1%), even if there were no significant differences between ACEIs and other
antihypertensive drugs, including
calcium channel blockers (CCBs), β-blockers and
diuretics on above outcomes except for kidney events. ARB monotherapy and combination
therapy of an ACEI plus an ARB showed no more advantage than CCBs, β-blockers and
diuretics in all primary outcomes. In the subgroup of non-dialysis
diabetic kidney disease patients, no drugs, including ACEIs or ARBs, significantly lowered the odds of cardiovascular events and all-cause death. However, ACEIs were still better than other
antihypertensive drugs including ARBs in all-cause death but not ARBs in cardiovascular events according to the SUCRA. Only ARBs had significant differences in preventing the occurrence of kidney events compared with placebo (OR 0.82, 95% CI 0.72-0.95). Both ACEI/ARB monotherapy and combination
therapy had higher odds of hyperkalaemia. ACEIs had 3.81 times higher odds than CCBs (95% CI 1.58-9.20), ARBs had 2.08-5.10 times higher odds than placebo and CCBs and combination
therapy of an ACEI and an ARB had 4.80-24.5 times higher odds than all other treatments. Compared with placebo, CCBs and β blockers, ACEI
therapy significantly increased the odds of
cough (OR 2.90, 95% CI 1.76-4.77; OR 8.21, 95% CI 3.13-21.54 and OR 1.80, 95% CI 1.08-3.00). There were no statistical differences in
hypotension among all comparisons except ACEIs versus placebo.
CONCLUSIONS: Although ACEIs increased the odds of hyperkalaemia,
cough and
hypotension, they were still superior to ARBs and other
antihypertensive drugs and had the highest benefits for the prevention of kidney events, cardiovascular outcomes, cardiovascular death and all-cause mortality in non-dialysis CKD3-5 patients. In patients with advanced
diabetic kidney disease, ACEIs were superior to ARBs in lowering risk of all-cause death but not in kidney events and cardiovascular events.