Twenty-one studies (n=654) were included: 5 parallel-group trials (n=281) and 16 crossover trials (n=373).
Crossover trials (16 randomised controlled trials).
Five studies included patients with non-diabetic renal disease, 7 studies included diabetic patients, and 4 studies included patients with both diabetic and non-diabetic renal disease. The Jadad scores for these trials were considered to be moderate to high (median score 3.5); 4 studies were deemed to be of a low quality. All studies were short term (range: 4 to 16 weeks).
When all 16 studies were pooled, a significant decrease in proteinuria was found with combination therapy compared with ACE inhibitor alone (WMD 440 mg/day, 95% CI: 289, 591); statistically significant heterogeneity was found (Q=84.9, p<0.01). A significant reduction in proteinuria was also found when only studies that predominantly included patients with diabetic nephropathy or non-diabetic proteinuric CKD were pooled; statistically significant heterogeneity was found in both analyses.
Significant decreases in systolic BP (WMD 4.5 mmHg, 95% CI: 2.7, 6.4) and diastolic BP (WMD 2.5 mmHg, 95% CI: 1.6, 3.5) were found in favour of combination therapy when 14 studies were pooled; statistically significant heterogeneity was found (Q=46.7, p<0.01 and Q=28.2, p<0.01, respectively). A significant reduction in BP was found when only studies that predominantly included patients with diabetic nephropathy or non-diabetic proteinuric CKD were pooled; significant heterogeneity was not found for studies involving diastolic BP in non-diabetic proteinuric CKD.
A small but statistically significant decrease in serum potassium level was found in favour of combination therapy when 14 studies were pooled (WMD 0.11 mEq/L, 95% CI: 0.05, 0.17); significant heterogeneity was found (Q=34.7, p<0.01). A decrease in GFR was found with combination therapy compared with ACE inhibitors alone (WMD -1.4 mL/minute, 95% CI: -2.6, 0.2), but this was not statistically significant; no significant heterogeneity was found.
Parallel-group trials.
One study (n=263) found a significant percentage decrease in proteinuria in patients receiving combination therapy compared with immunotherapy (-75.6% versus -44.3%, p=0.01) at the 3-year follow-up; patients receiving combination therapy also demonstrated a significant decrease in serum creatinine level or end-stage renal disease compared with ACE-inhibitor therapy alone (11.5 versus 23%, p=0.018), but no significant difference was found between treatment groups for BP.
One study (n=36) found a significant decrease in mean protein excretion in the combination group compared with ACE-inhibitor monotherapy after 6 months, but no significant difference was found between treatment groups in BP, serum potassium levels or creatinine clearance.
One study (n=30) reported a decrease in proteinuria at the 2-month follow-up, but no significant difference was found at the 6-month follow-up and there were no significant between-group differences for BP or GFR.
One study (n=32) found no significant differences between treatment groups for proteinuria or systolic BP, although a significant decrease in diastolic BP was found in favour of combination therapy compared with enalapril monotherapy at the 3-month follow-up. A short-term decrease in creatinine clearance was also reported in the enalapril group.
One study (n=21) reported a greater decrease in proteinuria with combination therapy compared with temocapril monotherapy at the 6-month follow-up. No change from baseline was shown in GFR or serum potassium level. BP was found to decrease in the combination therapy group but not the temocapril group.